| |
Alzheimers & Amyloid, Mild Cognitive Impairment in HIV
|
| |
| |
Download the PDF here
Download the PDF here
.......old annual neuropathology meetings, the neurodegenerative disease/Alzheimer's scientific sessions. there was a huge amount of heated (and intimidating) argument between scientists who believed amyloid was a critical initiator for Alzheimer's Disease (AD), and scientists who believed that neuron pathologies (that we now understand are phospho-tau related) were the critical first indications of AD. That was 50 years ago. 50 years later the arguments continue, and in 2012 the leaders in the AD field went so far as to create a pathogenesis model that featured initial amyloid; it provided a conceptual basis for a large number of failed anti-amyloid trials.
the idea that amyloid is the cause of neuropathology, as opposed to a reaction to some other brain pathologic process, has never rested well with many, regardless of whether we are considering PLWH or those without. Scientists have known for decades that neuronal pathology precedes amyloid deposition in general population based neuropathology brain studies. With amyloid PET scanning, it has become evident that people can walk around with amyloid in their brain and be cognitively normal. The smalltalk last October, which described far more phospho-tau pathologies than amyloid pathologies in brains from our HIV donors, which was also the case for our HIV negative donors, is consistent with the idea that amyloid is coming later in the course of cognitive disease, not earlier; the PET scan studies tell us that it might also be occurring for reasons that don't immediately upset cognition. However, while there are many reasons to support the idea that amyloid is not the primary cause of cognitive disease, it is important to state that whether it is primary or a secondary reaction, amyloid in one's brain is not a good thing; if amyloid is being deposited, it can serve to enhance a deleterious process if one is going on.
And now, the question of Obj-SCD specifically for PLWH: First, the comment that the editorial makes is a very important one: the patient group in this report was a highly-educated, largely white population with minimal confounding conditions that might cause Obj-SCD. As the editorial states, it is unclear how generalizable this finding will be to other populations. We are seeing an incredible number of cognitive confounds in the HIV populations we are studying, which run the gamut from metabolic disorders (hypertension, hyperlipidemia, diabetes), to substance use issues, head traumas, and hepatitis co-infections. Any one of these can be a cause of cognitive impairment, and it would not progress in a manner similar to a neurodegenerative disease (that is, it would be unlikely to follow this Obj-SCD pattern). In fact, studies being published (the CHARTER longitudinal cognitive study comes to mind), as well as my observation of our cohorts here in NYC, confirm that while mild cognitive impairments are very common in PLWH, for the vast majority, they do not progress as rapidly as might be typical for AD or other age-related neurodegenerative diseases, or for that matter, like the Obj-SCD described in this article.
So, in one sense, yes, for PLWH, the issue is mild cognitive impairment, not amyloid. However, we know that this impairment is typically long-standing, and to date has not led to large numbers of pre-mature Alzheimer's (that is, disease onset in the 50's or early 60s). The important question that remains to be answered: will the mild cognitive impairments seen in PLWH result in a greater number of people eventually developing Alzheimer's as they age into their 70s and 80s? We don't know yet, because there are not large enough longitudinal studies available to look at people in this age range. The mean age of the longitudinal brain bank cohort in NYC for over 20 years is now 61; far too young to answer the question. If keeps working for another decade, we might have an answer for you!
New research is questioning the predominant hypothesis that a buildup of beta-amyloid causes Alzheimer's disease.......we expect that Obj-SCD, at best, would be associated with future MTL degeneration, but not increasing amyloid pathology......But what are Obj-SCD? In their paper, the investigators define them as "difficulties or inefficiencies on some sensitive cognitive tasks even though the overall neuropsychological profile is in the normal range......"This work [...] suggests that cognitive changes may be occurring before significant levels of amyloid have accumulated. It seems like we may need to focus on treatment targets of pathologies other than amyloid, such as tau, that are more highly associated with the thinking and memory difficulties that impact people's lives.""
Prior work has also demonstrated that subtle impairments on sensitive neuropsychological measures can in fact precede or emerge in tandem with amyloid positivity in participants who later progress toMCI and AD.4,16,33 However, this is the first study, to our knowledge, to investigate the relationship between Obj-SCD, defined using sensitive neuropsychological measures, and the trajectory of amyloid PET changes. In addition to participants with Obj-SCD showing faster
rates of amyloid accumulation, our results also demonstrated that relative to the CN group, the Obj-SCD group had faster thinning of the entorhinal cortex and nearly 3 times the proportion who are later classified as MCI over 48 months, whereas the MCI group showed faster thinning of the entorhinal cortex and hippocampal atrophy over 48 months.
--------------------------------------------
What causes Alzheimer's? Not toxic amyloid, new study suggests (Its NT NEW)
Many researchers have argued that the accumulation of toxic beta-amyloid in the brain causes Alzheimer's. However, a new study offers some evidence contradicting this sequence.
https://www.medicalnewstoday.com/articles/327412.php#1
New research is questioning the predominant hypothesis that a buildup of beta-amyloid causes Alzheimer's disease.
Alzheimer's disease affects over 5.5 million people in the United States and millions more around the globe.
Yet, researchers are still at a loss as to why this condition — which is characterized by memory impairment and many other cognitive problems — occurs in the first place. And until they fully understand the cause, investigators will remain unable to devise a cure.
So far, the prevailing hypothesis among experts has been that the excessive accumulation of a potentially toxic protein — beta-amyloid — in the brain causes Alzheimer's.
Researchers have argued that beta-amyloid plaques disrupt the communication between brain cells, potentially leading to cognitive function problems.
