Category Archives: CBD

Abnormal Proteins and Genetics in Frontotemporal Dementia

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Yesterday’s New York Times had a good article on three proteins involved in frontotemporal dementia (FTD) and the research being done at at the University of California San Francisco (UCSF) on these proteins.  Genetics are also addressed in this article.

In FTD, 40% of cases involve tau (which is also part of PSP, CBD, and Alzheimer’s Disease), 50% of cases involve TDP-43, and 10% of cases involve FUS.  There is a genetic component to about half of all FTD cases.

Dr. Bruce Miller at UCSF’s Memory and Aging Clinic comments on how to find those with FTD who are early in the disease course:

“What is so fascinating about this is, what do you define as ‘affected’ in somebody who carries a gene that is going to cause a slow, subtle social decline? What are good markers for someone who is starting to get sick? Addictive behaviors ­ drugs, alcohol, gambling ­ bad decision-making, alienation of other people around them. These are things that we never realized could represent the first symptoms of a degenerative disease.”

Here’s a link to the full article:

www.nytimes.com/2012/05/06/health/tying-genes-and-proteins-to-dementia.html

May 5, 2012
The New York Times
Studies Tie Abnormal Protein Buildup to Dementia
By Denise Grady

A few excerpts are copied below.

Robin

 

Excerpts from

Studies Tie Abnormal Protein Buildup to Dementia
New York Times
By Denise Grady
May 5, 2012

Scientists think that abnormal protein deposits inside brain cells
cause frontotemporal degeneration. The proteins vary, but they do not
include amyloid, the substance found in Alzheimer’s patients.

In about 40 percent of patients, the deposits are an abnormal form of
a protein called tau, which normally gives structural support to brain
cells. (Tau is also one of the proteins found in Alzheimer’s
patients.)

Two other types of deposits are abnormal versions of proteins involved
in other cell functions. In about half of all patients with
frontotemporal dementia, the protein is one known as TDP-43, and in
about 10 percent it is a substance called FUS.

But why do these protein deposits form? Often, the underlying reason
is not known.

At least half of all cases are sporadic, in people with no family
history of the disease and no known genetic disorder. About 40 percent
of patients do have a family history, and some may have an
identifiable genetic mutation.

In the remaining 10 percent…the disease is definitely inherited: a
dominant gene makes the symptoms inevitable, sometimes as early in
life as the 30s or 40s, in anyone who inherits a copy from an affected
parent. And each child of an affected parent has a 50-50 chance of
inheriting the bad gene.

So far, most inherited cases have been linked to mutations in two
genes, both on the same chromosome, number 17. One gene codes for tau.
The other gene codes for a protein called progranulin and causes a
deficiency of it, which appears linked to the buildup of TDP-43. Three
other genes are involved in some cases, and researchers are looking
for still more.

 

“When Illness Makes a Spouse a Stranger”

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Yesterday’s New York Times had a terrific general story about dementia turning a spouse into a stranger.  Those within Brain Support Network dealing with LBD, PSP, and CBD may find this article of interest.

It’s the story of a Manhattan-based couple.  Before the husband was diagnosed with frontotemporal dementia in his 60s, the wife was considering divorce.  The wife talks about losing control when dealing with her husband, and grieving though he’s still alive.  Eventually, the wife had to place him in a care facility for both of their safety.  She spends several hours a day with him.

The wife notes that MDs are at a loss to forecast the progression:

“They can tell you everything that’s ever happened to anyone, but they can’t tell you what’s going to happen to you,” she said.

Here’s a touching video about this couple:

www.nytimes.com/video/health/100000001343193/in-love-and-loss.html

Dr. Bruce Miller from UCSF’s Memory & Aging Center is quoted frequently as UCSF is one of the lead institutions in the US for FTD research.  He says:

“I think at least some subtypes of frontotemporal dementia will be the first neurodegenerative diseases we find a cure for.” 

According to this article, there are eight sub-types of FTD.  Sometimes CBD and, less often, PSP are considered FTD sub-types.

The first article has a short mention of Richard Rainwater, who has PSP:

“But even if treatments or cures for frontotemporal dementia do emerge, they will almost certainly come too late for people with advanced cases, like … Richard Rainwater, a billionaire investor who learned in 2009 that he had progressive supranuclear palsy, which some consider a form of frontotemporal dementia. Mr. Rainwater and his family have donated more than $20 million to a research consortium, but given that he has a rapidly progressive form, any advances from the consortium may be more likely to help others than to save him.”

(I assume that if Mr. Rainwater has a “rapidly progressive form” of PSP, this means he has the Richardson’s Syndrome form, which includes dementia as a primary symptom.)

