Neuropsychological decline in CBD and other FTLD subtypes

This abstract was published today on PubMed. CBD is considered a subtype of FTLD (frontotemporal lobar degeneration). This Drexel University study assessed whether the patterns of neuropsychological impairment in CBD, three other FTLD subtypes, and AD remain distinct over the duration of the disease or “devolve into a common, undifferentiated neuropsychological state.” The researchers found that the patterns remained distinct. For CBD, patients “presented with performance on visuoconstructional tests.” A quick Google search revealed several visuoconstructional tests including Constructional Praxis, Stick Design, and Bicycle Drawing. Perhaps the clock test is also a visuoconstructional test.
Robin

Neuropsychology. 2009 May;23(3):337-46.

Neuropsychological decline in frontotemporal lobar degeneration: A longitudinal analysis.

Libon DJ, Xie SX, Wang X, Massimo L, Moore P, Vesely L, Khan A, Chatterjee A, Coslett HB, Hurtig HI, Liang TW, Grossman M.
Department of Neurology, Drexel University College of Medicine.

Few studies have assessed whether the patterns of neuropsychological impairment in patients with different frontotemporal lobar degeneration (FTLD) subtypes remain distinct over the duration of their illness or devolve into a common, undifferentiated neuropsychological state.

A longitudinal neuropsychological analysis was obtained over 100 months assessing executive control, language/naming, and visuoconstruction in 441 patients diagnosed with Alzheimer’s disease (AD) and four FTLD subtypes, i.e., a social comportment/dysexecutive (SOC/EXEC) disorder; progressive non-fluent aphasia (PNFA); semantic dementia (SemD); and corticobasal degeneration (CBD).

Initial group differences on each measure were maintained over the duration of illness, including several double dissociations. For example, AD patients exhibited a decline in ‘animal’ fluency; PNFA patients had difficulty on tests of executive control, SemD maintained their impairment on tests of naming, and CBD had presented with performance on visuoconstructional tests.

None of the group by neuropsychological task interactions evaluating longitudinal decline was significant, suggesting that performance does not converge onto a common subtype over time. These data indicate that distinct patterns of neuropsychological impairment are maintained longitudinally, reflecting the unique anatomic distribution of relative disease burden in AD and FTLD.

PubMed ID#: 19413447 (see pubmed.gov for abstract only)

Advocate for NIH Funding

This email about NIH funding may be of interest here. I received it earlier today from the Association for Frontotemporal Dementias. (CBD is a subtype of FTD, and PSP is considered a related disorder.)

Date: Mon, 2 Feb 2009 20:44:56 +0000 (GMT)
From: <[email protected]>
To: Robin Riddle
Subject: Advocate for NIH Funding

Dear AFTD Community:

Here is a quick and easy way to contact your local Senators to support science investment in the Economic Recovery Package!

Senator Arlen Specter (R-PA) is prepared to offer an amendment on the Senate floor as early as today, Monday, February 2, 2009 to provide $10 billion for the National Institutes of Health (NIH) in the economic recovery package. Please take five minutes to ask your senator to support this crucial amendment today.

This amendment would provide funding for grants that could be distributed by NIH right away. NIH funding is fundamental in promoting research to improve the diagnosis, treatment and quality of life for people suffering from neurological and psychological disorders, including Frontotemporal Dementias. Attaching this amendment to the Economic Recovery Project highlights the importance of science funding for its potential to create jobs and stimulate state and local economic growth.

Our colleagues at the American Brain Coalition are urging all of us to join them in voicing our support for expanding research funding at the NIH. Please follow this link and with a few clicks of the mouse, you can send letters to your Members of Congress. Please visit http://capwiz.com/americanbraincoalition/home/. There will be a ‘Take Action Now’ box. Simply click on “Contact Senators to Support Science Investment in Economic Recovery Package” and follow the steps. The suggested text is fully editable and we encouraged you to personalize your message.

As a community, we can effect change and make sure that FTD gets the awareness and funding it deserves!

Thank you for your immediate attention to this initiative.

Sincerely,

Louise O’Conner and Bill Brown
Co-Chairs
AFTD Advocacy Committee

Tau aggregation, 12/08 research (Japan)

Here’s the most interesting part of this new abstract on research into tau aggregation: “It is believed that aberrant modifications of tau, including phosphorylation, truncation, and conformational changes, induce filamentous aggregation. However, the mechanism underlying the conversion of tau protein from a soluble state to one of insoluble aggregates still remains elusive. ”

Current Alzheimer Research. 2008 Dec;5(6):591-8.

Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration.

