Probable Corticobasal Degeneration Research Articles

“Probable 4R‐tauopathy” criteria in a Corticobasal Syndrome cohort: diagnostic accuracy, clinical, metabolic and volumetric patterns in a multimodal PET/MRI study

AbstractBackgroundCorticobasal syndrome (CBS) is a neurodegenerative disease related to multiple underlying pathologies, including four‐repeat (4R) tauopathies, namely corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), among others. The Movement Disorders Society‐PSP clinical criteria proposed a diagnostic category “probable 4R‐tauopathy” to include the phenotypic overlap between PSP and CBD. These criteria were specific for 4R‐tauopathies in a previous post‐mortem validation study. We aimed to investigate this proposed criteria in a cohort of patients clinically diagnosed with probable CBS, comparing the CBS‐4R tau group regarding neurological assessment, brain atrophy patterns, functional and disease‐specific imaging biomarkers. Also, we compared this group with CBS patients that matched the clinical research (cr) criteria for CBD.MethodThirty‐two patients diagnosed with probable CBS were prospectively enrolled and clinically evaluated. They were split into those who fulfilled criteria for probable 4R‐tauopathy (CBS‐4RT = 12) and probable CBD (CBS‐CBD = 28). They underwent [18F]fluorodeoxyglucose‐positron emission tomography (FDG‐PET) and [11C]Pittsburgh Compound‐B (PIB‐PET) on a hybrid PET‐MRI to assess their amyloid status. PIB‐PET images were classified individually based on visual and 3D‐SSP semi‐quantitative analysis. Quantitative group analyses were performed with SPM12, to check both brain atrophy patterns using voxel‐based morphometry (VBM), and regional brain hypometabolism patterns with FDG‐PET. A healthy control group of 30 subjects, matched by age and education, was also included.ResultOnly one patient classified as CBS‐4RT was positive at PIB‐PET (p = 0.010), compared to 12 among 28 CBS‐CBD subjects (p = 0.458). The CBS‐4RT clinical classification had 52.6% sensitivity, 92.3% specificity, and 68.7% accuracy in predicting a negative PIB‐PET result. Also, CBS‐4RT patients presented dysarthria (p = 0.017) and motor perseveration (p = 0.032) more often than the whole group. CBS‐4RT patients showed asymmetric hypometabolism in the inferior, middle, and superior frontal gyri, supplementary motor area, and caudate compared to controls. They also demonstrated brain atrophy in the superior and inferior frontal gyri and basal ganglia.ConclusionThe new proposed clinical 4R‐tauopathies criteria demonstrated high specificity to detect amyloid‐negative CBS patients. Patients fulfilling the criteria presented specific metabolic and volumetric patterns. Moreover, they presented clinical characteristics such as dysarthria and motor perseveration previously related to tauopathies.

Improving the early diagnosis of corticobasal syndrome: a large clinico-pathological study

BackgroundCorticobasal syndrome is associated with a heterogeneous spectrum of pathologies, with low predictive value for Corticobasal degeneration (CBD) pathology. Here, we validate the Armstrong criteria and interrogate clinical features to improve accurate diagnosis ante-mortem.MethodsWe applied Armstrong criteria to all archived cases with a clinical diagnosis of CBS or CBS- overlap syndrome over disease course. Clinical and radiological features were compared by pathologi- cal substrate.Results105 of 123 patients met diagnostic criteria for either Probable or Possible CBS/CBD of whom 38 (36%) had CBD and 79 (75%) had 4-repeat tauopathies (4RT). 3 years from onset, 8/22(36%) of those with Probable CBD and 19/48(40%) Possible CBD had pathology-confirmed CBD, whilst 11/35 (31%) were ‘Armstrong-negative”. Over disease course, PPV for CBD was similar (36%). Criteria were better at predicting 4RT, 82% and 75% within 3 years of onset and over disease course, respectively. Addition of specific language or behavioural abnormalities did not improve PPV. 46% patients met MDS PSP/CBS criteria over disease course, with 92% PPV for 4RT. No individual clinical feature was found to singularly predict underlying pathology.ConclusionThe Armstrong criteria have low predictive value for CBD both in early disease and over disease course. However, it has >80% prediction of 4RT. A combination of more specific biomarkers are required to improve diagnosis.d.lux@ucl.ac.uk