Here’s a link to the full article:

www.nytimes.com/2012/05/06/health/a-rare-form-of-dementia-tests-a-vow-of-for-better-for-worse.html

New York Times
The Vanishing Mind
When Illness Makes a Spouse a Stranger
By Denise Grady
May 5, 2012

Robin

 

Guide to PSP and CBD for General Practitioners

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This terrific guide for general practitioners on two disorders — progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).  The guide was published by the PSP Association, based in the UK (pspeur.org).  The guide covers many topics including diagnosis, treatment (management, medication), difficult conversations, cognition and behavior, end-of-life care, support for carers, and stem cell treatment.

Here’s a link to the guide:

www.pspeur.org/user/docs/PSPA%20GP%20Guide%20April%202012.pdf

A Guide to PSP and CBD for General Practitioners and Community Nurses
PSP Association, UK
June 2010

Probably many of us are envious of the “multi-disciplinary care team” available to those in the UK.  Note that a lot of the terms and certainly medication names are specific to the UK.

Looking at MRIs of autopsy-confirmed PSP and MSA

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This is a well-done study out of Queen Square Brain Bank in London.  Many progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) families have donated loved one’s brains to this brain bank, and a great team has been doing research there for a decade or more.

This latest research takes the MRIs from 22 people with autopsy-confirmed PSP, 13 with autopsy-confirmed MSA, 7 with autopsy-confirmed Parkinson’s Disease (PD), 6 with autopsy-confirmed corticobasal degeneration (CBD), and 9 controls.  People, without knowledge of the clinical diagnoses or post-mortem diagnoses, were shown MRIs.  Seventy-two percent of the PSP cases were correctly assessed.  Seventy-six percent of the MSA cases were correctly assessed.  “No PSP case was misclassified as MSA or vice versa.”  The authors note this is about as good as clinical diagnosis.

The authors “suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy.”

When I get a chance, I’ll read the full study….  Or one of you can!  The abstract is copied below.

Robin

——————-

Movement Disorders. 2012 Apr 4.  [Epub ahead of print]

Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy.

Massey LA, Micallef C, Paviour DC, O’Sullivan SS, Ling H, Williams DR, Kallis C, Holton JL, Revesz T, Burn DJ, Yousry T, Lees AJ, Fox NC, Jäger HR.
Sara Koe PSP Research Centre, UCL Institute of Neurology, University College London, London, United Kingdom; Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, United Kingdom; Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, University College London, London, United Kingdom. [email protected].

Abstract
Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied.

cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson’s disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed.

Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen’s kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa.

MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA.

The “hummingbird” and “morning glory” signs were highly specific for PSP, and “the middle cerebellar peduncle sign” and “hot cross bun” for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy.

cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy.

Copyright © 2012 Movement Disorder Society.

PubMed ID#:  22488922  (see pubmed.gov for this abstract only)

Most frequent pathologies behind corticobasal syndrome

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Too bad this full article is in Japanese as it might be a very good review of corticobasal syndrome.

Most impressive to me about the abstract is the long list of disorders that can look like corticobasal syndrome — CBD, AD, PSP, FTLD with TDP-43, Pick’s disease, Lewy body disease, CJD, etc.

Clearly, the only way to be sure of the diagnosis is for the brain to be examined upon death.  If you haven’t made arrangements for that but would like to, please let me know, as we can help with this.  Half of our local group members are involved with brain donation!

Robin

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Brain & Nerve. 2012 Apr;64(4):462-73.

[Corticobasal syndrome: recent advances and future directions].
[Article in Japanese]

Aiba I.
Department of Neurology, National Hospital Organization Higashinagoya National Hospital.

Abstract
Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder described by Rebeiz et al. It is characterized by progressive, asymmetric, cortical (eg, apraxia, alien limb phenomena, cortical sensory loss, and myoclonus), and extrapyramidal (eg, rigidity, bradykinesia, dystonia, and tremor) dysfunction.

However, CBD has many clinical phenotypes, and the features used for predicting CBD have low sensitivity.

Therefore, the term corticobasal syndrome (CBS) has been used to characterize such clinical features, whereas the term CBD is used to refer to the pathological disorder.

The most frequent causes of CBS are CBD, followed by Alzheimer’s disease, progressive supranuclear palsy, frontotemporal lobar degeneration with TDP-43 pathology (sporadic and familial), Pick’s disease, Lewy body disease, frontotemporal lobar degeneration with fused in sarcoma-positive inclusions, Creutzfeldt-Jakob disease, and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes.

The topography of neurodegeneration dictates the clinical syndrome not according to the underlying pathology.

Researchers have attempted to develop fluid biomarkers or imaging analysis for diagnosing CBS. The aim of this review was to highlight recent advances in CBS diagnosis and discuss future directions.

PubMed ID#:  22481519  (see pubmed.gov for this English-language abstract only)