Benzodiazaphines, pathological dementia and drug induced dementias

I'm adding a quick disclaimer based on some feedback

DISCLAIMER:  drug induced dementia is not the same as pathological dementia.  I think the news in the paper below is good news in that respect .  I personally had a hard time linking benzodiazaphines to pathological dementias like Alzheimer's and vascular dementia, which account for the majority of pathological dementia..... I'm no expert in this area, so if someone knows more about "drug induced dementias"  and if there are any therapies for it, please post. The best thing to do is get off the drug.  There are tons of links on drug induced dementia.

And here's more good news. The body has an amazing ability to heal.

https://www.ncbi.nlm.nih.gov/pubmed/27025096

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Many drugs have been reported to induce not only delirium but also cognitive impairment. Some types of drugs are reported to induce dementia, and prolonged hypotension or hypoglycemia induced by overuse of antihypertensive drugs or oral antidiabetic drugs could result in dementia. Recently, taking multiple drugs with anticholinergic activity are reported to cause cognitive decline and anticholinergic burden should be avoided especially in patients with dementia. Drug-induced dementia can be prevented by avoiding polypharmacy and adhering to the saying 'start low and go slow' . Early diagnosis of drug-induced dementia and withdrawal of the offending drug is essential to improve cognitive function.

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Hi all, I'm posting this for a fellow BB who is in need and also for others as an FYI

This topic is branched from the main thread here on interdose withdrawal modeling

http://www.benzobuddies.org/forum/index.php?topic=184940.0

From the research that I have done, I don't believe benzodiazaphines directly cause pathological dementia (for example Alzheimer's or vascular dementia).  The data is too inconsistent and sparse.

However , in my opinion, I think that chronic benzodiazaphine use can induce secondary issues that might make one more predisposed to these types of dementia.  This opinion has no clinical studies to back it up, and is my own opinion based on what I've read.

There are clinical studies of drug induced dementia with antihyoertensives, anticholinergics, and benzodiazaphines

The formatting was lost from the original word document, but I have bolded out the main sections. There are many more references in addition to those presented in the paper, but time and space are limited.

It's very long and divided into 2 parts

Benzodiazaphines and dementia PART I

1.Introduction

One of the main pitfalls of poorly designed studies, is to attribute something that is characteristic to a disorder or disease, as something that is causal to the disorder or disease.  Some of the material below might fall into that bucket, but the information is provided because it might provide insight to someone who is more well versed in dementia, Alzheimer’s, etc.  I’m far from being an expert in this area, but I’ve learned several new things during the process of writing this post.  I hope it’s informative to all.

It’s no coincidence that many of the studies are Alzheimer’s related, as Alzheimer’s accounts for 50-70% of all cases of the broader dementia.

There are basically two approaches to a paper like this.  The first one is to provide the meta-data statistical studies on the association of benzodiazaphines and dementia or Alzheimer’s.  These have several shortcomings, namely confounding factors, that will be explained in detail in several of the quotes.  The writers of these papers are very smart people, and do acknowledge these potential shortcomings.  I think these are the studies that we are all familiar with, and that received the most publicity during 2015-2016, linking dementia and benzodiazaphines . There was another such study in 2016 that contradicted these findings.

  The second approach is a scientific physiological and pathological clinical study showing that it causes the disease.    For example, a benzodiazaphine is administered in a controlled lab environment, and then the brain of the animal is studied pathologically.  Understandably, there are very few studies in this area. Most likely because dementia is a very slow process, involving multiple factors, thus it would is very difficult to recreate intentionally, especially given its complexity of etiology.  One study involved a PET scan of the brain for amyloid plaques that are found in Alzheimer’s.  These studies are hard to find.

The biggest challenge involved in trying to determine benzodiazaphines’ involvement in the pathology of a specific disease like Alzheimer’s, or even more challenging an umbrella disorder like dementia, is direct  cause and effect, because these disorders are so complex, and their development and etiology is still not fully understood.  Linking benzodiazaphine use to something like interdose withdrawal is much more straightforward (but still challenging) , because the cause of interdose withdrawal is in large part, due to the benzodiazaphine itself.  It would not be there without the benzodiazaphine.  One can’t say the same for Alzheimer’s and dementia.  These occur in patients who have used benzodiazaphines, and in those who have not.  Furthermore, as we will see,  these confounding factors make determination of a specific and single causative agent much more difficult.  For example, a large group of seniors are on many medications that can compromise acetylcholine homeostasis, and much to my surprise they are on a lot of  psychotropics…...  Anticholinerginics and blood pressure medications have been correlated, along with benzodiazaphines, with medication induced dementia (reference below, but I was not able to get free access to the full study).  I’m no expert in this area, but I assume that medication induced dementia, pathologically is quite different from Alzheimer and classical dementia pathology, but this is just my opinion.

To make things even more complicated, as alluded to above, there are many different types of dementia, as will be seen in the Wikipedia link below.  The etiology of these various dementias differ. Benzodiazaphines might induce a very specific “dementia” in terms of pathology, perhaps due to compromised ACh and GABAa receptor physiology, and/or dysregulated Glutamate systems.  See Pers’ paper on Organic Brain Syndrome at this link

http://www.benzobuddies.org/forum/index.php?PHPSESSID=0diiqhf4agnuug1h82adcldbo6&topic=138101.0

  Alcohol has its own type of dementia, and perhaps the same is true for benzodiazaphines.  CTE outwardly resembles Alzheimer’s, but pathologically it is very different (I discuss CTE briefly in the Section 2).    In three words,  “it’s very complicated “

I found the article on anticholinergenics, anti hypertensives, and benzodiazaphines and their link to dementia very interesting.

There are lots of studies in this area of dementia and benzodiazaphines , but unfortunately  no clear conclusion, nor any clear exact mechanism by which this can occur.  Perhaps Glutamate toxicity from LTP, but LTP usually will only occur with abrupt withdrawal.  Furthermore, as will be seen, Alzheimer’s is actually associated with LTD (long term synaptic depression), not LTP (long term synaptic potentiation). So clearly, if LTP neurotoxicity is causing dementia, then the physiology must be quite different from that of Alzheimer’s.  Alcohol related dementia is well known, but alcohol, in and of itself is neurotoxic, and binge drinking , i.e. Kindling, induces massive releases of extracellular Glutamate.

  Another thesis is that because  benzodiazaphines affect Glutamate, cholinergenic, and GABAa systems, and Alzheimer’s and dementia patients have GABA dysfunction, ACh dysfunction, and obvious Glutamate dysfunction, that the two are somehow linked.  However, this is far from being indicative of a causal effect.  While I do agree that it’s very coincidental, it’s not proof that benzodiazaphines cause Alzheimer’s or dementia.  I do explore these areas, but I attempt to put it in the proper perspective. It’s also important not to confuse the physiology of the disease markers with the cause of the disease itself.  (This is analogous to findings that ALS patients have elevated levels of aluminum in the brain.  Even if this is true, aluminum accumulation might be the result of the disease process,  rather than the cause of the neurodegenerative process).

So, not to imply causation, I just wanted to expand a bit on 3 areas:

1. The depressed cholinergenic system is implicated in Alzheimer’s, in part.  See bishop reference with scopolamine(anitcholinergenic)  below,  and a few others above it.  Also, benzodiazaphines impair the release of ACh In certain regions of the brain.  I think acetylcholine dysfunction is one link , if there is one, between benzodiazaphines and dementia.  The changes in ACh with benzodiazaphines might predispose one to dementia.(complete theory here).  It’s not entirely clear if this is related to extracellular ACh levels, ACh receptor dysfunction or both.  References allude to both of these areas.  It’s very interesting, in one study, that chronic diazepam use was associated with lower ACh in a particular part of the brain, while abrupt antagonist withdrawal was  associated with elevated ACh levels in the same part of the brain.  The author attributed withdrawal symptoms, in part,  to the spike in ACh.  Could this drug induced withdrawal and dysregulation of the ACh system manifest itself as some sort of drug induced dementia?

2. Changes in GABAa receptors occur in Alzheimer’s.  Although this  in no way implies cause and effect from benzos to Alzheimer’s, much like acetylcholine, it should be noted.  As we know, benzodiazaphines profoundly affect GABAa receptors, and perhaps this might predispose one or make it more likely that one can develop Alzheimer’s or dementia.  (Complete theory here)

3. Similarly, Glutamate systems are affected in benzodiazaphine use, and Glutamate systems are impaired in Alzheimer’s and in many dementias.    Glutamate toxicity has been linked with Alzheimer’s.  The number of references in this area is huge as will be seen in a simple google search, in the later section.  Benzodiazaphines influence on the Glutamate system could, once again, predispose one to dementia (complete theory).  However,  the link is not as direct as one would assume.  One Alzheimer’s study indicated that the glutamate receptors are actually downregulated (NMDA and AMPA) , synaptic plasticity reduced (LTD) when the amyloid plagues start to appear, and this causes a build up of extracellular Glutamate which leads to excitotoxicity.  Not at all what we would expect to see if benzodiazaphines were abruptly stopped.  They then  used GABAa agonists to induce hyperpolarization , which reduced amyloid toxicity.  Not exactly what we wanted to hear.  However, I surmise that long term effects of chronic benzodiazaphine use would produce a much different effect in this study, especially once homeostatic tolerance has built up.

The only link I can think of is a complete theoretical one, that of benzodiazaphines destabilizing all of the systems above and predisposing one to dementia.  But this is complete theory.  No clear cause and effect mechanism.

Intact GABAA signaling is required in adult neurogenesis as well, see reference below. Also, neurotrophic signaling is decreased with diazepam due to downregulated BDNF. Neurotrophic signaling is necessary for proper neuronal function. See reference below. Benzodiazaphines also impair recovery from stroke and other forms of brain damage.  I have not provided references for this but a quick google search will show the references for those interested.Once again no cause and effect, but benzodiazaphines appear to impair the brains natural ability to repair itself.

We know that abrupt discontinuation of benzodiazaphines can cause long term potentiation of the Glutamate receptors, both an upregulation and an increase in sensitivity.  Glutamate toxicity that results can cause brain damage, but how this could be related to a pathological process like dementia is an entirely different discussion.  As mentioned above, Alzheimer’s exhibits LTD, not LTP.  So a direct link via benzodiazaphine induced LTP is unclear.

Kindling has a similar effect on the neurons, but linking neuro-kindling to dementia is not straightforward.  We know kindling eventually  downregulates GABAa receptors via increased endocytosis (due to changes in the phosphorylation of the receptors). But in some epilepsy types like TLE, the extra synaptically vs. synaptic GABAa receptor distribution is altered.  Some receptor subtypes are upregulated while others are downregulated.  I would guess that differing types of dementia have different dysfunctional aspects of the GABAa receptors, complicating the issue.  As mentioned earlier, we  know that Alzheimer’s has dysfunctional GABAa receptor activity(references are below). 

Futhermore, the meta-data results show very confusing results in regards to short acting benzos vs long acting benzos, indicating that there is no correlation of kindling to dementia.  Dementia is such a complex condition, it would not surprise me that the link would be difficult to uncover,  I think there are are far too many confounding issues with the meta-data studies to derive any useful data from them.

Immune dysregulation is linked with benzodiazaphine use, and this area will be briefly explored, because immune dysregulation can cause microglia in the CNS to release extrasynaptic Glutamate and NO.  I posted an earlier document on this.  I don’t know how this correlates with autoimmune disease. There is a reference below on vasculitis, immune dysregulation, and stress, caused by xanax.  This was 4 week dosing…...  It might be relevant in kindled used of xanax. Vasculitis can cause strokes, which could exhibit as dementia like symptoms, but not pathological dementia.

Finally, I wanted to take a closer look at one type of dementia, called vascular dementia and determine if there is any references on benzodiazaphines and this specific type of dementia.