Sahara N, Maeda S, Takashima A.
Laboratory for Alzheimer’s Disease, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases, including Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and frontotemporal dementia with Parkinsonism linked to chromosome 17, all known collectively as tauopathies. Tau protein is a member of microtubule (MT)-associated proteins. Tau is a highly soluble and natively unfolded protein dominated by a random coil structure in solution. It is believed that aberrant modifications of tau, including phosphorylation, truncation, and conformational changes, induce filamentous aggregation. However, the mechanism underlying the conversion of tau protein from a soluble state to one of insoluble aggregates still remains elusive. The importance of tau aggregation intermediates (e.g. tau dimer, tau multimer, and granular tau oligomer) in disease pathogenesis was suggested by recent studies. Here, we review the latest developments in tracking the structural changes of tau protein and discuss the utility improving our understanding of tau aggregation pathway leading to human tauopathies.

PubMed ID#: 19075586 (see pubmed.gov for abstract only)

Notes from PSP/CBD Webinar (10/14/08)

I thought the webinar was excellent. I hope many of you were able to attend either by the combo of web and phone, or by phone alone (as I did).

Apparently CurePSP intends to post Dr. Golbe’s PowerPoint presentation to its website some time soon. I do not believe a recording of the webinar was made, unfortunately.

“PSP” was mentioned much more often than CBD. It was unclear if some of the information was PSP-only or applied equally to both PSP and CBD. I think each item would need to be addressed with Dr. Golbe.

The following are some notes I took during the presentation. The notes include what I could recall of the questions and answers. If any of you attended the webinar, please share your notes and key take-aways!

There are two types of PSP: Richardson’s Syndrome and PSP-Parkinsonism. The most common type is RS. One-third of those with PSP have PSP-Parkinsonism (PSP-P). PSP-Parkinsonism looks like Parkinson’s Disease. People with PSP-P live longer. They are less likely to have dementia or visual problems, and they are less likely to fall. Those with PSP-P are more likely to experience tremor. (Robin’s note: If the head of the CurePSP Scientific Advisory Board is using the “two types of PSP” terminology, I conclude that it has gained acceptance among PSP experts.)

On average, those with PSP live 7 years after symptom onset. Broken down, those with RS live 5.9 years after symptom onset and those with PSP-P live 9.1 years after symptom onset. On average, those with PSP are diagnosed 3.5 years after symptom onset. This does not allow for much time for treatment. If you have an earlier age of onset, you survive longer.

In order to get people diagnosed earlier, we need to educate MDs. If MDs see unexplained falls, they should immediately think of PSP. MDs should check for eye movement problems.

There’s a list of supportive features. These are not required for a PSP diagnosis. They are simply “common symptoms” that can be “helpful clues” to an MD in making a diagnosis. (Examples: symmetric bradykinesia, retrocollis.)

In all his years caring for those with PSP, Dr. Golbe has never seen someone with Whipple’s Disease, though it is commonly screened for as part of the PSP diagnosis.

A defect in the protein tau causes: 1) disintegration of microtubules, and 2) clumping. The disintegration of microtubules causes problems in the brain. The tau tangles are the result of problems with tau.

There are three key issues in PSP:
1) too much 4-repeat tau is produced.
2) there is too much oxidation. (Rusting is one form of oxidation.) Too much oxidation damages molecules.
3) the mitochondria is not working properly.

These three key issues lead to the creation of tau tangles. Any treatment in PSP likely to have some success in slowing the disease progression needs to effect one of these three key problems.

The incidence of PSP is 1 per 100,000 people. The prevalence of PSP is 6 per 100,000 people. By comparison, Alzheimer’s Disease is 800 per 100,000 people. (Robin’s note: I believe 800 is a prevalence number.) The incidence of CBD is thought to be less than 1 per 100,000 but the incidence and prevalence of CBD have never been studied.

Of the brains at the PSP Brain Bank where the patients was diagnosed in life with PSP, only 70% actually had PSP. Those who were misdiagnosed actually had: CBD (8%), a continuum of DLBD/PD (3%), ALS (1%), and FTD (1%). FTD is “another tau disorder.” (Robin’s note: Some FTD disorders are not tau disorders but are ubiquitin disorders, so Dr. Golbe’s comment is confusing to me.)

In looking at first-degree relatives of those with PSP, 39% showed abnormalities on various rating scales. This 39% figure suggests that something genetic is going on.

There is evidence of environmental toxins. An example of this is tropical fruit. There is currently research going on into the dietary habits of those with PSP.

In research conducted 20 years ago, there was a *slim* suggestion that those with PSP were less likely to be educated, and more likely to be a factory worker or exposed to toxins used on a farm.

