Monthly Archives: September 2011

Mayo Clinic research on forms of Alzheimer’s, including hippocampal sparing

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One of Brain Support Network’s missions is to assist families around the United States with brain donation.  We have helped over 100 families donate a loved one’s brain.  Half of the confirmed diagnoses are different from the clinical diagnoses! We often see one diagnosis “wrong” more often than others – corticobasal degeneration. Often, those with supposed CBD have an atypical form of Alzheimer’s confirmed through brain donation.  And we sometimes see the same pattern in frontotemporal dementia (FTD).

Recently, the Mayo Clinic published research on the various types of Alzheimer’s Disease (AD).  Two atypical forms of AD were specifically highlighted — hippocampal sparing (HpSp) and limbic-predominant (LP).  We’ve seen this HpSp type on several neuropathology reports for people who were thought to have CBD and a few for FTD.

Here’s a link to the Mayo research:

ncbi.nlm.nih.gov/pmc/articles/PMC3175379/

Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: A retrospective study

by Melissa E. Murray, PhD, Neill R. Graff-Radford, MBBCh, FRCP (London), Owen A. Ross, PhD, Ronald C. Petersen, MD, Ranjan Duara, MD, and Dennis W. Dickson, MD

Lancet Neurol. 2011 Sep; 10(9): 785–796.
Published online 2011 Jul 27. 

Well worth reading…

Robin

 

“Rapidly Progressive” (3 Mos) Corticobasal Syndrome (CBS) Turns out to be Creutzfeldt-Jakob disease (CJD)

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“Case Reports in Neurology” is a new open access journal. The articles are available online only and at no charge.

A report was published recently on a case of “rapidly progressive” corticobasal syndrome. “A 74-year-old woman presented with language impairment, difficulty in walking and poor attentiveness that had begun 10 days before. Other symptoms, such as asymmetrical extra-pyramidal dysfunction, limb dystonia and ‘alien limb’ phenomena, were established over the next 2 months, with rapid progression.”

After three months, the woman died. Upon brain autopsy, it was determined that she had CJD (Creutzfeldt-Jakob disease), sometimes called the human version of “mad cow disease.” (In the US, special precautions are taken when someone with a rapidly progressive dementia donates his/her brain. Presumably the same is true in Portugal, where this woman lived.)

A few people here have reported this same outcome — CJD is found upon brain autopsy. But I think all the people here whose loved ones had a confirmed CJD diagnosis had received clinical diagnoses of PSP rather than CBD.

The authors seem to imply that they used MRI scan to diagnose this woman while alive with CJD. They describe how an MRI is helpful in diagnosing CBD: “On MRI, CBD patients may present asymmetric frontoparietal and midcallosal atrophy. Additionally, on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, they may also show putaminal hypointensity and subtle subcortical periventricular hyperintensity. On DWI, extensive hyperintensity in the frontoparietal white matter, especially on the predominant side of cortical atrophy, has been described. These features are especially evident in the early course of CBD.”

I’ve copied the abstract below.

The link to get to the article (PDF) online is very long:

http://content.karger.com/ProdukteDB/pr … elNr=32982\
0&Ausgabe=255291&ProduktNr=238704&filename=329820.pdf

It might be easier to go first to the journal’s home page here:
http://content.karger.com/ProdukteDB/pr … roduktNr=2\
38704

Then click on the “May – August” issue. Then click on the article that begins
on page 185.

Robin

Case Reports in Neurology. 2011 May;3(2):185-190. Epub 2011 Aug 23.

Rapidly Progressive Corticobasal Degeneration Syndrome.

Valverde AH, Costa S, Timoteo A, Ginestal R, Pimentel J.
Department of Neurology, Hospital Prof. Dr. Fernando Fonseca, EPE, Amadora, EPE/Hospital de Santa Maria, Lisbon, Portugal.

Abstract
INTRODUCTION:
Corticobasal syndrome (CBS) has a heterogeneous clinical presentation with no specific pathologic substratum. Its accurate diagnosis is a challenge for neurologists; in order to establish CBS definitively, postmortem confirmation is required. Some clinical and radiological features can help to distinguish it from other neurodegenerative conditions, such as Creutzfeldt-Jakob disease (CJD).