As a whole, my personal opinion is that proving benzodiazaphines directly cause dementia is very difficult.  I think benzodiazaphines can predispose one to dementia via altered ACh, GABAa, and Glutamate systems, as well as impaired neurogenesis and neurotrophic signaling.  This is complete theory.  I also think that Benzodiazaphines can and do affect the immune system and this can affect secondary systems like the Glutamate system, and blood vessels, and produce inflammatory substances like NO,  that can predispose one to very specific types of dementia and/or induce brain injury.  Brain injury like strokes, hypoglycemia, and epilepsy give rise to an imbalance in excitatory  glutamatergic neurotransmission that can trigger massive cell death.  Cognitive impairment and dementia are commonly seen in recovery from such injuries , providing a possible link between the mechanisms involved in these types of injury and in  dementias like Alzheimer’s via dysfunctional glutamatergic systems.(see reference below)  So a history of these types of insults could be a precursor to dementia, and some of the insults could indeed be due directly to benzodiazaphine use. Pathologically,  very different from Alzheimer’s and classic dementias , but very similar dementia-like symptoms.

Clearly, benzodiazaphines have the potential to cause drug induced dementia because of their effects on the Glutamate, ACh, GABA systems, seizure threshold, and immune system, and the brain’s natural neurogenesis protective processes.  This is no way can lead one to conclude that it is related to pathological dementias. Drug induced dementias are not the same as pathological dementias. Pers published a paper on organic brain injury cited above , and this is not the same as pathological dementia.

Finally, “healthy” memory is tied to proper endogenous (not external pills) benzodiazaphine, GABAa and ACh systems(reference below).  Benzodiazaphines clearly disrupt all of these processes, without question .    https://link.springer.com/chapter/10.1007%2F978-1-4615-9843-5_20

(If anyone has full access to this paper please let me know)

2.Meta-data statistical studies

Some confusing data from these studies

-the studies that found a link, found that it was proportional to use, implying kindling has no effect on dementia, and in fact less use (more erratic) might be better in this respect?

-long acting benzos were worse in one study than short acting benzos, once again possibly implying kindling has no effect on dementia.

- conflicting conclusions from different meta-data studies

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446315/pdf/pone.0127836.pdf

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The percentage of benzo- diazepine use in subjects aged 65 years and over is 18j.9% [5] and 15.0% [6] in Germany and Canada, respectively. In China, nearly one-third of patients with insomnia take benzodiaze- pines [7].

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I had no idea so many elderly people were on benzodiazaphines .  Elderly people are usually on a lot of other prescriptions, so a good study will have to statistically adjust for these confounding elements.  Confounding is the correct word for this, as there are a lot of different elements mixing into the equation when analyzing something as complex as dementia. 

Also, just an interesting side note, there is something called CTE, or chronic traumatic encephalitis.  It’s causes by repeated blows to the head and/or sheer forces hat cause the brain to bounce around inside of the skull.  It’s a very slow and insidious process.  You might have heard of all the NFL players filing class action lawsuits.  Many boxers also succumb to this as well.

Here is a link on it below……The reason why I am bringing it up is because I did my own little study of boxers from the old days, after reading about it.  His was a long time back.  The symptoms of CTE are very broad.  Some exhibit ALS like symptoms, and others dementia like symptoms, and others both.  Upon autopsy, there are clear definitive differences in the pathology of the specimens of Alzheimer’s vs. CTE victims.  Thus,  the dementia aspects of CTE are clearly different pathologically than that of Alzheimer’s.  It is a tauopathy, like Alzheimer’s, and there are neurofibrillary tangles .  However, there beta-amyloid depositions in CTE are relatively uncommon, whereas they are very common in Alzheimer’s …..also the tau proteins look differently under the microscope .  And to further extend this discussion, dementia is yet a broader classification under which Alzheimer’s falls.  I don’t know much about these areas medically speaking, but I am bringing  up this topic because dementia is a terribly broad and complex  area that can have many different and multiple causative factors.  I think in this respect, the studies below of its correlation with benzodiazaphines should be taken in this context.

My little study of old time boxers was interesting.  I’m a big fan of boxing as a sport, even though I do believe it’s medically detrimental to the brain physiology.  The sub-concussions that occur, like in football are numerous, and the clinical data clearly is pointing in the direction of these sub-concussive forces, repeatedly, over long periods of time to be the major instigator of CTE pathological changes.  Back in the old old days like in  the 1920s and 1930s, I did a search on how a lot of these famous boxers died.  There were a lot of them that died young say in their 50s, but the ones that lived into their 70s and 80s typically died in rest homes with presumed dementia, and later on presumed (not pathology) Alzheimer’s, when Alzheimer’s became so well known…..    I would argue that if an autopsy were feasible , that many of these boxers probably had severe CTE.  I’m  discussing all this just to make the point that symptoms don’t always point to the same pathology, and thus disease process.  With benzodiazaphines this complicates the studies. A benzodiazaphine induced dementia might be completely different pathology wise from Alzheimer’s, and it might be completely reversible, unlike Alzheimer’s

To summarize CTE, and the points above regarding pathology:

https://en.m.wikipedia.org/wiki/Chronic_traumatic_encephalopathy

The neuropathological appearance of CTE is distinguished from other tauopathies, such as Alzheimer's disease. The four clinical stages of observable CTE disability have been correlated with tau pathology in brain tissue, ranging in severity from focal perivascular epicenters of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions.[4]

The primary physical manifestations of CTE include a reduction in brain weight, associated with atrophy of the frontal and temporal cortices and medial temporal lobe. The lateral ventricles and the third ventricle are often enlarged, with rare instances of dilation of the fourth ventricle.[5] Other physical manifestations of CTE include anterior cavum septi pellucidi and posterior fenestrations, pallor of the substantia nigra and locus ceruleus, and atrophy of the olfactory bulbs, thalamus, mammillary bodies, brainstem and cerebellum.[6] As CTE progresses, there may be marked atrophy of the hippocampus, entorhinal cortex, and amygdala.[2]

On a microscopic scale, the pathology includes neuronal loss, tau deposition, TAR DNA-binding Protein 43 (TDP 43)[4] beta-amyloid deposition, white matter changes, and other abnormalities. The tau deposition occurs as dense neurofibrillary tangles (NFT), neurites, and glial tangles, which are made up of astrocytes and other glial cells[5] Beta-amyloid deposition is a relatively uncommon feature of CTE.

A small group of individuals with CTE have chronic traumatic encephalomyopathy (CTEM), which is characterized by symptoms of motor-neuron disease and which mimics amyotrophic lateral sclerosis (ALS). Progressive muscle weakness and balance and gait problems (problems with walking) seem to be early signs of CTEM.[5]

Exosome vesicles created by the brain are potential biomarkers of TBI, including CTE.[7]

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I also wanted to include an link to dementia just to be clear on what we are talking about.

https://en.m.wikipedia.org/wiki/Dementia

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The most common type of dementia is Alzheimer's disease, which makes up 50% to 70% of cases. Other common types include vascular dementia(25%), Lewy body dementia (15%), and frontotemporal dementia.[2][3] Less common causes include normal pressure hydrocephalus, Parkinson's disease, syphilis, and Creutzfeldt–Jakob disease among others.[12] More than one type of dementia may exist in the same person.[2] A small proportion of cases run in families.[13] In the DSM-5, dementia was reclassified as a neurocognitive disorder, with various degrees of severity.[14] Diagnosis is usually based on history of the illness and cognitive testing with medical imaging and blood work used to rule out other possible causes.[4] The mini mental state examination is one commonly used cognitive test.[3] Efforts to prevent dementia include trying to decrease risk factors such as high blood pressure, smoking, diabetes, and obesity.[2] Screening the general population for the disorder is not recommended.[15]

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I noticed that many of the symptoms of dementia  overlap with benzodiazaphine withdrawal,  because both of these have an incredibly wide spectrum of symptoms. This complicates things further.

Reversible causes of dementia.

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There are four main causes of easily reversible dementia: hypothyroidism, vitamin B12 deficiency, Lyme disease, and neurosyphillis. All people with memory difficulty should be checked for hypothyroidism and B12 deficiency. For Lyme disease and neurosyphilis, testing should be done if there are risk factors for those diseases in the person. Because risk factors are often difficult to determine, testing for neurosyphillis and Lyme disease as well as the other mentioned factors may be undertaken as a matter of course in cases where dementia is suspected.[11]:31–32

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Ironically, benzodiazaphines are mentioned in the dementia link above

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The use of drugs to alleviate sleep disturbances that people with dementia often experience has not been well researched, even for medications that are commonly prescribed.[93] In 2012 the American Geriatrics Society recommended that benzodiazepines such as diazepam, and non-benzodiazepine hypnotics, be avoided for people with dementia due to the risks of increased cognitive impairment and falls.[94] In addition, there is little evidence for the effectiveness of benzodiazepines in this population.[93][95] There is no clear evidence that melatonin or ramelteon improves sleep for people with dementia due to alzheimers disease.[93] There is limited evidence that a low dose of trazodone may improve sleep, however more research is needed.[93]

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The epidemiology is interesting.  Lots of it in the United States.  I wonder how things would look if we overlayed a similar picture for benzodiazaphine usage based on prescriptions per capita.

https://upload.wikimedia.org/wikipedia/commons/thumb/b/bc/Alzheimer%27s_disease_and_other_dementias_world_map-Deaths_per_million_persons-WHO2012.svg/2560px-Alzheimer%27s_disease_and_other_dementias_world_map-Deaths_per_million_persons-WHO2012.svg.png

Back to the Benzo study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446315/pdf/pone.0127836.pdf

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Several observational studies investigated the association between long-term benzodiaze- pine use and risk of dementia but presented mixed results. Some studies revealed an increased risk of dementia [12–16] among benzodiazepine users, whereas other studies revealed a de- creased risk of dementia [17].

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They went through 1573 studies in this link above and performed a statistical meta-analysis.

They narrowed it down to 6 papers for the study.

See table 1 in the link above, pages 6-7

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The association between long-term benzodiazepine use and risk of dementia has received sig- nificant attention but is still in debate. A most recent systematic review of observational studies (cohort and case-control studies) found that the long-term users of benzodiazepines have a 1.5- to 2-fold increased risk of developing dementia compared with never users [28]. On the basis of nested case-control and prospective cohort studies, our meta-analysis found that com- pared with never users, long-term benzodiazepine users (ever, recent and past users) were at an elevated risk of dementia when we pooled either unadjusted RRs or adjusted RRs, which was consistent with the findings of previous review [28].

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This is an interesting and very good point.  A confounding factor, of which I mentioned earlier.  This is one reason why it’s so hard to correlate things like benzodiazaphines to dementia.

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The prodromal symptoms of dementia, including sleep disturbance, anxiety and depression [29–31], can occur around 10 years preceding a clinical diagnosis of dementia [32]. The pres- ence of these psychiatric symptoms may motivate physicians to prescribe benzodiazepines. Thus, some researchers raise concerns that the observed association between benzodiazepine use and dementia may be due to confounding by indication and reverse causation [31, 33]. Nonetheless, the following facts possibly attenuate these concerns. First, it is found that the frequency of prodromes increases when dementia onset is approaching [32]. On the basis of this fact, the strength of the association for recent users should be stronger than that for past users if reverse causation is the case in the association of benzodiazepine use and dementia. However, our review observed similar risk estimates for recent and past users. Second, when we confined our analyses to RRs with adjustment for anxiety or depression, most but not all pooled results persisted. Third, a significant dose-response pattern was observed in the present study, although it was derived from limited numbers of included studies. Such finding supports a causal relationship between benzodiazepine use and dementia. Finally, our results are consis- tent with findings from an individual study [12] that had a mean follow-up of 22 years. The fol- low-up length in that study [12] was long enough to overcome the hypothesis of reverse causation.

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This is a big one.  Note also z-drugs were mixed into some of the studies used in this paper

Other psychotropic drug use is a big one as it is common in he elderly.

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The prevalence of psychotropic medication use among the elderly is high [34, 35], with a re- ported prevalence of up to 73% in subjects aged 65 years and over [34]. Use of psychotropic medications except benzodiazepines has been found to be associated with an increased risk of dementia [36, 37]. These facts provide a critical reminder that our findings might be biased by use of other psychotropic medication among included study population. There are two extreme conditions regarding this bias: one is that subjects in the exposure group concurrently use other psychotropic medications but those in the non-exposure group not, another is that sub- jects in the non-exposure group use other psychotropic medications but those in the exposure group not. The former condition results in an overestimated risk of dementia associated with benzodiazepine use, while the latter condition will underestimate that risk. Due to complex cir- cumstances in the real world, unfortunately, we cannot ascertain the specific effect of use of other psychotropic medications on the magnitude and direction of the association between benzodiazepine use and dementia. Nonetheless, several included studies [13, 14, 27] treated benzodiazepine-related drugs, such as Z-drugs, as benzodiazepines, which produced a possibil- ity of overestimating the risk of dementia in relation to benzodiazepine use.