The Non-motor Symptoms, Disability Progression, and Survival Analysis of Atypical Parkinsonism: Case Series from Eastern India and Brief Review of Literature

Objective The objectives of this study are (1) to describe the non-motor profile, the motor disability progression, and survival analysis of atypical parkinsonism in a tertiary care hospital of eastern India and (2) to elucidate the neurocircuitry and the putative substrates responsible for non-motor manifestations. Methods In this prospective observational study, patients were diagnosed based on Consensus Criteria for Progressive Supranuclear Palsy (PSP), The Fourth Consensus Report of the Dementia with Lewy Body (DLBD) Consortium 2017, The Autonomic Neuroscience 2018 Criteria for Multiple System Atrophy (MSA), and Armstrong 2013 Criteria for Corticobasal Degeneration (CBD). Disease severity was assessed at baseline and 6 months of follow-up using the Unified Parkinson's Disease Rating Scales (UPDRS). For PSP and MSA, the PSP-Clinical Deficits Scale (PSP-CDS) and the Unified MSA Rating Scale (UMSARS), respectively, were used. Cox regression analysis and the hazard ratio were calculated. Results Out of 27 patients, the diagnosis was probable PSP in 12, probable MSA in 7, probable CBD in 5, and probable DLBD in 3. Non-motor symptoms were highly prevalent across all subtypes. Motor disability progression as assessed by UPDRS parts 2 and 3 showed significant deterioration over 6-month follow-up across all groups ( p < 0.05). Disease progression assessed by PSP-CDS and UMSARS over 6 months was significant ( p < 0.05). One PSP and two MSA patients died during a 6-month follow-up period. The hazard ratio in MSA was 3.5 (95% confidence interval: 0.31–0.38) with p = 0.306. Conclusion Atypical parkinsonian disorders are rare, and usually more severe than idiopathic parkinsonism. As no definitive treatment is available, symptomatic management involving a multidisciplinary team approach must be prioritized.

Cerebrospinal fluid biomarker profiling in corticobasal degeneration: Application of the AT(N) and other classification systems

IntroductionTotal tau (τT), phosphorylated tau (τP-181) and amyloid beta (Aβ42) are cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). There is no consensus on the interpretation criteria of these biomarkers. The aim of this study was to apply three different sets of criteria for CSF AD biomarker interpretation in a cohort of corticobasal degeneration (CBD) patients. MethodSForty patients fulfilling diagnostic criteria for “probable CBD” were included. The AT(N), BIOMARKAPD/ABSI and the τP-181/Aβ42 ratio criteria were applied. ResultsThe AT(N) criteria categorized 50% of “probable CBD” patients as AD, and 62.5% as harboring amyloid pathology. The BIOMARKAPD/ABSI and τP- 181/Aβ42 criteria categorized ~40% of “probable CBD” patients as AD. DiscussionUse of different interpretation criteria for CSF AD biomarkers produces diverse results. AD pathology is common in patients fulfilling “probable” CBD criteria. CBD diagnostic criteria may have suboptimal positive predictive value. A consensus regarding interpretation criteria of CSF AD biomarkers is pivotal.

Grand Total EEG Score Can Differentiate Parkinson's Disease From Parkinson-Related Disorders.