CLINICAL CASE:
A 74-year-old woman presented with language impairment, difficulty in walking and poor attentiveness that had begun 10 days before. Other symptoms, such as asymmetrical extra-pyramidal dysfunction, limb dystonia and ‘alien limb’ phenomena, were established over the next 2 months, with rapid progression. Death occurred 3 months after symptom onset. Laboratory results were normal. Initially, imaging only showed restricted diffusion with bilateral parieto-occipital gyri involvement on DWI-MRI, with unspecific EEG changes. An autopsy was performed. Brain neuropathology confirmed sporadic CJD (sCJD).

CONCLUSIONS:
CBS is a heterogeneous clinical syndrome whose differential diagnosis is extensive. CJD can occasionally present with clinical characteristics resembling CBS. MRI detection of abnormalities in some sequences (FLAIR, DWI), as previously reported, has high diagnostic utility for sCJD diagnosis – especially in early stages – when other tests can still appear normal. Abnormalities on DWI sequencing may not correlate with neuropathological findings, suggesting a functional basis to explain the changes found.

PubMed ID: #21941496 (see pubmed.gov for this abstract only)

Features of Corticobasal Degeneration Presenting as Corticobasal Syndrome or PSP-Richardson’s Syndrome

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Here’s another important paper on autopsy-confirmed cases of CBD (corticobasal degeneration) from Mayo researchers.

As we’ve learned many times of the last couple of years, those with autopsy-confirmed CBD can have many different clinical presentations including corticobasal syndrome (CBS), progressive non-fluent aphasia, behavioural variant frontotemporal dementia, and the Richardson syndrome form of PSP (progressive supranuclear palsy). “Due to the rarity of autopsy-confirmed corticobasal degeneration, the exact proportion of the various clinical presentations is unknown.”

In this study, 26 cases of autopsy-confirmed CBD are analyzed. Eleven presented with corticobasal syndrome (CBD-CBS), “characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus.” Fifteen presented by the Richardson syndrome type of PSP (CBD-RS), “characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia.”

(Note that the Williams and colleagues criteria for Richardson syndrome is: “gradual onset of postural instability and falls within the first 2 years of disease, along with vertical supranuclear gaze palsy, a frontal dysexecutive syndrome, and rigidity and bradykinesia that is unresponsive to levodopa.”)

“The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome or Richardson syndrome with respect to demographic, clinical and neuropathological features.” The researchers found differences in the distribution of tau in the brain.

These 26 autopsy-confirmed CBD cases were compared with 15 autopsy-confirmed PSP/Richardson syndrome cases (PSP-RS). Clinically, the CBD cases “had more cognitive impairment and frontal behavioural dysfunction.” The behavioral problems seen “included disinhibition, social withdrawal, apathy, agitation and impatience.”

How do you tell while someone is alive that they have CBD or PSP, when they present with Richardson syndrome? The researchers say: “Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.” Cases with CBD-CBS and CBD-RS “had marked atrophy of the anterior corpus callosum compared with patients with PSP-RS.”

In their conclusion, the authors address future treatments: “If future disease-modifying therapies are discovered that target specifically 4R tau dysfunction, there would be little significance in differentiating CBD-RS from PSP-RS. On the other hand, if the factors that drive cellular and anatomical specificity in corticobasal degeneration differ meaningfully from progressive supranuclear palsy, making this distinction may eventually be of more than academic interest. To that end, additional research is needed to determine if corticobasal degeneration and progressive supranuclear palsy have the same pathogenesis.”

From the article, we learned that between 1999 and 2009, 108 autopsy-confirmed CBD cases had been donated to the Mayo Jax brain bank. Of those 108, 41 had features consistent with Richardson syndrome (CBD-RS), 21 had features consistent with corticobasal degeneration (CBD-CBS), and the others had different presentations. Perhaps some of you donated family members’ brains in that time frame! If there were complete medical records at Mayo Jax, those family members potentially are included in this study.