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And this

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Under this condition, the exact definitions of recent and past use of benzodiaze- pines for the pooled results are uncertain. Consequently, the utility value of the findings associated with recent and past use of benzodiazepines may be affected to some extent. None- theless, our findings regarding recent and past use of benzodiazepines may provide an impor- tant implication that stopping use of benzodiazepines cannot significantly reduce the risk of developing dementia.

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And this

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Long-term benzodiazepine use has been linked with increased risks of injurious falls [41] and hip fracture [42]. On the basis of limited studies, we observed that long-term benzodiazepine use was associated with an in- creased risk of dementia. If these observed associations are causal, for reducing possible adverse reactions, ideally, medical practitioners should limit benzodiazepine use to several weeks as recommended by international guidelines [8].

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On the basis of either unadjusted or adjusted risk estimates, our study consistently indicates that long-term benzodiazepine use is associated with an increased risk of dementia. Due to lim- ited studies, especially dose-response analysis, and potential reverse causation, these findings should be treated with caution.

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http://www.bmj.com/content/349/bmj.g5205

This one is interesting.  Higher exposure density, i.e. Days of exposure, and longer half life increased the risk further.

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Results Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).

Conclusion Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.

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This is an article(not a study) based on the study above

https://www.health.harvard.edu/blog/benzodiazepine-use-may-raise-risk-alzheimers-disease-201409107397

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The association isn’t surprising given past research on the subject, but it still should be viewed with caution. “Benzodiazepines are risky to use in older people because they can cause confusion and slow down mental processes, ” says Dr. Anne Fabiny, chief of geriatrics at Harvard-affiliated Cambridge Health Alliance. “However, although there is an association, we still can’t say that benzodiazepines actually cause Alzheimer’s,” she cautions.

People who had taken a benzodiazepine for three months or less had about the same dementia risk as those who had never taken one. Taking the drug for three to six months raised the risk of developing Alzheimer’s by 32%, and taking it for more than six months boosted the risk by 84%.

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Quote

The type of drug taken also mattered. People who were on a long-acting benzodiazepine like diazepam (Valium) and flurazepam (Dalmane) were at greater risk than those on a short-acting one like triazolam (Halcion), lorazepam (Ativan), alprazolam (Xanax), and temazepam (Restoril).

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And the same confounding factor note

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The researchers acknowledge that the use of benzodiazepines could be just a signal that people are trying to cope with anxiety and sleep disruption—two common symptoms of early Alzheimer’s disease. If that’s true, their use of a benzodiazepine may not be a factor in causing dementia but an indication it is already in progress.

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I’ve noticed this myself. See below.  The benzos made my sleep worse.  The less stimulation to GABAa receptors, including PAMS , the more we will improve, in this area, but there are a LOT of windows and waves during the process.  See below,

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Although these medications are taken to help people get a good night’s rest, they can have the opposite effect. “When they’re taken over time, they can actually interfere with normal sleep,” says Dr. Fabiny. The quest to sleep through the night can lead to prescriptions for higher doses or longer-lasting benzodiazepines—and even greater side effects.

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And this study : no causal relationship

http://www.bmj.com/content/352/bmj.i90

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Results Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed Alzheimer’s disease. For dementia, the adjusted hazard ratios associated with cumulative benzodiazepine use compared with non-use were 1.25 (95% confidence interval 1.03 to 1.51) for 1-30 TSDDs; 1.31 (1.00 to 1.71) for 31-120 TSDDs; and 1.07 (0.82 to 1.39) for ≥121 TSDDs. Results were similar for Alzheimer’s disease. Higher benzodiazepine use was not associated with more rapid cognitive decline.

Conclusion The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.

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3.Physiological studies

This one stating no correlation with Alzheimer’s and benzodiazaphine use

This goes to show you, underlying pathology vs. symptom based studies.  This was more of a physiological study using Pet scan analysis.

http://www.medscape.com/viewarticle/864099

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"Benzodiazepines are very commonly prescribed to curb anxiety, agitation, and anxiety in older adults, and there has been some controversy as to whether their use is linked to increased cognitive decline," said Dr Graff-Guererro.

"Studies investigating the effects of benzodiazepines on progressive cognitive decline in older individuals have yielded conflicting results, but in our pilot study, previous benzodiazepine use was actually associated with lower levels of cortical amyloid-beta in nondemented elderly controls," he added.

In this cross-sectional, prospective study, the researchers investigated the effects of benzodiazepine use on beta-amyloid deposition in adults aged 55 to 90 years who did not have dementia.

They used data from the ADNI database to determine whether the level of cortical beta-amyloid was decreased in elderly benzodiazepine users compared with matched patients who did not use benzodiazepines.

They also analyzed whether long-term benzodiazepine use was linked to progressive cognitive decline over 2 years of follow-up.

The analysis included 15 elderly adults without dementia who were prescribed benzodiazepines for at least 1 year (range, 1-25 years; mean, 7.47 years). These patients were matched to 15 nonusers.

Cortical levels of beta-amyloid were assessed by positron emission tomography radiotracer florbetapir F-18 (Amyvid, Avid Radiopharmaceuticals, Inc). Changes in global cognitive function and verbal memory performance over 2 years were assessed using the Montreal Cognitive Assessment score and the Rey Auditory Verbal Learning Test.

The analysis of the ADNI data showed that for previous benzodiazepine users, cortical beta-amyloid levels were lower in the frontal (F [1, 26 \] = 8.82, P = .006), cingulate (F [1,126) = 8.58, P = .007), parietal (F [1, 26) = 7.31, P = 0.012), and temporal (F [1, 26] = 7.67, P = 0.010) regions of the brain in comparison with patients who had not used benzodiazepines.

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Quote

"The conclusions are at best inconclusive," said Josepha Cheong, MD, professor of psychiatry, University of Florida College of Medicine, Gainesville, who was asked to comment on this study for Medscape Medical News.

"Just because it does not 'prove' that there is a direct link between benzodiazepine use and the development of cognitive decline or dementia, it does not necessarily disprove that there is a link between benzodiazepines and cognitive decline," Dr Cheong said.

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This is a great article.  Something all of us can relate to

The references to changes in brain pathology are startling.

https://en.m.wikipedia.org/wiki/Effects_of_long-term_benzodiazepine_use

Quote

A study of 50 patients who attended a benzodiazepine withdrawal clinic found that long-term use of benzodiazepines causes a wide range of psychological and physiological disorders. It was found that, after several years of chronic benzodiazepine use, a large portion of patients developed various mental and physical health problems including agoraphobia, irritable bowel syndrome, paraesthesiae, increasing anxiety, and panic attacks, which were not preexisting

The mental health and physical health symptoms induced by long-term benzodiazepine use gradually improved significantly over a period of a year following completion of a slow withdrawal. Three of the 50 patients had wrongly been given a preliminary diagnosis of multiple sclerosis when the symptoms were actually due to chronic benzodiazepine use

The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal-type symptoms emerged, despite the administration of stable prescribed doses.[50] Another theory is that chronic benzodiazepine use causes subtle increasing toxicity, which in turn leads to increasing psychopathology in long-term users of benzodiazepines.[51]

……

In a study in 1980 in a group of 55 consecutively admitted patients having abused exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. These results suggested a relationship between abuse of sedatives or hypnotics and cerebral disorder.[68]

A publication has asked in 1981 if lorazepam is more toxic than diazepam.[69]

In a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean ventricular-brain ratio measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings was unclear.[70]

In 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to alcohol-related brain damage.[71]

In 1987, 17 high-dose inpatient abusers of benzodiazepines have anecdotally shown enlarged cerebrospinal fluid spaces with associated brain shrinkage. Brain shrinkage reportedly appeared to be dose dependent with low-dose users having less brain shrinkage than higher-dose users.[72]

However, a CT study in 1987 found no evidence of brain shrinkage in prescribed benzodiazepine users.[73]

In 1989, in a 4- to 6-year follow-up study of 30 inpatient benzodiazepine abusers, Neuropsychological function was found to be permanently affected in some chronic high-dose abusers of benzodiazepines. Brain damage similar to alcoholic brain damage was observed. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics, sedative hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in sedative hypnotic benzodiazepine abusers, it is often permanent.[74]

A CT study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group.[75]

A study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities.[76]

Withdrawal from high-dose abuse of nitrazepam anecdotally was alleged in 2001 to have caused severe shock of the whole brain with diffuse slow activity on EEG in one patient after 25 years of abuse. After withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose abuse of nitrazepam.[77]

Professor Ashton, a leading expert on benzodiazepines from Newcastle University Institute of Neuroscience, has stated that there is no structural damage from benzodiazepines, and advocates for further research into long-lasting or possibly permanent symptoms of long-term use of benzodiazepines as of 1996.[78] She has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the GABAA benzodiazepine receptor level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage.[79]

In 2014 studies have found an association between the use of benzodiazepines and an increased risk of dementia but the exact nature of the relationship is still a matter of debate.[80] A later study found no such effects.[36]

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Quote

Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use.[113] Benzodiazepines, along with antihypertensives and drugs affecting the cholinergic system, are the most common cause of drug-induced dementiaaffecting over 10 percent of patients attending memory clinics.[114][115] Long-term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including drowsiness, ataxia, fatigue, confusion, weakness, dizziness, vertigo, syncope, reversible dementia, depression, impairment of intellect, psychomotor and sexual dysfunction, agitation, auditory and visual hallucinations, paranoid ideation, panic, delirium, depersonalisation, sleepwalking, aggressivity, orthostatic hypotension and insomnia. Depletion of certain neurotransmitters and cortisol levels and alterations in immune function and biological markers can also occur.[116] Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of post-operative confusion.[117] Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine hypnotic users without worsening of insomnia.[118]

A review of the evidence has found that whilst long-term use of benzodiazepines impairs memory, its association with causing dementia is not clear and requires further research.[119] A more recent study found that benzodiazepines are associated with an increased risk of dementia and it is recommended that benzodiazepines be avoided in the elderly.[120] A later study, however, found no increase in dementia associated with long-term usage of benzodiazepine.[36]

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Reference 70

http://www.benzo.org.uk/lennane.htm

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….third is the risk of permanent brain damage, analogous to alcohol-related damage, which it seems may occur with long-term usage.(37)

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From the above this is very interesting.  As will be pointed out, anomalies in ACh and GABAa systems have been found in Alzheimer’s patients.  Whether this is cause and/or effect we don’t know….

AntiCholinergic , anti hypertensives and benzos cause drug induced dementia

The references are interesting.  The suggestion to use shorter acting preparations seems counterintuitive in regards to benzodiazaphines and kindling.

114. Starr JM, Whalley LJ (November 1994). "Drug-induced dementia. Incidence, management and prevention". Drug Saf. 11 (5): 310–7. PMID 7873091. doi:10.2165/00002018-199411050-00003.

115. Inada K, Ishigooka J (January 2004). "[Dementia induced by antianxiety drugs]". Nippon Rinsho (in Japanese). 62 Suppl: 461–5. PMID 15011406.

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Drug-induced dementia. Incidence, management and prevention.

Starr JM1, Whalley LJ.

Author information

Abstract

Drugs are a frequently cited cause of dementia. There is a paucity of data regarding the incidence of drug-induced dementia, but it has been estimated that over 10% of patients attending memory clinics have iatrogenic disease. Drugs may impair cognition indirectly via metabolic effects, such as hypoglycaemia, by alterations of immunological factors within the CNS, and by actions that interfere with synaptic transmission. Classes of drugs most frequently responsible are the benzodiazepines, antihypertensives and drugs with anticholinergic properties. Each of these classes is likely to produce a different pattern of neuropsychological deficits. Prevention of drug-induced dementia will be aided by: (i) minimising the number of drugs prescribed; (ii) using shorter-acting preparations; (iii) avoiding agents that cross the blood-brain barrier where possible; (iv) evaluating renal and hepatic function regularly; and (v) briefly assessing cognitive function before treatment.

