Best Post of September 2018: A Case of Posterior Cortical Atrophy

The next in our "Best of the Month" series is from September 7, 2018:

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterised by progressive decline in visuospatial, visuoperceptual, literacy, and praxic skills. The progressive neurodegeneration affecting parietal, occipital, and occipitotemporal cortices that underlies PCA is attributable to Alzheimer's disease in most patients. However, alternative underlying causes, including dementia with Lewy bodies, corticobasal degeneration, and prion disease, have also been identified, and not all patients with PCA have atrophy on clinical imaging. (Crutch, S. J., Lehmann, M., Schott, J. M., Rabinovici, G. D., Rossor, M. N., & Fox, N. C. (2012). Posterior cortical atrophy. Lancet Neurology, 11(2), 170-178)

This is a case of a 60-year-old female with PCA:

Although there is diffuse neocortical atrophy, note the prominent occipital lobe atrophy

Tau stain of temporal lobe section highlights Alzheimer pathology

Pallor of the substantia nigra was noted, and Lewy bodies noted microscopically (see inset)

Alpha-synuclein staining showed neocortical Lewy bodies (here in the frontal lobe)

The final diagnosis was Alzheimer disease and Diffuse Neocortical Lewy Body Disease in the setting of Posterior Cortical Atrophy.

TBI Linked to Increased Dementia Risk Over Several Years

The following is adapted from a recent post on practiceupdate.com:

Traumatic brain injury (TBI) is associated with persistently increased risk of dementia, according to a study published online Jan. 30 in PLOS Medicine.

Anna Nordström, M.D., Ph.D., and Peter Nordström, M.D., Ph.D., both from Umeå University in Sweden, tracked dementia and TBI diagnoses among all 3,329,360 individuals in Sweden

The correlation was strongest in the first year after TBI (odds ratio, 3.52) and persisted at >30 years (odds ratio, 1.25). A weaker association with dementia was seen for single mild TBI versus more severe TBI or multiple TBIs (odds ratios, 1.63 versus 2.06 and 2.81, respectively). Among sibling pairs with discordant TBI status, TBI correlated with increased risk of dementia diagnosis (odds ratio, 1.89).

"The risk of dementia diagnosis decreased over time after TBI, but it was still evident >30 years after the trauma," the authors write.

Amyloid-beta and neurofilament in 3D

Three-dimensional immunohistological visualization of Aβ (green) and neurofilament (red) in a 500-micron thick block of human post-mortem Alzheimer disease tissue.
 
From:Kunie A, et al. Inside Alzheimer brain with CLARITY: senile plaques, neurofibrillary tangles and axons in 3D. Acta Neuropathologica. September 2014, Volume 128, Issue 3, pp 457-459.

Thanks to Dr. Mark Cohen of Case Western for sending me the link.

New study suggests "glymphatic system" flushes brain of toxins during sleep

Douglas Shevlin, MD

A new study published in the journal Science on Thursday and reported in the Washington Post suggests that a so-called "glymphatic system" seems capable of flushing toxins (including perhaps beta-amyloid) from brain -- particularly during sleep.“Sleep puts the brain in another state where we clean out all the byproducts of activity during the daytime,” said study author and University of Rochester neurosurgeon Maiken Nedergaard. (Thanks to avid NP Blog reader and friend, Dr. Doug Shevlin, for alerting me to this significant new finding.)

The biggest Alzheimer Disease discovery in 2012

Kári Stefánsson

Perhaps the biggest discovery in the Alzheimer research world last year was the identification of a mutation in APP that significantly decreases its cleavage by β-secretase, leading to 40% less production of amyloidogenic peptides in vitro. The researchers found the mutation (A673T) in the APP gene protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease.

Future drugs that can recreate this Aβ-reducing effect “should perhaps be given not only to people at risk of Alzheimer’s but to all elderly people,” says Kári Stefánsson, senior investigator of the study, which came out of Iceland and appears online in Nature.

Landreth scores a hit against Alzheimer's with bexarotene

Tomorrow’s edition of the journal Science will report on how Professor Gary Landreth, about whom I recently posted, and his team discovered that the cancer drug bexarotene can quickly reverse Alzheimer’s symptoms in animal models. Within 72 hours of administration, the medication  halved the number of plaque deposits closely associated with this degenerative brain disease.  Additionally, the signs of cognitive and memory deficits disappeared within that same brief time period.

For more details, watch this two-minute video from Case Western: http://www.youtube.com/user/case#p/a/u/0/HdYdYeNAYpU.

