Clinical diagnosis of CBD; autopsy showed CJD

In case you needed more evidence that CBD mimics other disorders… This is a case of a 73-year-old Japanese woman who “showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. … The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively.”

She died at age 81. A brain autopsy was performed. It revealed she had a genetic form of Creutzfeldt-Jakob disease.


Neuropathology. 2011 Jan 27. [Epub ahead of print]

An autopsied case of V180I Creutzfeldt-Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type.

Iwasaki Y, Mori K, Ito M, Nagaoka M, Ieda T, Kitamoto T, Yoshida M, Hashizume Y.
Departments of Neurology Pathology, Oyamada Memorial Spa Hospital Department of Neurology, Yokkaichi Municipal Hospital, Yokkaichi Division of CJD Science and Technology, Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.

A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia.

One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2-weighted images in the initial stage, and a later high-signal intensity region was observed in the cerebral cortex in diffusion-weighted images.

The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp-wave complexes.

Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129.

This patient’s clinical symptoms and disease course were atypical for Creutzfeldt-Jakob disease (CJD), and a stable state with nasal tube-feeding lasted several years.

She died of respiratory failure at the age of 81, 102 months after the onset.

Autopsy revealed widespread spongiform degeneration with weak synaptic-type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long-term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic-type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque-like PrP deposition. Western blot analysis of protease-resistant PrP showed a characteristic pattern without a diglycoform band.

V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings.

© 2011 Japanese Society of Neuropathology.

PubMed ID#: 21269331 (see for this abstract only)

Clinical-pathological correlates in PSP (and MSA)

This is a terrific little study done comparing brain tissue of 15 PSP cases, 12 MSA cases, 8 PD cases, and 8 healthy controls, and correlating the pathology with clinical variables (age at onset, disease duration, and symptoms).

The study was done in Australia using tissue donated to the Sydney Brain Bank. I say it was a “little” study because the previous clinical-pathological correlation study in MSA and PSP had much larger numbers — 110 PSP cases and 83 MSA cases. That larger Queen Square Brain Bank (UK) study “did not consider the pathological severity of disease or assess pathological correlations to clinical features.” (This is O’Sullivan’s “Clinical outcomes” article published in the journal Brain in 2008.  We have posted about that here.)

The symptoms studied include the:

“presence or absence of…bradykinesia and rigidity, resting tremor, postural instability, response to levodopa (L-dopa) therapy, dementia as indicated from the last Clinical Dementia Rating (CDR) score, early falls (within the first 2 years of onset), supranuclear vertical gaze abnormalities (abnormal or slow vertical gaze and/or supranuclear gaze palsy), dysarthria, dysphagia, postural hypotension, autonomic and urinary dysfunction, and gait ataxia. The severity of parkinsonism was assessed using the last Hoehn and Yahr (H&Y) score prior to death.”

Here’s some key data on the clinical variables:

Age at onset
PSP: 67 years +/- 9 years

Disease duration
PSP: 7 years +/- 4 years

Phenotype (parkinsonian: parkinsonian-plus)
PSP: 5:10

% L-dopa responsive
PSP: 47%

% demented
PSP: 67%
MSA: 0%

% early falls
PSP: 93%

% gaze abnormalities
PSP: 73%

% dysarthria
PSP: 60%

% autonomic dysfunction
PSP: 47%

% gait ataxia
PSP: 40%

The researchers divide cases by phenotype — parkinsonian or parkinsonian-plus. My assumption is that, for PSP, the parkinsonian phenotype is called PSP-Parkinsonism and the parkinsonian-plus phenotype is called RS (Richardson’s Syndrome).

“As expected, response to L-dopa was associated with a parkinsonian phenotype across all groups, although resting tremor was not associated with either phenotype. The presence of supranuclear vertical gaze abnormalities and early falls was associated with a parkinsonian-plus phenotype across groups, although autonomic dysfunction and gait ataxia were not associated with either phenotype.”

I’ve copied the abstract below.



Movement Disorders. 2011 Jan 21.

Clinical correlates of similar pathologies in parkinsonian syndromes.

Song YJ, Huang Y, Halliday GM.
Neuroscience Research Australia and the University of New South Wales, Randwick, New South Wales, Australia.

BACKGROUND: There have been no previous studies assessing the severity of regional atrophy, cell loss and lesion densities between the overlapping conditions of Parkinson’s disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) and relating these pathologies to different clinical features.