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Quote

Very interesting. Presented earlier

80 Lawrence, Janna (27 September 2014). "Benzodiazepine use is associated with Alzheimer's disease, study finds". The Pharmaceutical Journal. 293 (7829). Retrieved 2014-10-10.

https://www.ncbi.nlm.nih.gov/pubmed/19546656

2009 study

Quote

RESULTS:

Subjects with dementia had higher cumulative dose, longer duration of BZDs exposure, and more likelihood to be long-term BZDs users.

CONCLUSION:

Our findings suggest that long-term use of BZDs is associated with an increased risk for dementia, but the underlying mechanisms remain unclear, and further investigations are needed. Long-term use of BZDs should be avoided among the elderly, who may be at a higher risk for developing dementia, in addition to other health problems.

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2005 study

https://www.ncbi.nlm.nih.gov/pubmed/16240487

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The acute use of alcohol and several other licit and illicit drugs can affect mental state and cognitive function. The chronic use of certain drugs may also increase the risk of cognitive impairment and perhaps dementia in later life. This paper focuses on the long-term cognitive consequences of using alcohol, benzodiazepines, tobacco and cannabis. Currently available evidence indicates that mild to moderate alcohol consumption is not associated with increased risk of cognitive decline and may in fact have a protective effect against dementia, although heavy, long-term consumption is likely to have a negative impact on cognitive function. The degree that alcohol-related cognitive impairment must reach to be classified as dementia is currently obscure. Longer-term smoking is associated with increased risk of cognitive impairment and possibly dementia.

The chronic use of benzodiazepines has been associated with increased risk of cognitive impairment but information relating to dementia remains inconclusive. The chronic use of cannabis may impair intellectual abilities but data on this topic remain sparse and difficult to interpret. In conclusion, there is evidence that some drugs contribute to the causal pathway that leads to the development of cognitive impairment but currently available data do not support the introduction of a separate diagnostic category of drug-induced dementia (such as alcohol-related dementia). Health promotion programs designed to decrease tobacco smoking and "harmful" alcohol use (and possibly other drug use) may decrease the burden of cognitive impairment and perhaps dementia in later life.

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4.Altered Acetylcholine and GABA  systems in dementia and benzodiazaphine use, adult neurogenesis, and BDNF

Benzodiazaphines are associated with lowered ACh levels and obvious GABAa receptor dysfunction.

Alzheimer’s patients have altered ACh function as well as GABAa dysfunction.  While this in no way proves cause and effect of benzodiazaphines and Alzheimer’s, perhaps benzodiazaphines may predispose one to the disease if that person is genetically vulnerable.  Both ACh and GABAaRs are critical to working memory.  Adult neurogeneisis (integrated of new neurons) is heavily dependent  on the neurotransmitter GABA.  Acute Benzo administration also resulted in reductions in BDNF.

https://en.m.wikipedia.org/wiki/Brain-derived_neurotrophic_factor

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BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.[6][7] In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.[8] It is also expressed in the retina, motor neurons, the kidneys, saliva, and the prostate.[9]

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BDNF is also important for long term memory.

I found this interesting discussion.  Not a clinical study

https://www.researchgate.net/post/Benzodiazepines_tied_to_Dementia10

Alzheimer’s is known to be related to cholinergic system deficits.  This study was interesting

https://www.ncbi.nlm.nih.gov/pubmed/9877014

Scopolamine is hyocine, an anticholinergic(antimuscarinic to be specific)

https://en.m.wikipedia.org/wiki/Hyoscine

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An investigation of the effects of benzodiazepine receptor ligands and of scopolamine on conceptual priming.

Bishop KI1, Curran HV.

Author information

Abstract

Scopolamine and lorazepam both produce anterograde impairments of explicit memory but only lorazepam impairs implicit memory as assessed by perceptual priming tasks. The main aim of the two experiments reported in this article was to determine the effects of these drugs on conceptual priming. Experiment 1 compared the effects of lorazepam (1,2 mg PO) with scopolamine (0.3,0.6 mg SC) and placebo in a study with 60 healthy volunteers. Experiment 2 compared the separate and combined effects of lorazepam (2 mg PO) and flumazenil (2 mg IV) with placebo in a study with 48 healthy volunteers. We found that conceptual priming in category generation tasks was intact following lorazepam in both studies. This preservation of conceptual priming contrasted with lorazepam-induced impairments on explicit memory tasks. In conjunction with previous findings, these results are interpreted as providing further support for the notion that conceptual and perceptual priming are subserved by distinct memory systems, one based on the operations of semantic memory, the other possibly based on a perceptual representation system. That lorazepam impairs perceptual but not conceptual priming suggests that the neurochemical substrates of the two kinds of priming are distinct.

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Benzos can inhibit ACh release and this might be a part of the causative factor in drug induced dementia. Here they used a neurosteroid as a PAM on the GABAa receptor, and a benzodiazaphine midazolam

https://www.researchgate.net/file.PostFileLoader.html?id=506c6544e24a467f2d000004&assetKey=AS%3A271744521179141%401441800350648

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The neurosteroid allopregnanolone is a potent and efficacious modulator of y-aminobutyric acid (GABA) type A receptors. The effects of intracerebroventricular injection of allopregnanolone (5 to 15 /zg/5 /xl) on basal and stress-induced release of acetylcholine were investigated in various regions of the brain areas of freely moving rats and compared with those of the benzodiazepine midazolam (1 to 10 /zg/5 #1). Allopregnanolone inhibited (20-55%) basal acetylcholine release from the prefrontal cortex and hippocampus, but not from the striatum, in a dose-dependent manner. At a dose of 10 /zg, allopregnanolone also completely prevented the increase in hippocampal acetylcholine release induced by foot-shock stress. Midazolam, inhibited basal acetylcholine release in all three brain regions as well as stress-induced acetylcholine release in the hippocampus, and showed a greater potency in these effects than allopregnanolone. These results suggest that endogenous neurosteroids may participate in the GABAergic modulation of central cholinergic function during basal conditions as well as after stress.

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https://en.m.wikipedia.org/wiki/Clonazepam

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Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[105][106] Clonazepam decreases release of acetylcholine in the feline brain[107] and decreases prolactin release in rats.[108] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[109] Benzodiazepines acted via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.[110]

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https://www.ncbi.nlm.nih.gov/pubmed/6133407

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Effects of some benzodiazepines on the acetylcholine release in the anterior horn of the lateral cerebral ventricle of the cat.

Petkov V, Georgiev VP, Getova D, Petkov VV.

Abstract

Studies were made of the effects of the benzodiazepines clonazepam (Cz), flunitrazepam (Fz) and Diazepam (Dz) on the spontaneous release of acetylcholine (ACh) in the anterior horn of the lateral cerebral ventricle of cats superficially anaesthetized with urethane. The amount of released ACh was determined in 15-min samples by a bioassay on a segment from isolated guinea-pig ileum. It was found that benzodiazepines applied i.p. in doses of: 5 mg/kg (Dz), 10 mg/kg (Cz) and 0.5 mg/kg (Fz) decreased the ACh release in the effluent flowing out through the cannulated aqueduct. If the released ACh in the sample taken immediately before the administration of benzodiazepine was considered to be 100 per cent its amount in the samples after injection of benzodiazepine changed as follows (in per cent): for Dz - 34.2, 70.2, 65.7, 40; for Cz - 46.3, 33.1, 26, 50.6; and for Fz - 46.1, 46.1, 28.2, 39.4. It is assumed that the benzodiazepine-induced reduced release of ACh from the caudate nucleus--a main structure participating in the building up of the anterior horn of the lateral cerebral ventricle--is a manifestation of inhibition of ACh turnover which might be due to inhibition of the activity of the serotoninergic neurons in the raphe nuclei. The decreased ACh release might also be due to inhibition by benzodiazepines of the Ca2+-dependent release of ACh.

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https://www.ncbi.nlm.nih.gov/pubmed/1358120

Cholinergic mechanisms in physical dependence on barbiturates, ethanol and benzodiazepines.

Nordberg A1, Wahlström G.

Author information

Abstract

The aim of this review is to summarize the effects of acute and chronic treatment with barbiturates, ethanol and benzodiazepines on cholinergic mechanisms in the brains of experimental animals. A single dose of each of these substances reduces the turnover of ACh in the brain. Long-term treatment has the opposite effect; complicated interactions including decreased content of ACh are induced. Barbiturates have been shown to bind stereospecifically to muscarinic and nicotinic receptors in the brain, but this has not been observed for ethanol or the benzodiazepines. The effects on the cholinergic system are affected by the length of treatment and choice of treatment regimen. No effect on cholinergic parameters, such as muscarinic receptors, in the brain is observed on withdrawal of ethanol or barbiturate treatment when the animals are still tolerant towards the substances. The increase in the number of muscarinic receptors observed in several brain regions on withdrawal is seen as a sign of cholinergic supersensitivity. The number of receptors returns to normal when abstinence convulsions have occurred. The assumption of a cholinergic influence is supported by the finding that atropine, given as a single dose on the day of withdrawal of barbital, can prevent the muscarinic receptor changes.

Furthermore, long-term barbital or ethanol treatment can induce permanent persistent changes in the cholinergic system in the brain.

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And note this

Quote

Cognitive defects and a significant permanent reduction in the content of ACh can be measured in rats which have had long-term barbital treatment. Similarly, a reduced number of muscarinic receptors has been measured in different brain regions of chronic alcoholics. Accumulating data support the role of the cholinergic system in expressing symptoms of physical dependence on barbiturates, ethanol and benzodiazepines as well as in the permanent long-term effects observed after end of treatment.

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This study is very interesting in that chronic diazepam dosing causes a decrease in ACh in the nucleus accumbens, whereas abrupt withdrawal causes ACh to spike.  Clearly benzodiazaphines and abrupt withdrawal have distinct effects on ACh dysregulation.  Part of the theory is that it is the rise in ACh that causes withdrawal symptoms in acute withdrawal, ie an overaroused hyper excitability.

https://www.ncbi.nlm.nih.gov/pubmed/15680263

Quote

Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency.

Rada P1, Hoebel BG.

Author information

Abstract

Diazepam is a benzodiazepine used in the treatment of anxiety, insomnia and seizures, but with the potential for abuse. Like the other benzodiazepine anxiolytics, diazepam does not increase dopamine in the nucleus accumbens. This raises the question as to which other neurotransmitter systems are involved in diazepam dependence. The goal was to monitor dopamine and acetylcholine simultaneously following acute and chronic diazepam treatment and after flumazenil-induced withdrawal. Rats were prepared with microdialysis probes in the nucleus accumbens and given diazepam (2, 5 and 7.5 mg/kg) acutely and again after chronic treatment. Accumbens dopamine and acetylcholine decreased, with signs of tolerance to the dopamine effect. When these animals were put into the withdrawal state with flumazenil, there was a significant rise in acetylcholine (145%, P<0.001) with a smaller significant rise in dopamine (124%, P<0.01). It is suggested that the increase in acetylcholine release, relative to dopamine, is a neural component of the withdrawal state that is aversive.

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And this with muscarinic receptors (mAChR M2), estradiol and their positive role in working memory

https://www.researchgate.net/file.PostFileLoader.html?id=506c672ae4f076882a00002d&assetKey=AS%3A271750821023745%401441801852338

Quote

Elevated levels of circulating estrogen in female rats result in increased spine and synapse density and parallel increases in NMDA receptor binding in area CA1 of the hippocampus. Es- trogen also influences cholinergic neurochemistry in the basal forebrain and hippocampus. The objectives of the present study were to determine the role of acetylcholine in the estrogen-induced increase in NMDA receptor binding in CA1 of the hippocampus and to investigate the relationship between increased NMDA receptor binding in CA1 and performance on a task of working memory. In the current experiments, elevating endogenous levels of acetylcholine in ovariectomized rats by 3 d of continuous administration of physostigmine, an acetylcholines- terase inhibitor, increased NMDA receptor binding in CA1 as measured by quantitative autoradiography. This increase was comparable with the increase in NMDA receptor binding induced by injections of estradiol benzoate 72 and 48 hr before death. Additionally, the administration of 5,11-dihydro-8-chloro-11-[[4-[3- [(2,2-dimethyl-1-oxopentyl)ethylamino]propyl]-1-piperidinyl]acetyl]- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (BIBN 99), an M2 re- ceptor antagonist, blocked the ability of both estrogen and physostigmine to increase NMDA receptor binding. The regimen of estradiol replacement that was demonstrated to increase NMDA receptor binding in CA1 of ovariectomized rats also im- proved arm-choice accuracy in a working memory task in an eight-arm radial maze. The estrogen-induced improvement in working memory performance was blocked by BIBN 99, which also blocked the increase in NMDA receptor binding. These re- sults indicate that acetylcholine acts at M2 muscarinic receptors to mediate the estrogen-induced increase in NMDA receptor bind- ing in CA1 of the hippocampus as well as the associated improve- ment in working memory.