Time to revise your Alzheimer brain autopsy template

Time to put the NIA-Reagan criteria for the neuropathologic diagnosis of Alzheimer's behind you and revise your autopsy reports to reflect the consortium report by the National Institute on Aging and Alzheimer's Association (the NIA-AA criteria). Neuropathologist Tom Montine, MD, PhD headed up the effort to revise the 1997 criteria. According to Medscape News, Montine said there were three main points to be made regarding the new criteria:

Dr. Thomas Montine

'"The first is that it's no longer necessary that someone carry a clinical diagnosis of dementia in order to make a pathological diagnosis of [AD]. We have separated those 2 entities because we now understand that there is a preclinical stage of the disease. That's the major philosophical point... The second point is more on the technical side," he said. The guidelines recommend the "ABC" staging protocol for the neuropathologic changes of AD, based on 3 morphologic characteristics of the disease: A is for amyloid, B is for Braak neurofibrillary tangle staging protocol, and C is for the Consortium to Establish a Registry for AD neuritic plaque scoring system. For all cases, regardless of clinical history, the guidelines state that reporting should follow the format of these examples: 'Alzheimer Disease Neuropathologic Changes: A1, B0, C0' or 'Alzheimer Disease Neuropathologic Changes: A3, B3, C3.' The ABC score is then transformed into 1 of 4 levels of AD neuropathologic change: not, low, intermediate, or high." The third point deals with comorbidity. Although AD is the most common cause of dementia and can exist in a "pure" form, it commonly coexists with pathologic changes of other diseases that can also contribute to cognitive impairment, the document notes. The most common comorbidities are Lewy body disease, vascular brain injury, and hippocampal sclerosis, as well as other neuropathologic changes such as argyrophilic grain disease and TDP-43 inclusions. The new recommendations more explicitly define the manner in which these comorbidities are to be evaluated.

Here's the reference you can put at the end of your new reports:
Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging - Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. Volume 8: Issue 1. Pages 1-13, January 2012.

Case Western's Gary Landreth explores bexarotene as a pontential Alzheimer therapeutic

Gary Landreth, PhD

Dr. Mark Cohen tells me that a guy worth watching on the Alzheimer research front it Dr. Gary Landreth from Case Western Reserve University. And, as anyone who reads this blog regularly knows, when Mark Cohen talks, I listen. According to the Alzheimer Research Forum (from which I am blatantly plagarizing in the remainder of this post),  Landreth works on ApoE-directed therapeutics. As one of the genes involved in cholesterol homeostasis, ApoE is regulated transcriptionally by receptors which form heterodimers with the retinoid X receptor (RXR). Working with APP transgenic mice, Landreth found that an RXR agonist, bexarotene, induces brain ApoE quickly and robustly. This induction precedes a rapid decline in brain amyloid, an increase in plaque-clearing microglia, and improvements in cognitive performance. Landreth noted that bexarotene is an FDA-approved chemotherapeutic that readily crosses the blood-brain barrier and has minimal side effects, most of which are associated with its action on lipid homeostasis. Hence, this drug minimally represents a test of the role of Aβ in AD and, maximally, may represent an AD therapeutic. These finding raise the question of the utility of the drug in ApoE4-positive individuals. You go, Gary!

Best Post of July 2011: Formal Guidelines for Alzheimer's Genetic Testing Issued

The next in our "Best of the Month" series is from July 19, 2011:

Dr. Edward B. Lee

In recent posts, I discussed the availability of direct-to-consumer ApoE testing and the fact that I myself submitted buccal cells to 23andMe.com to discover my own ApoE status. The illustrious Eddie Lee, MD, PhD just emailed me news that the American College of Medical Genetics and the National Society of Genetic Counselors have recently issued formal guidelines regarding ApoE testing in patients. Reported and discussed on the Alzheimer Research Forum, the guidelines, published in the June issue of Genetics in Medicine, identify which individuals may benefit from genetic testing.

Attractive Neuropathology Postdoc Position in Neurodegenerative Disease Now Available at UCSF

Lea T. Grinberg, MD, PhD.