Now, a new study from the University of California San Diego School of Medicine and the Veterans Affairs San Diego Healthcare System suggests that while the buildup of beta-amyloid has associations with Alzheimer's, it may not actually cause the condition.
In a study paper that appears in the journal Neurology, the researchers explain what led them to reach this conclusion.
"The scientific community has long thought that amyloid drives the neurodegeneration and cognitive impairment associated with Alzheimer's disease," says senior author Prof. Mark Bondi.
He notes that "[t]hese findings, in addition to other work in our lab, suggest that this is likely not the case for everyone and that sensitive neuropsychological measurement strategies capture subtle cognitive changes much earlier in the disease process than previously thought possible."
What comes first?
In their study, the researchers worked with a total of 747 participants with different levels of cognitive health. All of the study participants agreed to undergo neuropsychological assessments, as well as PET and MRI brain scans
Of the participants, 305 were cognitively healthy, 289 had mild cognitive impairment, and 153 displayed markers of what the investigators call "objectively-defined subtle cognitive difficulties (Obj-SCD)."
Experts define mild cognitive impairment as a state of cognitive impairment that is more severe than what one would normally experience with age, but not yet severe enough for a dementia diagnosis.
However, mild cognitive impairment does develop into dementia in a significant number of people.
But what are Obj-SCD? In their paper, the investigators define them as "difficulties or inefficiencies on some sensitive cognitive tasks even though the overall neuropsychological profile is in the normal range."
That is, they are a measurement of experienced, subtle cognitive functioning problems that occur in the absence of any visible signs of brain or psychological issues. To find out whether someone is experiencing Obj-SCD, researchers assess, among other factors, how efficiently that person can learn and retain new information.
Previous research has suggested that individuals with Obj-SCD are at a higher risk of mild cognitive impairment and forms of dementia.
In the current study, Prof. Bondi and the team found that beta-amyloid built up at a faster rate in the participants with Obj-SCD compared with those who were deemed cognitively healthy. Moreover, brain scans of people with Obj-SCD showed that these individuals experienced a thinning of brain matter in a region called the entorhinal cortex.
Past research has shown that the entorhinal cortex decreases in volume in people with Alzheimer's disease. This is significant because this brain region plays a role in memory and spatial orientation.
The researchers also found that while people with mild cognitive impairment had higher quantities of beta-amyloid in their brains at the beginning of the study, this protein did not seem to build up any faster in these participants than it did in cognitively healthy individuals.
But why do the current findings potentially contradict a decades-old hypothesis about the development of Alzheimer's? Prof. Bondi explains:
"This work [...] suggests that cognitive changes may be occurring before significant levels of amyloid have accumulated. It seems like we may need to focus on treatment targets of pathologies other than amyloid, such as tau, that are more highly associated with the thinking and memory difficulties that impact people's lives."
"While the emergence of biomarkers of Alzheimer's disease has revolutionized research and our understanding of how the disease progresses, many of these biomarkers continue to be highly expensive, inaccessible for clinical use, or not available to those with certain medical conditions," adds first author Kelsey Thomas, Ph.D.
The new study's findings could help change that by refocusing the research approach on more subtle markers of Alzheimer's, such as those assessing for Obj-SCD.
"A method of identifying individuals at risk for progression to [Alzheimer's disease] using neuropsychological measures has the potential to improve early detection in those who may otherwise not be eligible for more expensive or invasive screening," says Thomas.
-----------------------------
December 30, 2019
Editorial
Do subtle cognitive deficits precede amyloid accumulation?
Cart before the horse
Beth E. Snitz, Adam M. Brickman
December 30, 2019
Over the last decade, a hypothesized model of dynamic sequential biomarker changes dominated the Alzheimer disease (AD) research field. The model, informed by the amyloid hypothesis,1 proposed a prototypical cascade, lasting up to decades, in which brain β-amyloid initiates acceleration of tau pathology, which in turn drives neurodegeneration and associated cognitive symptoms. In this issue of Neurology®, Thomas et al.2 tested the specific hypothesis that if amyloid deposition occurs long before downstream detectable effects on cognition, the presence of cognitive deficits should not precede accumulating rates of amyloid deposition. They found, however, that they do: in a large cohort of older adults without dementia, a subgroup with objectively defined subtle cognitive difficulties identified on neuropsychological testing at baseline showed increasing brain amyloid deposition on PET imaging over 4 years, despite having baseline amyloid levels that were similar to those characterized as cognitively normal. This subgroup also showed faster entorhinal cortical thinning compared to those without subtle cognitive difficulties. By comparison, participants with frank, though mild, cognitive impairment did not show faster amyloid accumulation relative to cognitively normal individuals but did have faster entorhinal cortical thinning and hippocampal atrophy over 4 years, consistent with Braak-staged spreading of tau neuropathology.3
------------------------------------
December 30, 2019
Objective subtle cognitive difficulties predict future amyloid accumulation and neurodegeneration
Kelsey R. Thomas, Katherine J. Bangen, Alexandra J. Weigand, Emily C. Edmonds, Christina G. Wong, Shanna Cooper, Lisa Delano-Wood, Mark W. Bondi, for the Alzheimer's Disease Neuroimaging Initiative
December 30, 2019
we aimed to determine whether Obj-SCD appears after amyloidosis and neurodegeneration or, instead, predicts future amyloid accumulation and medial temporallobe (MTL) neurodegeneration. If, according to the NIAAA criteria1 and amyloid cascade model,2,17 amyloid does invariably accumulate (stage 1) prior to neurodegeneration (stage 2) and detectable cognitive changes (stage 3), we expect that Obj-SCD, at best, would be associated with future MTL degeneration, but not increasing amyloid pathology.
|
|
| |
| |
|
|
|