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Acetylcholine in dementia

Acetylcholine receptors(nAChRs)  in dementia and mild cognitive impairment

https://www.researchgate.net/file.PostFileLoader.html?id=506c6928e24a46ff6e000034&assetKey=AS%3A271750821023747%401441801852717

Quote

Antibodies raised against human A2-6 and B2-4 nicotinic receptor subunits were utilized to fractionate 3H-epibatidine binding in human temporal cortex and striatum. The predominant receptor subtypes in both regions contained A4 and B2 subunits. In normal cortex, 10% of binding was also associated with A2 subunits, whereas in the striatum, contributions by A6 (17%) and B3 (23%) were observed. Minimal binding ( 5%) was associated with A3. In Alzheimer’s disease and dementia with Lewy bodies, cortical loss of binding was associated with reductions in a4 (50%, P < 0.01) and B2 (30–38%, P < 0.05). In Parkinson’s disease and dementia with Lewy bodies, striatal deficits in a6 (91 and 59% respectively, P < 0.01) and B3 (72 and 75%, P < 0.05) tended to be greater than for A4 and B2 (50 – 58%, P < 0.05). This study demonstrates distinct combinations of subunits contributing to heteromeric nicotinic receptor binding in the human brain that are area/pathway specific and differentially affected by neurodegeneration.

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These are articles on changes in GABAa receptors in Alzheimer’s .  Note just because Alzheimer’s has altered GABAa function does not directly implicate benzos in causing dementia.  One article suggests that upregulating GABAA receptors might protect neurons for neurofibrillary pathology in Alzheimer’s.

Benzodiazaphines are contraindicated in dementia, and perhaps it is because they downregulate GABAa receptors.  I can certainly understand how benzodiazaphines could make existing dementia worse, and this would confound the mata-data studies even further……They might be making the an existing  dementia worse in those studies, but not causing it.

It would be interesting, but unethical, to determine if benzodiazaphines make preemptive dementia worse in this repspect.

https://www.ncbi.nlm.nih.gov/pubmed/22691495

Quote

The cholinergic and glutamatergic neurotransmission systems are known to be severely disrupted in Alzheimer's disease (AD). GABAergic neurotransmission, in contrast, is generally thought to be well preserved. Evidence from animal models and human postmortem tissue suggest GABAergic remodeling in the AD brain. Nevertheless, there is no information on changes, if any, in the electrophysiological properties of human native GABA receptors as a consequence of AD. To gain such information, we have microtransplanted cell membranes, isolated from temporal cortices of control and AD brains, into Xenopus oocytes, and recorded the electrophysiological activity of the transplanted GABA receptors. We found an age-dependent reduction of GABA currents in the AD brain. This reduction was larger when the AD membranes were obtained from younger subjects. We also found that GABA currents from AD brains have a faster rate of desensitization than those from non-AD brains. Furthermore, GABA receptors from AD brains were slightly, but significantly, less sensitive to GABA than receptors from non-AD brains. The reduction of GABA currents in AD was associated with reductions of mRNA and protein of the principal GABA receptor subunits normally present in the temporal cortex. Pairwise analysis of the transcripts within control and AD groups and analyses of the proportion of GABA receptor subunits revealed down-regulation of α1 and γ2 subunits in AD. In contrast, the proportions of α2, β1, and γ1 transcripts were up-regulated in the AD brains. Our data support a functional remodeling of GABAergic neurotransmission in the human AD brain.

End Quote

https://www.ncbi.nlm.nih.gov/pubmed/19019179

Quote

Immunohistochemical characterization of the distribution of GABA(A) receptor subunits gamma1/3 and 2 in the hippocampus relative to neurofibrillary tangle (NFT) pathology staging was performed in cognitively normal subjects (Braak stage I/II, n = 4) and two groups of Alzheimer's disease (AD) patients (Braak stage III/IV, n = 4; Braak stage V/VI, n = . In both Braak groups of AD patients, neuronal gamma1/3 and gamma2 immunoreactivity was preserved in all hippocampal subfields. However, compared to normal controls neuronal gamma1/3 immunoreactivity was more intense in several end-stage AD subjects. Despite increased NFT pathology in the Braak V/VI AD group, GABA(A)gamma1/3 and gamma2 immunoreactivity did not co-localize with markers of NFT.

These results suggest that upregulating or preserving GABA(A)gamma1/3 and gamma2 receptors may protect neurons against neurofibrillary pathology in AD.

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https://www.ncbi.nlm.nih.gov/pubmed/21388375

Quote

In addition to progressive dementia, Alzheimer's disease (AD) is characterized by increased incidence of seizure activity. Although originally discounted as a secondary process occurring as a result of neurodegeneration, more recent data suggest that alterations in excitatory-inhibitory (E/I) balance occur in AD and may be a primary mechanism contributing AD cognitive decline. In this study, we discuss relevant research and reports on the GABA(A) receptor in developmental disorders, such as Down syndrome, in healthy aging, and highlight documented aberrations in the GABAergic system in AD. Stressing the importance of understanding the subunit composition of individual GABA(A) receptors, investigations demonstrate alterations of particular GABA(A) receptor subunits in AD, but overall sparing of the GABAergic system. In this study, we review experimental data on the GABAergic system in the pathobiology of AD and discuss relevant therapeutic implications. When developing AD therapeutics that modulate GABA it is important to consider how E/I balance impacts AD pathogenesis and the relationship between seizure activity and cognitive decline.

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Benzodiazaphines and dementia PART II

5.Adult neurogenesis and necessity of GABA neurotransmitter

https://www.ncbi.nlm.nih.gov/pubmed/16341203

Quote

GABA regulates synaptic integration of newly generated neurons in the adult brain.

Ge S1, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H.

Author information

Abstract

Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (gamma-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo.

Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

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6.Diazepam and BDNF decreased only with acute dosing (kindling?)

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084806

Quote

Benzodiazepines (BZs) are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the hippocampus (HIP), an area involved in drug-related plasticity, by investigating the regulation of immediate early genes following BZ administration. Previous studies have demonstrated that both brain derived neurotrophic factor (BDNF) and c-Fos contribute to memory- and abuse-related processes that occur within the HIP, and their expression is altered in response to BZ exposure. In the current study, mice received acute or repeated administration of BZs and HIP tissue was analyzed for alterations in BDNF and c-Fos expression.

Although no significant changes in BDNF or c-Fos were observed in response to twice-daily intraperitoneal (i.p.) injections of diazepam (10 mg/kg + 5 mg/kg) or zolpidem (ZP; 2.5 mg/kg + 2.5 mg/kg), acute i.p. administration of both triazolam (0.03 mg/kg) and ZP (1.0 mg/kg) decreased BDNF protein levels within the HIP relative to vehicle, without any effect on c-Fos. ZP specifically reduced exon IV-containing BDNF transcripts with a concomitant increase in the association of methyl-CpG binding protein 2 (MeCP2) with BDNF promoter IV, suggesting that MeCP2 activity at this promoter may represent a ZP-specific mechanism for reducing BDNF expression. ZP also increased the association of phosphorylated cAMP response element binding protein (pCREB) with BDNF promoter I. Future work should examine the interaction between ZP and DNA as the cause for altered gene expression in the HIP, given that BZs can enter the nucleus and intercalate into DNA directly.

End quote

There are many more references in these areas for those who are interested.

7.Glutamate toxicity, LTD(not LTP),  and Alzheimer’s

The number of references in this area is huge.

https://www.google.com/search?rlz=1C9BKJA_enUS593US593&hl=en-US&ei=jtGTWZOeD6vU0gLNl5ewDw&q=long+term+depression+glutamate+toxicity+and+dementia&oq=long+term+depression+glutamate+toxicity+and+dementia&gs_l=mobile-gws-serp.3...9213.14438.0.15934.22.22.0.0.0.0.527.3150.8j10j3j5-1.22.0....0...1.1.64.mobile-gws-serp..4.5.531...30i10k1.6vE_G4z22I4

http://journal.frontiersin.org/article/10.3389/fnins.2015.00469/full

Quote

Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

End quote

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-9-48

Quote

Alzheimer’s disease (AD) is a devastating disease characterized by synaptic and neuronal loss in the elderly. Compelling evidence suggests that soluble amyloid-β peptide (Aβ) oligomers induce synaptic loss in AD. Aβ-induced synaptic dysfunction is dependent on overstimulation of N-methyl-D-aspartate receptors (NMDARs) resulting in aberrant activation of redox-mediated events as well as elevation of cytoplasmic Ca2+, which in turn triggers downstream pathways involving phospho-tau (p-tau), caspases, Cdk5/dynamin-related protein 1 (Drp1), calcineurin/PP2B, PP2A, Gsk-3β, Fyn, cofilin, and CaMKII and causes endocytosis of AMPA receptors (AMPARs) as well as NMDARs. Dysfunction in these pathways leads to mitochondrial dysfunction, bioenergetic compromise and consequent synaptic dysfunction and loss, impaired long-term potentiation (LTP), and cognitive decline. Evidence also suggests that Aβ may, at least in part, mediate these events by causing an aberrant rise in extrasynaptic glutamate levels by inhibiting glutamate uptake or triggering glutamate release from glial cells. Consequent extrasynaptic NMDAR (eNMDAR) overstimulation then results in synaptic dysfunction via the aforementioned pathways. Consistent with this model of Aβ-induced synaptic loss, Aβ synaptic toxicity can be partially ameliorated by the NMDAR antagonists (such as memantine and NitroMemantine). PSD-95, an important scaffolding protein that regulates synaptic distribution and activity of both NMDA and AMPA receptors, is also functionally disrupted by Aβ. PSD-95 dysregulation is likely an important intermediate step in the pathological cascade of events caused by Aβ. In summary, Aβ-induced synaptic dysfunction is a complicated process involving multiple pathways, components and biological events, and their underlying mechanisms, albeit as yet incompletely understood, may offer hope for new therapeutic avenues.

End quote

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468881/

Quote

Literatures suggest that behavioral disturbance and cognitive impairment of Alzheimer’s disease may be associated with excitatory neurotoxic effects which result in impairment of neuronal plasticity and degenerative processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion in Alzheimer’s disease. On the other hand, some NMDA modulators which enhance NMDA function through the co-agonist binding site can also improve cognitive function and psychotic symptoms. We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms of Alzheimer’s disease. Prospective study

End quote

http://onlinelibrary.wiley.com/store/10.1111/jnc.12304/asset/jnc12304.pdf;jsessionid=636AFCE0204A36335D45D27457F5FFC7.f04t02?v=1&t=j6ekg1d0&s=1a0731a52a17bbd0dbbae173446cf4e1e1543da1

This reference is very interesting .

Quote

Abstract Alzheimer′s disease (AD) is the most common form of dementia in the elderly. Memory loss in AD is increasingly attributed to soluble oligomers of the amyloid-b peptide (AbOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be cen- trally involved in synaptic targeting by AbOs. Once bound to neurons, AbOs dysregulate the activity and reduce the surface expression of both N-methyl-D-aspartate (NMDA) and 2-amino- 3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types of glutamate receptors, impairing signaling pathways involved in synaptic plasticity. In the extracellular milieu, AbOs promote accumulation of the excitatory amino acids, glutamate and D-serine. This leads to overactivation of glutamate receptors,

triggering abnormal calcium signals with noxious impacts on neurons. Here, we review key findings linking AbOs to deregulated glutamate neurotransmission and implicating this as a primary mechanism of synapse failure in AD. We also discuss strategies to counteract the impact of AbOs on excitatory neurotransmission. In particular, we review evi- dence showing that inducing neuronal hyperpolarization via activation of inhibitory GABAA receptors prevents AbO- induced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD.