METHODS: Clinical indices and basal ganglia, brainstem, and cerebellar pathology from 43 longitudinally studied cases (PD = 8, PSP = 15, MSA = 12, controls = 8) were compared. A point-counting method was used to evaluate subregional volumes, and alpha-synuclein and phospho-tau immunohistochemistry was used to assess pathological inclusions and stage disease severity. Logistic regression analyses were used to identify pathological associations with clinical features.

RESULTS: All PD, PSP, and MSA cases had severe degeneration of the substantia nigra. Clinical features correlated with tissue loss and the severity of inclusion pathologies. Levodopa responsiveness and a lack of resting tremor was associated with preservation of pallidal volume, the presence of gait ataxia was associated with atrophy of the putamen, and the parkinsonian-plus phenotype with early falls and supranuclear vertical gaze abnormalities had more substantial midbrain atrophy and greater inclusion pathology in the caudate nucleus.

DISCUSSION: This is the first study to compare the severity of regional pathologies across parkinsonian conditions. The data show that tissue loss and inclusion densities in certain regions correlate with clinical indices, with regional volume changes likely to be the best indicator of clinical progression of disease.

Copyright © 2011 Movement Disorder Society.

PubMed ID#: 21259341 (see for the abstract only)

Alpha-synuclein in spinal fluid isn’t a parkinsonism biomark

Dutch researchers found that the amount of alpha-synuclein in cerebrospinal fluid (CSF) is not a tool for differentiating those who have Parkinson’s Disease from those who have an atypical parkinsonism disorder (MSA, DLB, PSP, CBD, and vascular parkinsonism). Alpha-synuclein in CSF is also not a tool for differentiating among the atypical parkinsonism disorders. The search for a biomarker continues.

Neurobiology of Aging. 2011 Jan 12. [Epub ahead of print]

CSF alpha-synuclein does not differentiate between parkinsonian disorders.

Aerts MB, Esselink RA, Abdo WF, Bloem BR, Verbeek MM.
Department of Neurology, Parkinson Center Nijmegen (ParC), and Alzheimer Centre Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, the Netherlands.

Differentiating between Parkinson’s disease (PD) and atypical Parkinsonism (AP) is clinically relevant but challenging.

A timely and correct diagnosis might result in better targeted treatment strategies, adequate patient counseling, and early recognition of disease-specific complications.

We aimed to investigate whether cerebrospinal fluid (CSF) concentrations of alpha-synuclein are of additional diagnostic value. We examined 142 consecutive patients with parkinsonism, mean disease duration 39.7 mo (Parkinson’s disease (PD), n = 58; MSA, n = 47; dementia with Lewy bodies (DLB), n = 3; VaP, n = 22; progressive supranuclear palsy (PSP), n = 10; CBD, n = 2).

Gold standard was the clinical diagnosis established after 2 years of clinical follow-up.

CSF concentrations of alpha-synuclein, blood pigments and the erythrocyte count were determined.

No differences between CSF alpha-synuclein concentrations of patients with PD with the reference values from our laboratory were observed.

We neither found significant differences between patients with PD and AP nor between AP subgroups. Adjustment for age, disease severity or presence of erythrocytes or blood pigments in CSF did not alter these results.

Our results imply that CSF alpha-synuclein is currently unsuitable as biomarker to differentiate between PD and AP.

Copyright 2011 Elsevier Inc. All rights reserved.

PubMed ID#: 21236518 (see for abstract only)

“Applause sign” may be due to frontal lobe impairment

PSP and CBD folks –

This is further evidence that the “applause sign” is not a very useful tool when diagnosing PSP or, by inference, CBD. This research shows that the applause sign can occur in FTD (only the behavioral variant of FTD was included) and AD. (Previously others have argued that it is unique to PSP. More recently, researchers have argued that it is specific to parkinsonian disorders.)

Here’s a description of the applause sign from the article: “The applause sign was detected using the three clap test which was administered and scored according to the literature: subjects were asked ‘to clap three times as quickly as possible after demonstration of the examiner’. The subject’s performance was considered normal when he/she clapped three times (score=3), abnormal when the subject clapped more than three times (2=four times, 1=five to ten times; 0= more than 10 times).”

“An abnormal applause sign was present in all patient groups (80% in PSP, 70% in FTD and 31% in AD) while it was absent in normal controls. …[P]oor specificity and low positive predictive value of the applause sign should raise questions about its diagnostic usefulness.”