We also learned that the Mayo Jax brain bank had over 600 autopsy-confirmed PSP cases had been donated to the Mayo Jax brain bank. We aren’t told how many have the Richardson syndrome form of PSP but previous studies show that 60% of PSP cases are Richardson syndrome. At present, neuropathology reports from Mayo Jax do not indicate if the case had a Richardson syndrome clinical presentation. Fifteen of these PSP cases were included in the study. (My father’s brain could be part of the study!)

A total of 41 brains were included in this study. “34% were followed at the Mayo Clinic, while 66% were referral cases to the CurePSP/Society for PSP Brain Bank.”

Thanks to all those who have donated brain tissue to the Mayo Clinic or elsewhere for making research like this possible!

I’ve copied the abstract below.

Robin

Here’s the abstract:

Brain. 2011 Sep 20. [Epub ahead of print]

Neuropathological features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome.

Kouri N, Murray ME, Hassan A, Rademakers R, Uitti RJ, Boeve BF, Graff-Radford NR, Wszolek ZK, Litvan I, Josephs KA, Dickson DW.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Abstract
Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge.

Corticobasal syndrome is the clinical phenotype originally described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus.

Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia.

The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15).

Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures.

Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction.

The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration.

Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.

PubMed ID#: 21933807 (see pubmed.gov for this abstract only)

Economic Costs of PSP and MSA in 3 European Countries

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This is a study of the economic costs of PSP and MSA in France, Germany, and the UK, looking at 742 people — 352 with PSP and 390 with MSA — over a 6-month time period. At the time of the study, the average disease duration was about 4 years. Included are “service costs,” which are the costs associated with seeing an MD or receiving tests, medication, treatment, or equipment, and “unpaid care costs,” which is the value of care provided by family and friends.

The authors state: “Measures of costs for a representative sample of patients allow us to determine relationships between care inputs and patient needs, assess the cost-effectiveness of specific treatments and highlight the impact that these conditions have on society as a whole.”

They found:

* “Unpaid care accounted for 68-76%” of the total costs.

* “Formal and unpaid costs were significantly higher the more severe the illness, as indicated by the Parkinson’s Plus Symptom scale.” And: “[Costs] increase with severity in each country for PSP patients. This is also generally the case for MSA patients, although in the UK the patients with the highest severity do not have the highest costs.”

* “This suggests that interventions which successfully modify disease progression may reduce the economic burden of these conditions.”

* “There was a significant inverse relationship between service and unpaid care costs.” I guess this means if someone is seeing an MD or receiving treatment, there’s less of a need for family and friends to provide “unpaid care.”

* “There was no relation between costs, formal or unpaid, and age or disease duration.”

* “The mean six-month service costs of PSP were €24,491 in France, €30,643 in Germany and €25,655 in the UK.”

25,000 Euros is about $34,000 US dollars. So this would mean that the annual costs are about $68K.

* “The costs for MSA were €28,924 [in France], €25,645 [in Germany] and €19,103 [in the UK].”

The authors compare their findings with data on the economic costs of other diseases: “Based on studies using a similar methodology, the six-month service costs of multiple sclerosis are around £8500 in the UK and €10000 in Germany. Likewise, the six-month costs of Alzheimer’s disease in the UK is approximately €13000 per person and schizophrenia €5500. Whilst these figures indicate the high care needs of PSP and MSA relative to other conditions, it should be recognised that the total ‘burden’ will be less given the lower prevalence rates. Of particular interest, and in common with other degenerative conditions, is the fact that unpaid family care accounts for most of the cost.”

I’ve copied the abstract below. The full article is available online at no charge through the PloS One journal’s website:
http://www.plosone.org/article/info%3Ad … ne.0024369

Robin

PLoS One. 2011;6(9):e24369. Epub 2011 Sep 8.

The Economic Costs of Progressive Supranuclear Palsy and Multiple System Atrophy in France, Germany and the United Kingdom.

McCrone P, Payan CA, Knapp M, Ludolph A, Agid Y, Leigh PN, Bensimon G; for the NNIPPS Study Group.
Health Service and Population Research Department, Institute of Psychiatry, King’s College London, London, United Kingdom.

Abstract
Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are progressive disabling neurological conditions usually fatal within 10 years of onset.