End quote

Quote

Acute brain insults including hypoglycemia, neurologic trauma, stroke, and epilepsy give rise to an imbalance in excitatory glutamatergic neurotransmission and are known to cause synapse dysfunction and massive cell death in the central nervous system (Esposito et al. 2011; Frasca et al. 2011).

Cognitive impairment and dementia are frequently associated with recovery from such insults, suggesting that common pathological mechanisms may be at play in those

neurological conditions and in other forms of dementia, including AD. Indeed, several neurodegenerative disorders have been linked to excitatory neuronal damage, including Parkinson’s disease and Huntington diseases, and amyo- trophic lateral sclerosis (Mattson 2003; Koutsilieri and Riederer 2007). Here, we review evidence that glutamate receptors are centrally involved in the mechanisms by which amyloid-b oligomers (AbOs) attack synapses and render them dysfunctional. In particular, we discuss the role of N-methyl- D-aspartate (NMDA) receptors as common initiators of various forms of neuronal dysfunction/damage instigated by AbOs. Finally, we discuss possible neuroprotective strategies to prevent excitotoxicity and synapse failure in AD.

End quote

An anecdotal article on benzodiazaphines and brain injury.  Bad combination .

https://www.lifeafterimpact.com/single-post/2016/1/8/Benzodiazepines-Doubly-Dangerous-for-those-with-Traumatic-Brain-Injuries

8.Off topic : Benzodiazaphines, immune system

https://en.m.wikipedia.org/wiki/Effects_of_long-term_benzodiazepine_use

Quote

Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department.[55] Diazepam and clonazepam have been found to have long-lasting, but not permanent, immunotoxic effects in the fetus of pregnant rats. However, single very high doses of diazepam have been found to cause lifelong immunosuppression in neonatal rats. No studies have been done to assess the immunotoxic effects of diazepam in humans; however, high prescribed doses of diazepam, in humans, has been found to be a major risk of pneumonia, based on a study of people with tetanus. It has been proposed that diazepam may cause long-lasting changes to the GABAA receptors with resultant long-lasting disturbances to behaviour, endocrine function and immune function.[56]

End quote

https://www.ncbi.nlm.nih.gov/pubmed/7908607

Quote

Immunodeficiency is frequently invoked as an ethiopathogenetic factor for many somatic diseases. On the other hand, stress, depression, and psychotic disturbances are associated with severe immunological disorders. Taking into account that the benzodiazepines (BZ) are the psychoactive drugs more widely used than any other to treat psychological disturbances, it seems important to elucidate the immuno-enhancing or immunosuppressant potential of such drugs. Our goal was easily reached, since 69% of the outpatients visiting our Institute are chronic BZ consumers and because neurochemical, hormonal, immunological, and psychiatric investigations are routinely performed on all of our patients. In the present study, immune function was investigated on two occasions: while the patient was on active medication and 15 days after discontinuation. We concluded that chronic consumption of BZ provokes significant immunological disorders that should be further investigated. Said disorders could not be linked to a pre-existing affective disease or psychosis, since we only selected those BZ users in whom psychiatric investigations ruled out a past or present history of major psychiatric disease.

End quote

https://www.ncbi.nlm.nih.gov/pubmed/16393867

Quote

It is well established that human diseases associated with abnormal immune function, including some common infectious diseases and asthma, are considerably more prevalent at younger ages. Although not established absolutely, it is generally believed that development constitutes a period of increased immune system susceptibility to xenobiotics, since adverse effects may occur at lower doses and/or immunomodulation may be more persistent, thus increasing the relative risk of xenobiotic exposure to the immunologically immature organism. To address this issue, a brief overview of immune maturation in humans is provided to demonstrate that functional immaturity alone predisposes the young to infection. Age-dependent differences in the immunotoxic effects of five diverse compounds, diethylstilbestrol (DES), diazepam (DZP), lead (Pb), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and tributyltin oxide (TBTO), which have undergone adult and developmental immunotoxicity testing in rodents, are then reviewed, as are human data when available. For all five chemicals, the developing immune system was found to be at greater risk than that of the adult, either because lower doses produced immunotoxicity, adverse effects were more persistent, or both.

End quote

https://www.ncbi.nlm.nih.gov/pubmed/2899983

Quote

Alterations of the immune-system by benzodiazepines are of minor degree in dependence of their central or peripheral activity. Regarding their central effects a modulation may be assumed via the endocrine system. In vitro and in vivo studies lead to the assumption, that benzodiazepines have a mutagenic effect, even though this hypothesis could not be confirmed by in vitro investigations. In vivo a possible mutagenic action could only be found in two patients after long term therapy. A more mitosis-inhibiting effect of diazepam was shown in in vitro studies. In animal experiments this observation could not be confirmed for the thymus. With regard to specific immunity, diazepam seems to have a stimulating effect on the T-helper cells. Locomotion and chemotaxis of human polymorphonuclear granulocytes is not influenced by anaesthetic doses of benzodiazepines. It is questionable whether benzodiazepines are of clinical importance for the immune-system of patients receiving anaesthetic doses. However, the presently generous use of benzodiazepines, e.g. on intensive care units, should be reconsidered in respect to immunological consequences.

End quote

https://www.ncbi.nlm.nih.gov/pubmed/1776530

Quote

Benzodiazepines (BDZ) are psychotropic drugs largely used in patients with affective disorders. As far as their effects on the immune system are concerned, a few studies have been carried out until now. Diazepam is inhibitory in vitro for the phagocytic functions and the antibody synthesis, being its action mediated via specific receptors on immunocompetent cells. On the contrary, alprazolam results to be enhancing for the antibacterial activity exerted by normal human peripheral blood T lymphocytes in vitro. Taken together, these data point out the different role which BDZ play on the immune response.

End quote

Autoimmune encephalitis and benzodiazaphines

No direct clinical studies linking the two

Here benzos masked the disease

http://www.shmabstracts.com/abstract/recurrent-antibody-mediated-autoimmune-encephalitis-masked-by-tca-and-benzodiazepine-overdose-a-case-report/

Benzos therapeutic for the disease 

https://www.researchgate.net/publication/236740297_Remarkable_effect_of_benzodiazepine_in_a_patient_with_anti-NMDA_receptor_encephalitis

This one is very relevant

Benzodiazaphine effects on immune and vascular system, vasculitis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203915/

Quote

Alprazolam was found to induce a significant increase in neutrophil count and a significant decrease in lymphocytes, anti-SRBC titer and IL-2 level with severe depletion of the splenic, thymal and nodal lymphocytes, accompanied by congestion and eosinophilic vasculitis of all organs tested in comparison to clonazepam treated rats. Stress enhanced the toxic effects. It was concluded that the immune system and blood vessels can be adversely affected to a greater

extent by short-term chronic administration of alprazolam than by clonazepam, and these toxic effects are aggravated by stress.

End quote

9.Off topic: benzodiazaphines and microglia(CNS immune system): the mystery of PBRs or peripheral benzodiazaphine receptors, more on the immune system .  Something very strange is going on here with these PBRs…….

Microglia are thought to be involved in many neurodegenerative diseases like Alzheimer’s

Peripheral benzodiazaphine receptors or PBRs are found to be

profoundly colocalized in microglia in neurodegenerative diseases and traumatic brain injury.  I don’t know the relevance of this to benzodiazaphines as a causal agent.  But therapeutic agents on the PBRs in regards to Alzheimer’s are very strange. See below…..

This one basically states that benzos lowered inflammatory markers

These were peripheral benzodiazaphine receptors

https://www.ncbi.nlm.nih.gov/pubmed/14678758

https://en.m.wikipedia.org/wiki/PK-11195

Quote

Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro.

Wilms H1, Claasen J, Röhl C, Sievers J, Deuschl G, Lucius R.

Author information

Abstract

Increased binding of a ligand for the peripheral benzodiazepine binding receptor is currently used in PET studies as an in vivo measurement of inflammation in diseases like multiple sclerosis and Alzheimer's disease. Although peripheral-type benzodiazepin receptors (PBRs) are abundant in many cell types and expressed in the CNS physiologically only at low levels, previous reports suggest that after experimental lesions in animal models and in human neurodegenerative/-inflammatory diseases upregulated PBR expression with increased binding of its ligand PK11195 is confined mainly to activated microglia in vivo/in situ. Because the functional role of the PBR is unknown, we confirm by immunohistochemistry and PCR (I) that this receptor is expressed on microglia in vitro and (II) that benzodiazepines modulate proliferation of microglial cells and the release of the inflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in cell culture supernatants of primary rat microglia. Compared to lipopolysaccharide-activated controls the release of NO was markedly decreased in cultures treated with benzodiazepines (clonazepam, midazolam, diazepam) and the PBR ligand PK11195. Moreover, release of TNF-alpha and proliferation was significantly inhibited in the benzodiazepine-treated groups. These findings link the in vivo data of elevated PBR levels in neurodegenerative/-inflammatory diseases to a functional role and opens up possible therapeutic intervention targeting the PBR in microglia.

End quote

Detail on microglia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1849976/

Quote

Microglia undergo changes from a resting phenotype to an activated phenotype in response to a wide variety of CNS insults. Various degrees of microglia activation are seen in neurodegenerative disorders. Neuritic plaques, which constitute the central pathology in Alzheimer's disease (AD), are surrounded by microglia (McGeer et al., 1988b). In multiple sclerosis, areas of demyelination are rich in activated microglia (Bauer et al., 1994). HIV- dementia is characterized by viral infection of microglia (Wiley et al., 1986). Activation of microglia in other neurodegenerative diseases such as Parkinson's disease (McGeer et al., 1988a), Creutzfeldt-Jakob disease (Muhleisen et al., 1995) and Amyotrophic Lateral Sclerosis (Sargsyan et al., 2005) is known but less well characterized.

…..

Recent studies indicate that it may be possible to image activated microglia in CNS disorders using Positron Emission Tomography (PET) with ligands targeted to the peripheral benzodiazepine receptor. In the following section we examine the rationale behind these studies and examine some of the initial findings suggesting the utility of this technique to quantify CNS microglial activation.

End quote

More on the PBR as a modulator of neuroinflammation

Quote

Evidence indicating that diazepam bound with high affinity in the rat kidney led to the postulation and later characterization of the peripheral benzodiazepine receptor (PBR) (Braestrup et al., 1977), named to differentiate it from the previously described diazepam binding sites in the CNS (central benzodiazepine receptor). Within the CNS, two pharmacologically distinct benzodiazepine receptors exist: the central and the peripheralbenzodiazepine receptors. The central benzodiazepine receptor is a part of the ionotropic GABA receptor located on the plasma membrane of GABA-ergic neurons (Stephenson, 1995). PBR is in contrast located on the outer membrane of mitochondria, and mainly in glial cells (Casellas et al., 2002) (figure 1). It is part of a hetero-oligomeric complex comprised of the voltage-dependent anion channel and an adenine nucleotide carrier forming the mitochondrial permeability transition pore (McEnery et al., 1992) (figure 1).

Outside the CNS, PBR is ubiquitously expressed and is particularly enriched in steroidogenic cells. Several functions have been attributed to PBR. It is thought to aid in the transport of cholesterol from the outer to the inner mitochondrial membranes and thus be vital in steroid synthesis (Papadopoulos, 2004; Papadopoulos et al., 1997). As a constituent of the mitochondrial permeability transition pore, PBR is believed to regulate cell death (McEnery et al., 1992) and mitochondrial respiration (Hirsch et al., 1989). PBR is also thought to play a role in cell proliferation, differentiation and protein and ion transport (reviewed in (Casellas et al., 2002; Gavish et al., 1999)) Less is known about the functions of this receptor within the CNS more specifically. It is thought to be involved in neurosteroid synthesis (Papadopoulos et al., 2006), regulating mitochondrial function (Casellas et al., 2002) and modulating neuroinflammation in microglial cells (discussed below). Although the role of this receptor in the CNS is not yet entirely clear, several studies have focused on changes in PBR expression in CNS diseases. End quote

PBRs in neurodegenerative diseases

Quote

Several studies have subsequently focused on changes in PBR expression in CNS disease. [3H]-PK11195 autoradiography was first used to label glioma cell lines implanted into mice brains (Starosta-Rubinstein et al., 1987). Several binding studies using homogenized brain tissue and autoradiography studies have now shown increased [3H]-PK11195 binding (reflecting increased in PBR protein expression) in a wide variety of neurological diseases (summarized in Table 1) and animal models. This includes conditions such as multiple sclerosis (Banati et al., 2000; Vowinckel et al., 1997), experimental autoimmune encephalitis (Vowinckel et al., 1997), stroke (Stephenson et al., 1995), brain trauma (Raghavendra Rao et al., 2000), facial nerve transaction (Banati et al., 1997; Gehlert et al., 1997), and SIVE (Mankowski et al., 2003) (Venneti et al., 2004). As discussed below, in the majority of these studies, cellular localization of increased PBR expression is specific to activated microglial elements.