Journal of Neurology, Neurosurgery and Psychiatry. 2011 Jan 18. [Epub ahead of print]

Applause sign: is it really specific for Parkinsonian disorders? Evidence from cortical dementias.

Luzzi S, Fabi K, Pesallaccia M, Silvestrini M, Provinciali L.
Department of Neuroscience, Polytechnic University of Marche, Ancona, Italy.


The applause sign, originally reported as a specific sign of progressive supranuclear palsy (PSP), has recently been found in several parkinsonian disorders. Its nature is still uncertain. It has been interpreted as a motor perseveration or a form of apraxia.

The present study aims to: (a) verify the specificity of the applause sign for parkinsonian disorders, examining the presence of the applause sign in cortical dementias which should be error free and (b) clarify the nature of the applause sign (resulting or not from apraxia).

77 subjects were included: 10 PSP, 15 frontotemporal dementia (FTD), 29 Alzheimer’s disease (AD) and 23 normal
controls. The presence of apraxia was an exclusion criterion. All patients underwent a detailed neuropsychological examination, and cognitive performance was correlated to the applause sign.

All patient groups showed the applause sign and differed significantly from normal subjects who were error free.

No difference was found when comparing PSP with FTD and FTD with AD.

AD differed significantly from PSP but they were not error free (31% of patients with AD showed the applause sign).

The only correlation with background neuropsychology was found for measures of executive functions.

The presence of the applause sign in cortical dementia does not confirm the specificity of the applause sign for parkinsonian disorders. The applause sign should be interpreted as a sign of frontal lobe dysfunction rather than a form of apraxia, and can likely be detected in any kind of disease which involves frontal lobe structures to some extent.

Pub Med ID#: 21245475 (see for this abstract only)

Patterns of brain atrophy – PSP, MSA, PD

This paper from Italian researchers addresses the amount of atrophy in various regions of the brain in those with clinical diagnoses of Parkinson’s Disease (PD), PSP, and MSA. I *think* standard MRIs were given and the volumetric analysis is done by software.

Researchers concluded: “Volumetric data obtained with automated segmentation of cerebral regions show a significant atrophy of different brain structures in parkinsonisms rather than in PD. Our study also demonstrates that the atrophy of the thalamus only occurs in PSP while the enlargement of the whole ventricular system characterizes both PSP and MSA-P.”


Parkinsonism and Related Disorders. 2011 Jan 12. [Epub ahead of print]

Patterns of brain atrophy in Parkinson’s disease, progressive supranuclear palsy and multiple system atrophy.

Messina D, Cerasa A, Condino F, Arabia G, Novellino F, Nicoletti G, Salsone M, Morelli M, Lanza PL, Quattrone A.
Institute of Neurological Sciences, National Research Council, Piano-Lago, Mangone, Italy; Institute of Neurology, University “Magna Graecia”, Germaneto, Catanzaro, Italy.

BACKGROUND AND PURPOSE: Quantitative analysis of brain atrophy may be useful in differentiating Parkinson’s Disease (PD) from Progressive Supranuclear Palsy (PSP) and parkinsonian variant of Multiple System Atrophy (MSA-P); the aim of this study was to identify the volumetric differences of subcortical structures in patients with PD, PSP and MSA-P using a novel and validated fully-automated whole brain segmentation method.

METHODS: Volumetric MRIs were obtained in 72 patients with PD, 32 patients with PSP, 15 patients with MSA-P, and in 46 control subjects. Subcortical volume was measured automatically by FreeSurfer. Multivariate analysis of covariance, adjusted for intracranial volume (ICV), sex and age, was used to explore group differences.

RESULTS: No volumetric differences were found between PD and controls group; otherwise the volumes of the cerebellum, the thalamus, the putamen, the pallidum, the hippocampus, and the brainstem were significantly reduced in PSP and MSA-P compared to patients with PD and control subjects. PSP and MSA-P patients only differed in thalamus volume which was smaller in PSP group (p < 0.001). Moreover, patients with PSP and MSA-P showed a ventricular system (including lateral, third and fourth ventricles) larger than that detected in PD and controls (p < 0.001).

CONCLUSIONS: Volumetric data obtained with automated segmentation of cerebral regions show a significant atrophy of different brain structures in parkinsonisms rather than in PD. Our study also demonstrates that the atrophy of the thalamus only occurs in PSP while the enlargement of the whole ventricular system characterizes both PSP and MSA-P.

Copyright 2010 Elsevier Ltd. All rights reserved.

PubMed ID#: 21236720 (see for this abstract only)