We can’t biopsy the brain and diagnose PSP or CBD. Confirmation of the diagnosis is only possible on post-mortem exam of brain tissue. (Robin’s note: It seems that one or two people on the CBGD_support Yahoo!Group have indicated that their loved ones *did* receive a biopsy and CBD was confirmed.)

A research paper will be published soon looking at the use of CSF (cerebrospinal fluid) in diagnosing PSP.

A family with a history of PSP was studied. We know the general location but not the specific gene associated with PSP.

Standard medication given to those with PSP and CBD includes levodopa (Sinemet) and amantadine. Levodopa sometimes helps with the slowness and stiffness. Amantadine can help sometimes for a few months.

Other medication has unproven benefits:
* amitriptyline (Elavil). Due to side effects from this medication, Dr. Golbe has stopped using it.
* ChEIs. Sometimes these help with dementia.
* SSRIs can help disinhibition.
* CoQ10 is focused on slowing the progression of PSP. It does *not* help with symptoms.

Namenda seems to be poorly tolerated in those with PSP.

Not all symptoms progress at the same rate. There is huge variability.

Sense of smell is reduced a little in PSP.

There are PSP animal models in a type of fish, fly, and worm, and in rats.

An ’05 study showed that lithium reduced hyperphosphorylation of tau. The NIH decided to fund a lithium trial in PSP and CBD. No site involved in the study has received approval yet to proceed recruiting patients. It was noted that the info on the NIH-funded lithium trial is not on the curepsp.org website.

CurePSP is funding the PSP Genetics Consortium. The goal was to have 1000 PSP brains to include in the study. They’ve ended up with 1300 brains. This is a DNA study, a genome study.

There was a question about estimating survival time in someone with PSP. Dr. Golbe replied that the best tool for prognosticating is the PSP Rating Scale he developed. Generally, patients decline at a rate of 10-12 points per year. When a patient gets to 70 points, they usually live for six months. Often the issue is the immobility leads to medical complications. (Robin’s note: You can find the PSP Rating Scale on the CurePSP website — https://www.psp.org/materials/rating_scale.pdf I used this with my dad and found it accurate.)

There was a question about the experimental drug Rember that was discussed at a recent Alzheimer’s Disease conference. Dr. Golbe said he and others are skeptical of the results reported at the conference. There are problems with the design of the trial and the data. The analysis was also suspect. The principal investigator of the trial has a conflict of interest.

There was a question about stem cell research. (Robin’s note: I’m not confident I got all of Dr. Golbe’s statements down correctly so if others listened in please help me out here!) Dr. Golbe noted that there are currently no treatment trials for stem cell therapy. We can’t replace all the dead cells in the brain. He said that stem cell therapy in the early stages of PD is relevant to the PSP world. The closest approach with relevance to PSP is to encourage cells to produce chemicals.

“Antipsychotics Dangerous for Elderly With Dementia”

This post will be of interest to those dealing antipsychotics (such as Haldol, Seroquel, or Risperdal) in the elderly with dementia.  Many with Lewy Body Dementia take this type of medication.  I have heard of a few people with Progressive Supranuclear Palsy, Corticobasal Degeneration, and even Multiple System Atrophy taking this type of medication.

HealthDay News (at everydayhealth.com) published a news article earlier this week on a new study showing that:

“Elderly people with dementia who are given antipsychotics, even for a very short period of time, are more likely to end up in the hospital or even die, new research shows.”

This is some follow-up to Canadian research published in June ’07 on the same subject (PubMed ID#17548409).  (Many of the researchers are the same on the two studies.)

The news article included reference to an Alzheimer’s Association (alz.org) publication on using antipsychotics in those with AD.  This publication is worth reading:

www.alz.org/national/documents/statements_antipsychotics.pdf

There is an FDA “black box” warning on the atypical antipsychotics.  You can find the April ’05 FDA warning on fda.gov at:

www.fda.gov/cder/drug/advisory/antipsychotics.htm

The HealthDay News article follows.  Below that is the abstract of the medical journal article.

Robin

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tinyurl.com/5xuj95

Antipsychotics Dangerous for Elderly With Dementia
HealthDay News
Published: 05/27/08

MONDAY, May 26 (HealthDay News) — Elderly people with dementia who are given antipsychotics, even for a very short period of time, are more likely to end up in the hospital or even die, new research shows.

However, the problems underlying the need for such medications, behavioral problems such as aggression and agitation, are very real, and the alternatives to antipsychotics are limited, the researchers added.