End quote

Why are they colocalized in areas of injury with increased cytokine levels

Quote

In experimental autoimmune encephalitis, IL-6 and TNF-α expression profiles correlate with increase in spinal cord [3H]-PK11195 binding (Agnello et al., 2000). These data suggest that cytokines increase PBR expression in various cell types including microglia. However, the mechanisms mediating the functional consequences of PBR-ligand binding increases are not known. It has been proposed that cellular upregulation of PBR in these systems may serve as a protective strategy against cytokine toxicity. Since activated microglia themselves are sources of cytokines, increase in PBR expression would be an autocrine-paracrine phenomenon.

End quote

Quote

Microglia change from a ramified morphology to an amoeboid morphology on activation (Kreutzberg, 1996). These changes may also be accompanied by morphological alterations in the mitochondria (Banati et al., 2004). However, the subcellular changes in PBR in microglia on activation are not known. Increases in cell size due to evolution to an ameboid morphology upon activation may result in an increase in the mitochondrial population in each microglial cell without change in the number of PBR per mitochondrion. Hence it is possible that increased PBR in activated microglia actually reflect an increase in mitochondrial number. On the other hand, the number of mitochondria may not change significantly, but the number of PBR per mitochondrion may increase. However, the most likely possibility is that the number of mitochondria as well as the number of PBR per mitochondria increases with activation in each microglial cell. While these possibilities need to be confirmed experimentally, it is important to note that activation of microglia may result in mitochondrial changes that may influence the functioning of these cells.

End quote

What is PBRs function in the microglia??

Quote

The functional consequences of increased PBR expression in microglia are unknown. PBR is thought to play a role in modulating the activation of microglia. For example, treating primary human embryonic microglia with PK11195 decreases expression of COX2 and TNF-α and decreases intracellular calcium levels (Choi et al., 2002). Further, PK11195 decreases microglial activation, iNOS, IL-1β, IL-6, TNF-α levels and the extent of neuronal damage in quinolinic acid-injected rats (Ryu et al., 2005). Diazepam is also speculated to inhibit HIV-tat induced microglial chemotaxis by acting on PBR (Lokensgard et al., 2001). Since PBR may play a role in regulating cell division, PBR may also play a role in the regulation of microglial proliferation upon neuronal injury. The association of PBR with the mitochondrial permeability transition pore suggests a role in the regulation of cell survival in microglia. At the mitochondrial permeability transition pore, PBR interacts with several resident mitochondrial proteins including the voltage dependent anion channel and the adenine nucleotide carrier (figure 1) that in turn interact with proteins regulating apoptosis (McEnery et al., 1992). Interestingly, forced macrophage-PBR overexpression in myxoma poxvirus-infected macrophages blocks apoptosis (Everett et al., 2002;Everett and McFadden, 2001). Forced PBR expression in neurons in vivo and Jurkat cells in vitro also protects these cells from apoptosis (Johnston et al., 2001;Stoebner et al., 2001). PBR upregulation in testicular Leydig cells protects them from cytokine-induced toxicity (Rey et al., 2000;Trincavelli et al., 2002). This is also seen in blood phagocytic cells where PBR protects against oxidant-induced cell death (Carayon et al., 1996). PBR expression in microglia may thus protect them from various toxins, thereby contributing to longer microglia life spans in the brain and perpetuating neuroinflammation (figure 2).

End quote

Quote

The low levels of mitochondrial PBR present in the normal CNS increase dramatically with injury and neurodegeneration, and predominantly in microglia, as suggested by several studies using animal models and human postmortem tissues. The mechanisms of PBR regulation and its functions in microglia are not known.

End quote

https://www.ncbi.nlm.nih.gov/pubmed/16866919

Quote

In vivo evidence for microglial activation in neurodegenerative dementia.

Cagnin A1, Kassiou M, Meikle SR, Banati RB.

Author information

Abstract

Evidence from numerous neuropathological observations and in vivo clinical imaging studies suggests a prominent role of activated microglia, the main effector cell of the brain's innate immune system, in Alzheimer's disease and other neurodegenerative diseases. Though the comprehensive molecular definition of the microglial activation process is still incomplete, the de novo expression of 'peripheral benzodiazepine-binding sites (PBBS)' by activated but not resting microglia has been established as a useful descriptor of functional state changes in microglia. As microglial transformation to an activated state is closely linked to progressive changes in brain disease, the detection of activated microglia can provide information about disease distribution and rate of disease progression. Positron emission tomography (PET) and [(11)C]®-PK11195, a specific ligand of the PBBS, have been used to study systematically microglial activation in vivo. Significant microglial activation is present in the brains of patients with neurodegenerative dementia even at early and possibly preclinical stages of the disease with a spatial distribution reflecting different clinical phenotypes. We review some of the posited functions of activated microglia in the pathophysiology of dementia and speculate on the relationship between increased regional [(11)C]®-PK11195 signals and the ensuing changes in brain volume. Finally, we provide a brief outlook on the development of new radioligands for the PBBS.

End quote

https://www.ncbi.nlm.nih.gov/pubmed/19075709

Quote

PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders.

Doorduin J1, de Vries EF, Dierckx RA, Klein HC.

Author information

Abstract

It is important to gain more insight into neurodegenerative diseases, because these debilitating diseases can not be cured. A common characteristic of many neurological diseases is neuroinflammation, which is accompanied by the presence of activated microglia cells. In activated microglia cells, an increase in the expression of peripheral benzodiazepine receptors (PBR) can be found. The PBR was suggested as a target for monitoring disease progression and therapy efficacy with positron emission tomograpy (PET). The PET tracer [(11)C]PK11195 has been widely used for PBR imaging, but the tracer has a high lipophilicity and high non-specific binding which makes it difficult to quantify uptake. Therefore, efforts are being made to develop more sensitive radioligands for the PBR. Animal studies have yielded several promising new tracers for PBR imaging, such as [(11)C]DAA1106, [(18)F]FEDAA1106, [(11)C]PBR28, [(11)C]DPA713 and [(11)C]CLINME. However, the potential of these new PBR ligands is still under investigation and as a consequence [(11)C]PK11195 is used so far to image activated microglia cells in neurological disorders. With [(11)C]PK11195, distinct neuroinflammation was detected in multiple sclerosis, Parkinson's disease, encephalitis and other neurological diseases. Because neuroinflammation plays a central role in the progression of neurodegenerative diseases, anti-inflammatory drugs have been investigated for therapeutic intervention. Especially minocycline and cyclooxygenase inhibitors have shown in vivo anti-inflammatory, hence neuroprotective properties, that could be detected by PET imaging of the PBR with [(11)C]PK11195. The imaging studies published so far showed that the PBR can be an important target for monitoring disease progression, therapy response and determining the optimal drug dose.

End quote

Here PBRs expressed after brain injury.  I don’t know the correlation to benzodiazaphines, but find it interesting that these receptors pop up where neurodegenerative processes are occurring.  They seem to be recruited to calm inflammatory cytokine responses , as mentioned above.

https://pdfs.semanticscholar.org/8bf0/e9989ccee6d35b1154c62c016cb4d28fc3a7.pdf

http://www.sciencedirect.com/science/article/pii/S0306452205006330

http://www.ingentaconnect.com/content/ben/cmc/2002/00000009/00000015/art00001

https://academic.oup.com/brain/article/123/11/2321/256076/The-peripheral-benzodiazepine-binding-site-in-the

http://www.sciencedirect.com/science/article/pii/S0165614706001532

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453598/

10.More on PBRs (TPSOs):  Very interesting and strange effects of PBR ligands on Alzheimer’s plaques.  I have to wonder how traditional Benzodiazaphines affect these PBRs in the context of microglia, immune function and neurodegenerative disease…….

https://en.m.wikipedia.org/wiki/Translocator_protein

Quote

PBRs (TSPOs) have many actions on immune cells including modulation of oxidative bursts by neutrophils and macrophages, inhibition of the proliferation of lymphoid cells and secretion of cytokines by macrophages.[13] Expression of TSPO is also linked to inflammatory responses that occur after ischemia-reperfusion injury, following brain injury, and in some neurodegenerative diseases.[citation needed]

End quote

Therapeutic modulation of PBRs

https://en.m.wikipedia.org/wiki/Alpidem

https://en.m.wikipedia.org/wiki/Emapunil

Note 11195 is an antagonist of the PBR

https://en.m.wikipedia.org/wiki/PK-11195

This one 4864 below,  and 11195 used in the Alzheimer’s study below

4864 is a benzodiazaphine derivative of diazepam.  However it’s effects are quite different (sedative but convulsant effects and produces anxiety effects) and it does not bind to the GABAa receptor……. It’s actually neuroprotective along with the antagonist 11195 in the Alzheimer’s study.      Something strange is going on here 

I wonder how traditional GABAa receptor Benzodiazaphines affect the PBRs in neurodegenerative disease…….

https://en.m.wikipedia.org/wiki/Ro5-4864

Quote

TSPO has been shown to be involved in a number of processes such as inflammation,[21] and TSPO ligands may be useful anti-cancer drugs.[22][23]

Pharmacological activation of TSPO has been observed to be a potent stimulator of steroid biosynthesis [24][25] including neuroactive steroids such as allopregnanolone in the brain, which exert anxiolytic properties.[26] Thus, TSPO ligands such as emapunil (XBD-173) or alpidem have been proposed to be useful as potential anxiolytics which may have less addiction-based side effects than traditional benzodiazepine-type drugs.,[27][28][29][30] though toxicity side-effects remain a significant barrier in drug development.[31]

A 2013 study led by researchers from USC Davis School of Gerontology showed that TSPO ligands can prevent and at least partially correct abnormalities present in a mouse model of Alzheimer's disease.[32]

TSPO as a biomarker is a newly discovered non-invasive procedure, and has also been linked as a biomarker for other cardiovascular related diseases including: myocardial infarction (due to ischemic reperfusion), cardiac hypertrophy, atherosclerosis, arrhythmias, and large vessel vasculitis.[14] TSPO can be used as a biomarker to detect the presence and severity of inflammation in the heart and atherosclerotic plaques.[15] Inhibiting the over-production of TSPO can lead to a reduced incidence of arrhythmias which are most often caused by ischemia reperfusion injury.[14] TSPO ligands are used as a therapy after ischemia reperfusion injury to preserve the action potentials in cardiac tissue and restore normal electrical activity of the heart.[11] Higher levels of TSPO are present in those with heart disease, a change that is more common in men than women because testosterone worsens the inflammation causing permanent damage to the heart.[15]

End quote

https://www.ncbi.nlm.nih.gov/pubmed/23678130

Quote

Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD-related neuropathology, including β-amyloid accumulation, gliosis, and behavioral impairment, were examined under both early intervention (7-month-old young-adult male mice with low pathology) and treatment (24-month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young-adult mice but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in nontransgenic mice. These findings suggest that TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.

End quote

http://www.ingentaconnect.com/content/ben/cpd/2007/00000013/00000023/art00006

11.Benzodiazaphines and vascular dementia.  Vasculitis can cause vascular dementia.  No association found

https://en.m.wikipedia.org/wiki/Dementia

Quote

Vascular dementia is the cause of at least 20% of dementia cases, making it the second most common cause of dementia.[34] It is caused by disease or injury affecting the blood supply to the brain, typically involving a series of minor strokes. The symptoms of this dementia depend on where in the brain the strokes have occurred and whether the vessels are large or small.[11] Multiple injuries can cause progressive dementia over time, while a single injury located in an area critical for cognition (i.e. hippocampus, thalamus) can lead to sudden cognitive decline.[34]

On scans of the brain, a person with vascular dementia may show evidence of multiple strokes of different sizes in various locations. People with vascular dementia tend to have risk factors for disease of the blood vessels, such as tobacco use, high blood pressure, atrial fibrillation, high cholesterol or diabetes, or other signs of vascular disease such as a previous heart attack or angina.

