Category Archives: PSP

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)

AgD (argyrophilic grain disease) – Alzheimer Europe description

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I ran across this short description of AgD (argyrophilic grain disease) recently on the Alzheimer Europe website. I’ve been sharing it with the folks I know whose family members are diagnosed upon brain autopsy with a neurodegenerative disease (such as PSP or CBD) *plus* AgD.

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http://www.alzheimer-europe.org/Dementi … isease-AGD

Argyrophilic Grain Disease (AGD)
Neuro-Degenerative Diseases

by André Delacourte & Kurt Jellinger

General outline

New disease, which is not fully characterised. A sporadic late-onset form of dementia characterised by a neuro-degenerative process, which mainly affects limbic structures (amygdala, hippocampus and mediobasal temporal/entorhinal cortex).

It is named after silver-staining (argyrophilic) grains or coiled bodies within the cytoplasm of neurons that consist mainly of tau protein isoforms with four microtubule-binding repeates (4-R tau).

Synonym:  Braak’s disease

Symptoms and course

Reduction of short-term memory, disorders of word finding, disorders of reading and writing, disorientation, behavioural disturbances (personality changes, emotional disorders with aggression and ill-temper) may precede or follow memory failure. Clinically it is hard to distinguish from late-onset AD.

The age of onset is around 70 years old. The duration of the disease is between 4 and 8 years.

Causes and risk factors

Neuron degeneration likely associated with dysfunction of tau protein. Grains are composed of abnormally phosphorylated tau protein with 4 repeats. Recent studies indicate that tau protein dysfunction in AGD in contrast to other 4-R-tauopathies (progressive supranuclear palsy, corticobasal degeneration).

Genetics

The disease arises irrespective of the genetic background regarding tau H1 or H2 haplotypes, at the opposite of PSP and CBD (Miserez A. R. et al, 2003). Lack of relationship with apolipoprotein E4.

Frequency

1 to 5% of AD patients (Togo T. et al, 2002).

Diagnostic procedures

It is almost impossible to distinguish from late-onset Alzheimer’s disease. The diagnosis is almost entirely made by post-mortem examination. AGD lesions are found in about 5% of Alzheimer’s disease (Togo T. et al, 2002).

Last Updated: Friday 09 October 2009

“I was diagnosed with PSP in 2009” – what are the stages?

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I received the following email:

“I was diagnossed with PSP only back in 2009. I started with the usual falling (bacwards of course and after reading the various posts, I quikly realised that this was normal as far as PSP goes.) I was very active before PSP. I also realize, that I am at the beginning stages from reading the posts. Where do I find the different stages? Are there such things – as stages? Can you help me?”

You can find some info on stages here at this post.  This document was written by laypeople (mostly caregivers). There has been discussion on the PSP Forum as to whether this document is of any value or not.

The best source of info on the clinical course “on average” of those with the two most common forms of PSP — Richardson’s Syndrome and PSP-Parkinsonism — is the “Clinical Outcomes” article by O’Sullivan, et al. Relevant posts are here.

Robin