“A misreading of the findings would be we don’t need to do something for these nursing home residents,” said study author Dr. Gary J. Kennedy, head of geriatric psychiatry for Montefiore Medical Center in New York City.

Many experts feel behavioral interventions should be tried first and antipsychotics used as a last resort, “when the behavior or the psychiatric symptoms are really out of control and causing complete distress not only for the person suffering from Alzheimer’s, but for caregivers all around them,” said Maria Carrillo, director of medical and scientific affairs at the Alzheimer’s Association in Chicago. “It’s important to work these things out with the physician and, of course, do follow-up very closely together, so you can make sure these antipsychotics are having the effect you want and, if not, discontinue them immediately.”

The findings were published in the May 26 issue of the Archives of Internal Medicine.

Antipsychotic drugs are commonly used to treat some of the behavioral complications of dementia, including delirium.

Newer antipsychotic medications such as Zyprexa (olanzapine) and Risperdal (risperidone) have been available for about a decade and have largely replaced their older counterparts.

Researchers from the Institute for Clinical Evaluative Sciences in Ontario, Canada, compared 20,682 older adults with dementia living in the community with 20,559 older adults with dementia living in a nursing home between April 1, 1997, and March 31, 2004.

Each group was divided into three subgroups: those not receiving any antipsychotics, those taking newer antipsychotics, and those taking older antipsychotics such as Haldol (haloperidol).

According to information gleaned from medical records, community-dwelling adults who had recently received a prescription for a newer antipsychotic medication were 3.2 times more likely than individuals who had received no antipsychotic therapy to be hospitalized or to die during 30 days of follow-up.

Those who received older antipsychotic therapy were 3.8 times more likely to have such an event, relative to their peers who had received no antipsychotic therapy.

A similar pattern, albeit less dramatic, emerged in the nursing home group. Individuals taking older antipsychotics were 2.4 times more likely to be hospitalized or die, while those taking newer drugs were 1.9 times more likely to die or be hospitalized during the 30 days of follow-up.

The study does, however, have its limitations. “It’s a carefully done study,” Kennedy said. “One flaw is that the [participants] weren’t randomly administered antipsychotics. There was some reason they were given an antipsychotic, such as aggression or agitation. It may have been done if they were recently admitted to the nursing home as part of the adjustment process.

Indeed, the authors acknowledged that about 17 percent of patients entering nursing homes start taking an antipsychotic within 100 days.

“For any of us, moving is like being sick. It takes a while to recover,” Kennedy said. “We need other sets of interventions besides medications. What that implies is more staffing and better training for staff, and that may not be a whole lot more expensive than medicines.”

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Here’s the abstract of the medical journal article:

Archives of Internal Medicine. 2008 May 26;168(10):1090-6.

Antipsychotic therapy and short-term serious events in older adults with dementia.

Rochon PA, Normand SL, Gomes T, Gill SS, Anderson GM, Melo M, Sykora K, Lipscombe L, Bell CM, Gurwitz JH.
Department of Medicine, University of Toronto, Canada.

BACKGROUND: Antipsychotic therapy is widely used to treat behavioral problems in older adults with dementia. Cohort studies evaluating the safety of antipsychotic therapy generally focus on a single adverse event. We compared the rate of developing any serious event, a composite outcome defined as an event serious enough to lead to an acute care hospital admission or death within 30 days of initiating antipsychotic therapy, to better estimate the overall burden of short-term harm associated with these agents.

METHODS: In this population-based, retrospective cohort study, we identified 20 682 matched older adults with dementia living in the community and 20 559 matched individuals living in a nursing home between April 1, 1997, and March 31, 2004. Propensity-based matching was used to balance differences between the drug exposure groups in each setting. To examine the effects of antipsychotic drug use on the composite outcome of any serious event we used a conditional logistic regression model. We also estimated adjusted odds ratios using models that included all covariates with a standard difference greater than 0.10.

RESULTS: Relative to those who received no antipsychotic therapy, community-dwelling older adults newly dispensed an atypical antipsychotic therapy were 3.2 times more likely (95% confidence interval, 2.77-3.68) and those who received conventional antipsychotic therapy were 3.8 times more likely (95% confidence interval, 3.31-4.39) to develop any serious event during the 30 days of follow-up. The pattern of serious events was similar but less pronounced among older adults living in a nursing home.

CONCLUSIONS: Serious events, as indicated by a hospital admission or death, are frequent following the short-term use of antipsychotic drugs in older adults with dementia. Antipsychotic drugs should be used with caution even when short-term therapy is being prescribed.

PubMed ID#: 18504337  (see pubmed.gov for the abstract)