Background: Semi-quantitative electroencephalogram (EEG) analysis is easy to perform and has been used to differentiate dementias, as well as idiopathic and vascular Parkinson's disease.Purpose: To study whether a semi-quantitative EEG analysis can aid in distinguishing idiopathic Parkinson's disease (IPD) from atypical parkinsonian disorders (APDs), and furthermore, whether it can help to distinguish between APDs.Materials and Methods: A comprehensive retrospective review of charts was performed to include patients with parkinsonian disorders who had at least one EEG recording available. A modified grand total EEG (GTE) score evaluating the posterior background activity, and diffuse and focal slow wave activities was used in further analyses.Results: We analyzed data from 76 patients with a final diagnosis of either IPD, probable corticobasal degeneration (CBD), multiple system atrophy (MSA), or progressive supra-nuclear palsy (PSP). IPD patients had the lowest mean GTE score, followed those with CBD or MSA, while PSP patients scored the highest. However, none of these differences were statistically significant. A GTE score of ≤9 distinguished IPD patients from those with APD (p < 0.01) with a sensitivity of 100% and a specificity of 33.3%.Conclusion: The modified GTE score can distinguish patients with IPD from those with CBD, PSP or MSA at a cut-off score of 9 with excellent sensitivity but poor specificity. However, this score is not able to distinguish a particular form of APD from other forms of the disorder.

Diagnoses of corticobasal syndrome and corticobasal degeneration

Experts use the term corticobasal syndrome (CBS) for patients with a clinical diagnosis of corticobasal degeneration (CBD), and reserve CBD for those whose conditions have been diagnosed on the basis of neuropathological analyses. Several studies demonstrated that patients with CBD may also present with progressive supranuclear syndrome (PSPS), aphasia, Alzheimer disease-like dementia or behavioral change, suggesting that CBS is merely one of the presenting phenotypes of CBD. Although previous CBD diagnostic criteria reflected only CBS, the international consortium proposed new diagnostic criteria for CBD in 2013 (Armstrong's criteria). The new criteria include 4 CBD subtypes; CBS, frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA)，and PSPS. These subtypes were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD (cr-CBD) and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies (p-CBD). Two studies have already revealed that the sensitivity and specificity of the criteria were not high. Because therapeutic interventions that target abnormally-phosphorylated tau have started, further refinement of the criteria is needed via biomarker researches with prospective study designs.

Criteria for the diagnosis of corticobasal degeneration

Corticobasal degeneration (CBD) is a distinct neurodegenerative disorder characterized by widespread neuronal and glial accumulation of abnormally phosphorylated tau protein. Patients with CBD often present with corticobasal syndrome (CBS) showing impairment of the motor system, cognition, or both. Several studies demonstrate that they may also present with progressive supranuclear palsy syndrome (PSPS), aphasia, Alzheimer disease-like dementia, or behavioral changes, suggesting that CBS is merely one of the presenting phenotypes of CBD. Accurate diagnosis is important for future clinical trials using drugs aimed at modifying the underlying tau pathology. Although previous CBD diagnostic criteria reflected only CBS, Armstrong et al. proposed new diagnostic criteria for CBD in 2013 (Armstrong's criteria). The new criteria include 4 CBD phenotypes, including CBS, frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and PSPS. These phenotypes were combined to create 2 sets of criteria: specific clinical research criteria for probable CBD (cr-CBD) and broader criteria for possible CBD that are more inclusive but have a higher probability of detecting other tau-based pathologies (p-CBD). However, two recent studies revealed that the sensitivity and specificity of these criteria were insufficient. Further refinement of the criteria is needed via biomarker research with prospective study designs. (Received August 19, 2014; Accepted December 26, 2014: Published April 1, 2015).

A disease-specific metabolic brain network associated with corticobasal degeneration

Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes.

Suppression of myoclonus in corticobasal degeneration by levetiracetam.

Myoclonus in corticobasal degeneration (CBD) has often been associated with severe and difficult to treat disabilities. Levetiracetam is a new antiepileptic agent with antimyoclonic effects. Herein, we present a 72-year-old woman with clinically probable CBD and with spontaneous rhythmic myoclonus in the right foot, which was markedly ameliorated through treatment with levetiracetam. The effect of levetiracetam was associated with the decreased amplitude of enlarged cortical somatosensory evoked potentials. This result suggests that the antimyoclonic effect of levetiracetam might be mediated through the suppression of increased cortical excitability.