End quote

Google search

https://www.google.com/search?rlz=1C9BKJA_enUS593US593&hl=en-US&ei=L8mUWfiZA-md0gKb57XYCA&q=vascular+dementia+and+benzodiazepines&oq=vascular+dementia+and+benzo&gs_l=mobile-gws-serp.1.0.33i21k1j33i160k1l3.98954.102733.0.104056.16.16.0.0.0.0.317.2262.1j14j0j1.16.0....0...1.1.64.mobile-gws-serp..8.8.1232...0j41j0i13k1j0i22i30k1.M55AZ1-8i4s

https://www.ncbi.nlm.nih.gov/pubmed/26123874

This case control study did not find a link

Quote

Benzodiazepine Use and Risk of Developing Alzheimer's Disease or Vascular Dementia: A Case-Control Analysis.

Imfeld P1,2, Bodmer M1, Jick SS3, Meier CR4,5,6.

Author information

Abstract

INTRODUCTION:

Previous observational studies have associated benzodiazepine use with an increased risk of dementia. However, limitations in the study methods leave questions unanswered regarding the interpretation of the findings.

METHODS:

A case-control analysis was conducted using data from the UK-based Clinical Practice Research Datalink (CPRD). A total of 26,459 patients aged ≥65 years with newly diagnosed Alzheimer's disease (AD) or vascular dementia (VaD) between 1998 and 2013 were identified and matched 1:1 to dementia-free controls on age, sex, calendar time, general practice, and number of years of recorded history. Adjusted odds ratios (aORs) were calculated with 95% confidence intervals (CIs) of developing AD or VaD in relation to previous benzodiazepine use, stratified by duration and benzodiazepine type.

RESULTS:

The aOR (95% CI) of developing AD for those who started benzodiazepines <1 year before diagnosis was 2.20 (1.91-2.53), and fell to the null for those who started between 2 and <3 years before [aOR 0.99 (0.84-1.17)]. The aOR (95% CI) of developing VaD for those who started benzodiazepines <1 year before diagnosis was 3.30 (2.78-3.92), and fell close to the null for those who started between 3 and <4 years before [aOR 1.16 (0.96-1.40)]. After accounting for benzodiazepine use initiated during this prodromal phase, long-term use of benzodiazepines was not associated with an increased risk of developing AD [aOR 0.69 (0.57-0.85)] or VaD [aOR 1.11 (0.85-1.45)].

CONCLUSION:

After taking a prodromal phase into consideration, benzodiazepine use was not associated with an increased risk of developing AD or VaD.

End quote

https://www.karger.com/Article/FullText/454881

Quote

Background: Benzodiazepines are a widely used medication in developed countries, particularly among elderly patients. However, benzodiazepines are known to affect memory and cognition and might thus enhance the risk of dementia. The objective of this review is to synthesize evidence from observational studies that evaluated the association between benzodiazepines use and dementia risk. Summary: We performed a systematic review and meta-analysis of controlled observational studies to evaluate the risk of benzodiazepines use on dementia outcome. All control observational studies that compared dementia outcome in patients with benzodiazepine use with a control group were included. We calculated pooled ORs using a random-effects model. Ten studies (of 3,696 studies identified) were included in the systematic review, of which 8 studies were included in random-effects meta-analysis and sensitivity analyses. Odds of dementia were 78% higher in those who used benzodiazepines compared with those who did not use benzodiazepines (OR 1.78; 95% CI 1.33-2.38). In subgroup analysis, the higher association was still found in the studies from Asia (OR 2.40; 95% CI 1.66-3.47) whereas a moderate association was observed in the studies from North America and Europe (OR 1.49; 95% CI 1.34-1.65 and OR 1.43; 95% CI 1.16-1.75). Also, diabetics, hypertension, cardiac disease, and statin drugs were associated with increased risk of dementia but negative association was observed in the case of body mass index. There was significant statistical and clinical heterogeneity among studies for the main analysis and most of the sensitivity analyses. There was significant statistical and clinical heterogeneity among the studies for the main analysis and most of the sensitivity analyses. Key Messages: Our results suggest that benzodiazepine use is significantly associated with dementia risk. However, observational studies cannot clarify whether the observed epidemiologic association is a causal effect or the result of some unmeasured confounding variable. Therefore, more research is needed.

End quote

12. Benzodiazaphines and stroke

An anecdotal reference, but these people already had Alzheimer’s. Interesting…

http://www.psychiatryadvisor.com/alzheimers-disease-and-dementia/increased-stroke-risk-in-patients-with-alzheimers-taking-benzodiazepines/article/637123/

Quote

Benzodiazepine use is associated with a 20% increased risk for stroke among older adults with Alzheimer's disease (AD), according to a new study published in International Clinical Psychopharmacology.

A group of Finnish researchers, headed by Heidi Tiapale from the Kuopio Research Centre of Geriatric Care at the University of Eastern Finland, investigated the risk for any stroke and for ischemic and hemorrhagic stroke associated with incident benzodiazepine (BZD) and related drug (BZDR) use among 45 050 community-dwelling individuals with newly diagnosed AD (mean age, 80 years). Participants were identified from the Medication Use and Alzheimer's Disease (MEDALZ) cohort, consisting of 70,718 Finnish individuals who received a clinically verified AD diagnosis between 2005 and 2011. To be considered "incident" use, a 12-month washout period was required in subjects who had previously used benzodiazepines.

End quote

A fellow BB sent me these very interesting links.  This reinforces what I've found.  Pathological dementias are very complex in their etiology, and linking benzodiazaphines to them is very difficult.  The clinical link is not there in my research above.

More on Alzheimer's

Rust and iron

http://www.abc.net.au/news/2017-07-25/rust-deposits-in-the-brain-linked-to-alzheimers-disease/8742498

Iron

http://www.sbs.com.au/news/article/2017/07/25/high-iron-levels-brain-linked-alzheimers-risk

Wow, dm, that was quick work!  Bravo!

I've extracted the main points that spoke to me and, based upon the bunch of studies I've read in the past, it looks like we've come to the same conclusions.

One of the main pitfalls of poorly designed studies, is to attribute something that is characteristic to a disorder or disease, as something that is causal to the disorder or disease.   Some of the material below might fall into that bucket, but the information is provided because it might provide insight to someone who is more well versed in dementia, Alzheimer’s, etc.  I’m far from being an expert in this area, but I’ve learned several new things during the process of writing this post.  I hope it’s informative to all.

The biggest challenge involved in trying to determine benzodiazaphines’ involvement in the pathology of a specific disease like Alzheimer’s, or even more challenging an umbrella disorder like dementia, is direct  cause and effect, because these disorders are so complex, and their development and etiology is still not fully understood.  Linking benzodiazaphine use to something like interdose withdrawal is much more straightforward (but still challenging) , because the cause of interdose withdrawal is in large part, due to the benzodiazaphine itself.  It would not be there without the benzodiazaphine.  One can’t say the same for Alzheimer’s and dementia.  These occur in patients who have used benzodiazaphines, and in those who have not.  Furthermore, as we will see,  these confounding factors make determination of a specific and single causative agent much more difficult.  For example, a large group of seniors are on many medications that can compromise acetylcholine homeostasis, and much to my surprise they are on a lot of  psychotropics…...  Anticholinerginics and blood pressure medications have been correlated, along with benzodiazaphines, with medication induced dementia (reference below, but I was not able to get free access to the full study).  I’m no expert in this area, but I assume that medication induced dementia, pathologically is quite different from Alzheimer and classical dementia pathology, but this is just my opinion.

 

To make things even more complicated, as alluded to above, there are many different types of dementia, as will be seen in the Wikipedia link below.  The etiology of these various dementias differ. Benzodiazaphines might induce a very specific “dementia” in terms of pathology, perhaps due to compromised ACh and GABAa receptor physiology, and/or dysregulated Glutamate systems.

Dementia is such a complex condition, it would not surprise me that the link would be difficult to uncover,  I think there are are far too many confounding issues with the meta-data studies to derive any useful data from them.

:thumbsup:

Really great job, dm! 

What I do think would be slightly more interesting would be meta-data studies utilizing patient population aged 20 to, say, 45 years.  Although even then, as you say, the confounding factors might still be too numerous.

I did also want to highlight these personal opinions/conclusions of yours so as to allay the fears of other members.  We have enough on our plates already dealing with our day to day symptoms, it's a pity to get caught up in this news media sensationalism.

dm, your brain must be working great to be able to understand and post all that scientific info.

No kidding, Becks! 

The formatting was lost from the original word document, but I have bolded out the main sections. There are many more references in addition to those presented in the paper, but time and space are limited.

Just another suggestion, if I may, dm.  I'm sure your posts are going waayyy over most of our heads but, not only that, these super long, highly scientific posts are extremely hard to scan ... even for the "skimmers" like me.  And that's a shame considering all the hard work you're doing.  How about also uploading the Word documents to Dropbox as well and sharing the link.  I imagine it'll be much easier to peruse with all the formatting in place.  And another thought moving forward, perhaps you can put the quotes in italics or even a different color.  I know when I'm skimming, I like to read your comments mainly and then decide whether I'm interested enough to read the actual scientific quotes or click on the study.  As it stands now, it's very, very difficult to even find your comments.

dm, your brain must be working great to be able to understand and post all that scientific info.

 

No kidding, Becks! 

 

 

The formatting was lost from the original word document, but I have bolded out the main sections. There are many more references in addition to those presented in the paper, but time and space are limited.

 

Just another suggestion, if I may, dm.  I'm sure your posts are going waayyy over most of our heads but, not only that, these super long, highly scientific posts are extremely hard to scan ... even for the "skimmers" like me.  And that's a shame considering all the hard work you're doing.  How about also uploading the Word documents to Dropbox as well and sharing the link.  I imagine it'll be much easier to peruse with all the formatting in place.  And another thought moving forward, perhaps you can put the quotes in italics or even a different color.  I know when I'm skimming, I like to read your comments mainly and then decide whether I'm interested enough to read the actual scientific quotes or click on the study.  As it stands now, it's very, very difficult to even find your comments.

 

Hi abcd

Im seeing what I can do

dm, your brain must be working great to be able to understand and post all that scientific info.

 

No kidding, Becks! 

 

 

The formatting was lost from the original word document, but I have bolded out the main sections. There are many more references in addition to those presented in the paper, but time and space are limited.

 

Just another suggestion, if I may, dm.  I'm sure your posts are going waayyy over most of our heads but, not only that, these super long, highly scientific posts are extremely hard to scan ... even for the "skimmers" like me.  And that's a shame considering all the hard work you're doing.  How about also uploading the Word documents to Dropbox as well and sharing the link.  I imagine it'll be much easier to peruse with all the formatting in place.  And another thought moving forward, perhaps you can put the quotes in italics or even a different color.  I know when I'm skimming, I like to read your comments mainly and then decide whether I'm interested enough to read the actual scientific quotes or click on the study.  As it stands now, it's very, very difficult to even find your comments.

 

 

 

 

Hi abcd

 

Im seeing what I can do

Hi all,

Here is a link to Dropbox.  I hope this nicely formatted version is more user friendly.  It's a PDF, so you will have to download it if you want to hyperlink directly from the doc in web based Dropbox.

If you have the Dropbox app, the links will work directly from Dropbox app....

My comments are in bold.

Just to reiterate, I think there is a lot of hope for drug induced dementia.

One last thing, formthose of you that want a trip into the very strange, like a twilight zone, read sections 9 and especially 10.  Very odd findings in that clinical study in section 10....

https://www.dropbox.com/s/*****?dl=0

Edit: Personal info was removed upon request

My, I believe that is the longest OP I ever saw. Must have taken a lot of work. Oscar would be proud of you.

. Writing is very cathartic

I hope the PDF is more legible.

A functional approach to Alzheimer's

It might be a little overly optimistic

https://chriskresser.com/new-hope-that-alzheimers-can-be-prevented-and-even-cured/

My, I believe that is the longest OP I ever saw. Must have taken a lot of work. Oscar would be proud of you.

. Writing is very cathartic

 

I hope the PDF is more legible.

:laugh: Nobody can call me a wall flower either.