I recently received an email from Lea T. Grinberg, MD, PhD, a neuropathologist originally from Sao Paulo, Brazil now working at UCSF. She is recruiting a postdoc to work with her. Dr. Grinberg specializes in aging and neurodegenerative diseases and was recently awarded an R01 grant to study early stages of AD and FTLD-TDP in postmortem human tissue. She has access to a large brain bank associated with the Brazilian Aging Brain Study Group as well as the UCSF Memory and Aging Center brain bank. The postdoc will learn state-of-the-art methods for studying human post mortem brains, such as stereology, immunohistochemistry and fluorescence, computer assisted 3D reconstruction, and whole brain processing. She writes of the UCSF Memory and Aging Center: "We are a team of 150 individuals and the division promotes weekly grand rounds, journal clubs, lab meetings and regular CPC sessions. I believe it is an excellent opportunity for a young neuropathologist aiming to have a career in neurodegenerative disease."

I would say so! Here's the official job listing:

Post Doctoral Position in Neurodegenerative Diseases

NIH-supported post-doctoral position is immediately available for a qualified and highly motivated researcher to study early stages of neurodegenerative disease in human postmortem tissue

The fellow will pursue a series of related experiments regarding brain areas involved in very early clinical stages of Alzheimer’s disease and frontotemporal dementia. The successful candidate will have access to very difficult to get tissue belonging to cognitively normal elderly who already showed neurodegenerative changes in the brain. In addition, the fellow will be trained in state-of-the-art neuropathological/neuroanatomical processing and sophisticated graphic and reconstruction software. The fellow will have the opportunity of further participate in ongoing experimental studies.

Preferred Qualifications
Strong interest in neurodegenerative disease

Training in quantitative neuropathology or neuropathology is a plus.

This project is part of a close collaboration with other groups; therefore, candidates must have the ability to work in an international team, show organizational skills, and be driven by an interest in a multidisciplinary research setting

Applicants should possess a recent (within last three years) MD or PhD degree in the neuropathology/neuroanatomy/ neurosiciences with strong experience in stereology.

Applicants should send a CV and 3 letters of recommendation to Dr. Grinberg lea.grinberg@ucsf.edu

Formal Guidelines for Alzheimer's Genetic Testing Issued

Dr. Edward B. Lee

In recent posts, I discussed the availability of direct-to-consumer ApoE testing and the fact that I myself submitted buccal cells to 23andMe.com to discover my own ApoE status. The illustrious Eddie Lee, MD, PhD just emailed me news that the American College of Medical Genetics and the National Society of Genetic Counselors have recently issued formal guidelines regarding ApoE testing in patients. Reported and discussed on the Alzheimer Research Forum, the guidelines, published in the June issue of Genetics in Medicine, identify which individuals may benefit from genetic testing.

I have discovered my ApoE status

I just got my ApoE results back from 23andMe.com.  When I ordered the test, the first question I posed to readers was whether it was wise to even find out whether or not I have the epsilon 4 allele. One commentator, "Agent 86", quoted the ancient Greek philosopher Epictetus for guidance on this issue. In 135 AD, Epictetus argued that one should emotionally separate oneself from those things which are not one's own -- i.e., those things over which one has no control. Therefore, had he known what a gene was at the time, Epictetus would have counted one's genome as among those things that is not one's own. As such, knowing his ApoE status would have been of no consequence either way to Epictetus. I do find it rather easy to take this Epictetusian attitude toward my ApoE status. But because I find it exceedingly difficult to adopt this attitude of separateness toward many other things in my life over which I have no control, I can certainly understand how others could feel emotionally affected by knowledge of their own ApoE status.

I then had a second question: Should I make my ApoE results public? I was surprised by the number of people who recommended against doing so. The main objection seemed to be the potential that an insurance company might refuse to cover me if it were known that I was at increased risk for the development of Alzheimer's disease. I agree with one commentator who stated that this is a "worst-case scenario" and continually worrying about worst-case scenarios is not a wise way to live one's life.  I might also add that it might be in an insurance company's best interest for me to get Alzheimer's disease at a relatively earlier age (in my 60's rather than in my 80's) as  I would likely die at a younger age and thereby cost the company less money over the long run. That being said, in deference to all those who weighed in on this matter, I have elected not to publicly share my ApoE status. I appreciate all those who engaged in this discussion; and I suspect that this kind of discussion will be ongoing in many circles in the decades to come as personalized medicine, based on genomic profiling, emerges in the new age of theragnostics.

What's wrong with finding out and releasing my ApoE status?