Pathology and sensitivity of current clinical criteria in corticobasal syndrome

The aim of this study was to investigate corticobasal syndrome with respect to underlying pathologies, the ability of current clinical criteria to detect early stages of disease, and symptoms and signs predicting background pathologies. We retrospectively analyzed the clinicopathological findings from patients with corticobasal syndrome. We also analyzed whether those findings fulfilled the diagnostic criteria for corticobasal degeneration (CBD). Finally, we investigated characteristic clinical features that are specific to each background pathology. Of 10 consecutive autopsied patients who had corticobasal syndrome (mean age ± standard deviation, 67.9 ± 9.3 years; male:female ratio, 6:4), three had corticobasal degeneration pathology, three had progressive supranuclear palsy, three had Alzheimer's disease, and one had atypical four-repeat tauopathy. Nine patients fulfilled Mayo criteria, and all 10 patients fulfilled modified Cambridge criteria at the later stage, but only two patients fulfilled either clinical criteria within 2 years of disease onset. Five patients fulfilled the clinical criteria for possible CBD (p-CBD), and one patient fulfilled the clinical research criteria for probable sporadic CBD (cr-CBD) at the later stage. Only two patients fulfilled the criteria for either p-CBD or cr-CBD within 2 years of disease onset. Although we could not find any predictive characteristic clinical features that were specific to CBD pathology, only patients with progressive supranuclear palsy developed apraxia of eyelid opening and cerebellar ataxia. Myoclonus and memory impairment, especially if they appear at an early stage of the disease, may predict Alzheimer's disease pathology. Sensitivity of the available clinical criteria for corticobasal syndrome was poor within 2 years of disease onset.

Normal dopamine transporter SPECT in neuropathologically confirmed corticobasal degeneration

The role of dopamine transporter imaging in the diagnosis of corticobasal syndrome (CBS) is unclear. In the largest clinical study so far, Cilia et al. [1] presented data from 36 patients with clinically probable corticobasal degeneration (CBD) with [I]FP-CIT (CIT-SPECT) and compared the results to patients with Parkinson’s disease and healthy controls. Their results showed high variability in dopamine transporter binding, and four of the clinically probable CBD patients had normal scans. As the authors acknowledged, the interpretation of the findings was limited by the lack of pathological confirmation of the diagnoses. There is one previously reported patient with ante mortem CIT-SPECT and post mortem confirmation of CBD diagnosis. O’Sullivan et al. [2] reported a 65-year-old woman who had typical symptoms and a clinical diagnosis of CBD together with normal CIT-SPECT 4 years after clinical onset. Here we report a 70-year-old woman, who was referred to a neurologist in 2006 due to symptoms in her left upper extremity that had started 6 months earlier. She complained that her left arm was making ‘‘strange movements’’ and she was not always aware of where her left arm was. The family history was unremarkable. A 1.5 T MRI scan of the brain in 2006 did not show clinically significant findings. Clinical examination showed bilateral apraxia and mild rigidity in the upper extremities, her left arm moved constantly during examination and there was left-sided dysdiadochokinesia. The patient also had mild hypokinesia and walking slowness. A diagnosis of CBS was suspected. CIT-SPECT was performed approximately 9 months after symptom onset and the striatal binding was visually estimated as normal although a retrospective semi-automated analysis (BRASS, Hermes Medical Solutions, Stockholm, Sweden) showed some asymmetry (Fig. 1a). Two years later the disease had clearly progressed: the patient was unable to walk without help, her left arm was now rigid without involuntary movements, and the right arm was constantly moving during examination. There was flexion contracture in the left hand, general hypokinesia and clear hypomimia and rigidity. Levodopa treatment was initiated at a dose of 300 mg/day. This dose did not have significant effects on clinical symptoms, and the patient died 7 months later before dose increases were possible. At autopsy, acute bronchopneumonia was found to be the immediate cause of death. In the neuropathological examination, the macroscopic findings included cerebral atrophy (brain weight 1,240 g), with the most atrophic gyri present in the frontal lobes. There was pallor of the substantia nigra and locus coeruleus. Microscopic examination showed widespread pathology of the cortex. This included neuronal loss, mild vacuolation and ballooned achromatic neurons. Additionally, astrocytic plaques were present (Fig. 1b). In the substantia nigra, there was a loss of pigmented neurons, and V. Kaasinen (&) M. Paivarinta Division of Clinical Neurosciences, Department of Neurology, University of Turku and Turku University Hospital, POB 52, 20521 Turku, Finland e-mail: valtteri.kaasinen@tyks.fi

Progressive crossed-apraxia of speech as a first manifestation of a probable corticobasal degeneration.