Little is known about the economic costs of these conditions. This paper reports service use and costs from France, Germany and the UK and identifies patient characteristics that are associated with cost. 767 patients were recruited, and 760 included in the study, from 44 centres as part of the NNIPPS trial. Service use during the previous six months was measured at entry to the study and costs calculated. Mean six-month costs were calculated for 742 patients.

Data on patient sociodemographic and clinical characteristics were recorded and used in regression models to identify predictors of service costs and unpaid care costs (i.e., care from family and friends).

The mean six-month service costs of PSP were €24,491 in France, €30,643 in Germany and €25,655 in the UK.

The costs for MSA were €28,924, €25,645 and €19,103 respectively.

Unpaid care accounted for 68-76%. Formal and unpaid costs were significantly higher the more severe the illness, as indicated by the Parkinson’s Plus Symptom scale. There was a significant inverse relationship between service and unpaid care costs.

PubMed ID#: 21931694

Biomarker confirmed PSP and symptom explanation

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One sentence in this hard-to-understand abstract caught my eye: “Thus, in a clinically diagnosed and biomarker-confirmed cohort with early PSP, we demonstrate that neostriatal volume and shape are significantly reduced in vivo.”

I wondered what they meant by biomarker-confirmed PSP. There is something called the “penguin” or “hummingbird” sign, which is how the pons and atrophic midbrain appear on a mid-sagittal MRI. It is present in even mild to moderate PSP. I have never heard of anyone in our local support group having an MRI that shows the penguin sign or hummingbird sign. Years ago, I visited the Mayo Jax Brain Bank; one of the researchers there showed me the hummingbird sign on several MRIs.

The point of this study of 15 Swedish PSP patients is that there’s an anatomical basis for “the neuropsychiatric manifestations of PSP, such as the dysexecutive syndrome, gaze palsy, obsessive–compulsive phenomena and utilization behavior.” (I’m not sure how gaze palsy is a neuropsychiatric symptom but anyway…) Similarly, there is an anatomical basis for “the movement disorders of PSP, bradykinesia, gait disturbance and rigidity.”

Here’s the abstract, which is loaded with anatomical terms.

Robin

Psychiatry Research. 2011 Sep 5. [Epub ahead of print]

Morphometric analysis of subcortical structures in progressive supranuclear palsy: In vivo evidence of neostriatal and mesencephalic atrophy.

Looi JC, Macfarlane MD, Walterfang M, Styner M, Velakoulis D, Lätt J, van Westen D, Nilsson C.
Research Centre for the Neurosciences of Ageing, Academic Unit of Psychological Medicine, School of Clinical Medicine, Australian National University Medical School, Canberra, Australia.

Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by gait and postural disturbance, gaze palsy, apathy, decreased verbal fluency and dysexecutive symptoms, with some of these clinical features potentially having origins in degeneration of frontostriatal circuits and the mesencephalon.

This hypothesis was investigated by manual segmentation of the caudate and putamen on MRI scans, using previously published protocols, in 15 subjects with PSP and 15 healthy age-matched controls.

Midbrain atrophy was assessed by measurement of mid-sagittal area of the midbrain and pons. Shape analysis of the caudate and putamen was performed using spherical harmonics (SPHARM-PDM, University of North Carolina).

The sagittal pons area/midbrain area ratio (P/M ratio) was significantly higher in the PSP group, consistent with previous findings. Significantly smaller striatal volumes were found in the PSP group – putamina were 10% smaller and caudate volumes were 17% smaller than in controls after controlling for age and intracranial volume. Shape analysis revealed significant shape deflation in PSP in the striatum, compared to controls; with regionally significant change relevant to frontostriatal and corticostriatal circuits in the caudate.

Thus, in a clinically diagnosed and biomarker-confirmed cohort with early PSP, we demonstrate that neostriatal volume and shape are significantly reduced in vivo.

The findings suggest a neostriatal and mesencephalic structural basis for the clinical features of PSP leading to frontostriatal and mesocortical-striatal circuit disruption.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PubMed ID#: 21899988 (see pubmed.gov for this abstract only)