In a recent blog post, I stated that I intended to publish my ApoE status on the blog when I get the results back from 23andMe.com. I was surprised to find that some people objected to this. One associate said that by publishing information about my genetic status, I would be "normalizing" the dissemination of information that should be confidential. That sets a bad precedent for the use of personal genomic data. Another individual emailed me the following suggestion: "Instead of posting your results, maybe you would consider instead the value of not doing so at the request of an 'anonymous' reader and keeping the information private in order to stimulate debate about finding out about a disease process for which there is no cure." Finally, "jd" commented in the original post about the wisdom of getting the test done at all: "Why would you do that? If you come back 4/4 or 3/4, that'll be hanging over you the rest of your life. If there were a cure for Alzheimer's, that'd be different."

And so, I pose this question to readers: Is there not intrinsic value in knowledge about one's genome, regardless of whether or not a related disease predisposition can be treated? Also, if I am willing to release my personal genetic information to the public, what harm am I causing myself or anyone else? At this point, I intend to find out my ApoE status when the information is made available to me, and I intend to discuss the results on this blog when I get them. But, if anyone can make a convincing argument otherwise,  I am willing to be convinced. I await comment.

Population prevalence of the ApoE4 gene

Regarding the Alzheimer genotype, I just did a little research regarding the prevalence of the ApoE epsilon 4 allele (the allele that predisposes to Alzheimer disease). Depending on the study you read, about 20% of the population has at least one epsilon 4 allele, while about 2% have two epsilon 4 alleles. As you'd expect, having two is worse than having one in terms of Alzheimer risk. I should add that the epsilon 4 allele also predisposes to a worse outcome in recovery from traumatic brain injury and is also over-represented among those football players who suffer from Chronic Traumatic Encephalopathy.

 

It's important to note that this data applies only to those of European ancestry. The rates of other ethnic groups are different. I saw one study showing, for example, that the rate of epsilon 4 prevalence is much, much higher among Australian aboriginal populations.   I recently sent in a saliva specimen to 23andMe.com to have their CLIA-approved lab run a genetic profile on me, which will include a report on my ApoE status. The service has dramatically decreased in price in recent years, so I finally broke down made the purchase. I'll report those results when I get them next month.

Neuropathologist bikes 140 miles to emphasize need for Alzheimer research funding

Chris Zarow, PhD (pictured in center), a neuropathology researcher at the University of Southern California, recently completed a 140-mile bike ride which was part of a cross-country ride where participants collected signatures to urge Congress to authorize more funding for Alzheimer research."Let's put ourselves out of a job, so to speak," Zarow said. Read more here.

Alzheimer patients to get nerve growth factor directly injected into brain

The Alzheimer’s Disease Cooperative Study, a 19 year project funded by the NIA, has embarked on a clinical trial that delivers Nerve Growth Factor (NGF) directly into the brain as a possible treatment for Alzheimer’s.

 

A Phase II clinical study of Ceregene's CERE-110, a gene therapy product designed to deliver nerve growth factor (NGF) to the brain for the treatment of Alzheimer's disease (AD) is currently in progress.

This Phase II study is a randomized, double blind, placebo-controlled trial and employs gene therapy to deliver nerve growth factor (NGF) directly into the brain. The rationale behind this study is that NGF is known to promote survival of cholinergic neurons, that degenerate in AD, and therefore may provide sustained functioning of these neurons. Direct delivery of CERE-110 into the brain aims to selectively target the Nucleus Basalis of Meynert (NBM), where cholinergic neuronal degeneration occurs in AD.

A Phase I study at Rush University and the University of California San Diego indicated that a single administration of the therapy was generally safe and well tolerated. The Phase I participants underwent cognitive testing, measures of activities of daily living, MRI scans and PET (positron emission tomography) scans. Increases in brain metabolism were observed in several cortical regions of the brain at six months and 12 months in some of the subjects, as compared to other severity-matched individuals with AD, suggesting a potential reversal of patterns typically observed in AD.

This Phase II study will examine the safety and effectiveness of NGF on Alzheimer's disease in 50 patients at 11 research sites throughout the United States. All eligible participants will be randomized equally to one of two treatment groups: half of the subjects will initially receive placebo surgery, but no administration of gene therapy. In the other half, CERE-110 will be injected into the NBM of the brain. At the completion of the trial, subjects in the placebo arm will be given the opportunity to switch to the active treatment protocol if the efficacy and safety data are supportive.

For more information go to: http://www.adcs.org/Studies/NGF.aspx  or  http://www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=308

Best Post of November '09" Finally, a simple cartoon depicting the anatomic location of the transentorhinal cortex

The next in our series of "Best Posts of the Month" is from November 17, 2009:

In our teaching and in our autopsy reports, we neuropathologists often make reference to the transentorhinal cortex as it is -- in the Braak and Braak staging system -- the region where the earliest Alzheimer pathology appears. I have found it difficult to find a clear illustration of the anatomic location of the transentorhinal cortex in texts or on the internet. However, I came across a nice cartoon of the divisions of the parahippocampal gyrus, including the transentorhinal cortex, in an online presentation by Prof. Jillian Kril of the Pathology Department at the University of Sydney, NSW. Prof. Kril kindly emailed me a copy of the illustration, which is depicted above with the addition of a label for the presubiculum.  Feel free to use this cartoon for teaching purposes with the following credit: Adapted from Harding AJ, Halliday GM, Kril JJ. Variation in hippocampal neuron number with age and brain volume. Cerebral Cortex (December, 1998) 8:710-718.

An unusual case of CADASIL? Or something else?

I recently did a brain autopsy on a 70-year-old woman who died from an intraparenchymal brain hemorrhage after a seven-year history of progressive dementia. The gross photograph (provided by Chad Jeffers, Memorial Medical Center, Springfield, IL)  follows:

I know what you're thinking: an amyloid angiopathic bleed, or perhaps a hypertensive bleed, in a patient with Alzheimer disease. That's what I was thinking until I saw in the chart that abnormal white matter changes on MRI prompted the neurologist to order Notch3 genetic testing on the patient, which surprisingly came back positive for a mutation. The patient therefore carried a clinical diagnosis of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), despite the fact that she had no clear family history indicative of this disease and despite the advanced age of symptom onset. At autopsy, there was no evidence of amyloid angiopathy on Congo red stain. She did appear to have the PAS-positive vessel wall deposits that would be consistent with a diagnosis of CADASIL (see photomicrographs below).  Plus, it is hard to refute a positive genetic test. The Notch3 test has excellent specificity, from what I hear. Although one does not typically think of intracranial hemorrhage in the context of CADASIL, a series out of Korea (Choi JC et al. Neurology 67(11), 12 December 2006, pp 2042-2044) found that 25% of their symptomatic patients with CADASIL had intracranial hemorrhage (ICH). If anyone has any other ideas about what might be the diagnosis in this case, I would love to hear from you.

Finally, a simple cartoon depicting the anatomic location of the transentorhinal cortex

In our teaching and in our autopsy reports, we neuropathologists often make reference to the transentorhinal cortex as it is -- in the Braak and Braak staging system -- the region where the earliest Alzheimer pathology appears. I have found it difficult to find a clear illustration of the anatomic location of the transentorhinal cortex in texts or on the internet. However, I came across a nice cartoon of the divisions of the parahippocampal gyrus, including the transentorhinal cortex, in an online presentation by Prof. Jillian Kril of the Pathology Department at the University of Sydney, NSW. Prof. Kril kindly emailed me a copy of the illustration, which is depicted above with the addition of a label for the presubiculum.  Feel free to use this cartoon for teaching purposes with the following credit: Adapted from Harding AJ, Halliday GM, Kril JJ. Variation in hippocampal neuron number with age and brain volume. Cerebral Cortex (December, 1998) 8:710-718.

High-Dose Bapineuzumab Puts Some Alzheimer Patients At Risk for Vasogenic Cerebral Edema

Dr. Stephen Salloway (pictured) reported at the recent American Academy of Neurology annual meeting on the much ballyhooed bapineuzumab study for Alzheimer patients. I take a particular interest in this topic: my own 89-year-old father was a subject in the study, but was removed from it due to the development of some kind of MRI changes. Salloway, Brown University neurologists and one of the study's lead investigators, reported that patients on the 2.0 mg/kg dose of bapineuzumab (the highest dose level in the study) had a significantly increased risk of developing vasogenic cerebral edema. Because it is a double-blinded study, I do not know what dose my dad was on (or if he was given a placebo). Bapineuzumab is an anti-beta-amyloid monoclonal antibody. It is thought that the antibody may have compromised cerebral blood vessel walls by attaching to mural amyloid, which tends to accumulate in Alzheimer patients. Investigators decided that "continued development of the highest dose was not advisable," said Carlos Paya, MD, PhD, president of the biotech firm Elan, which is working with Wyeth Pharmaceuticals to develop the antibody for clinical use. That being said, the antibody continues to show promise in slowing cognitive decline among patient who do not harbor a apolipoprotein E4 allele and will continue to accrue patients for the phase 3 study at lower doses.

Source: Neurology Today (May 21, 2009), page 4.