We present the longitudinal neurolinguistic, neuropsychological and neurologic follow-up of a 64 y.o. right-handed woman, who developed progressive apraxia of speech (PAOS), followed by peripheral agraphia then a left corticobasal syndrome (CBS). Neuroimaging (CT, MRI and FDG-PET) unequivocally showed progressive right hemispheric atrophy and hypometabolism. This particular evolution first confirms that PAOS is a phenotype of probable corticobasal degeneration (CBD). More importantly, this case underpins the neural organisation of motor planning processing in relation with speech, as well as graphic and limb praxis impairments, and constitutes a rare example of crossed-PAOS.

Progressive Crossed-Apraxia of Speech as a First Manifestation of a Probable Corticobasal Degeneration

We present the longitudinal neurolinguistic, neuropsychological and neurologic follow-up of a 64 y.o. right-handed woman, who developed progressive apraxia of speech (PAOS), followed by peripheral agraphia then a left corticobasal syndrome (CBS). Neuroimaging (CT, MRI and FDG-PET) unequivocally showed progressive right hemispheric atrophy and hypometabolism. This particular evolution first confirms that PAOS is a phenotype of probable corticobasal degeneration (CBD). More importantly, this case underpins the neural organisation of motor planning processing in relation with speech, as well as graphic and limb praxis impairments, and constitutes a rare example of crossed-PAOS.

Dopamine Transporter SPECT Imaging in Corticobasal Syndrome.

ObjectiveTo investigate dopaminergic function in a large cohort of patients with corticobasal syndrome (CBS) and describe its relationship with clinical features in comparison to Parkinson's disease and healthy control subjects. In addition, we assessed prevalence and features of individuals with CBS and in vivo evidence of preserved nigral neuronal density.BackgroundSubstantia nigra pars compacta (SNc) neuronal degeneration is a mandatory pathological criterion for definite corticobasal degeneration, though sporadic autopsy-proven cases with ante-mortem imaging evidence of preserved nigral terminals have been recently described.MethodsIn this multicenter study, we investigated presynaptic nigrostriatal function in 36 outpatients fulfilling clinical criteria for “probable corticobasal degeneration” (age 71±7.3 years; disease duration 3.9±1.6 years), 37 PD and 24 healthy control subjects using FP-CIT single photon emission computed tomography. Clinical, neuropsychological, and magnetic resonance imaging assessment was performed to characterize CBS patients. Linear discriminant analysis was used to categorize normal vs. pathological scans.ResultsFP-CIT binding reduction in patients with CBS was characterized by larger variability, more uniform reduction throughout the striatum and greater hemispheric asymmetry compared to PD. Moreover, there was no significant correlation between tracer uptake values and clinical features such as disease duration and severity. Despite all CBS subjects showed obvious bilateral extrapyramidal signs, FP-CIT uptake was found to be normal bilaterally in four CBS patients and only unilaterally in other four cases. Extensive clinical, neuropsychological and imaging assessment did not reveal remarkable differences between CBS subjects with normal vs. pathological FP-CIT uptake.ConclusionsOur findings support the hypothesis that extrapyramidal motor symptoms in CBS are not invariably associated with SNc neuronal degeneration and that supranigral factors may play a major role in several cases. CBS individuals with normal FP-CIT uptake do not show any clinical or cognitive feature suggesting a different pathology than CBD.

Diffusion Tensor Imaging Shows Different Topographic Involvement of the Thalamus in Progressive Supranuclear Palsy and Corticobasal Degeneration

In progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), postmortem studies show different topographic involvement of the thalamus, basal ganglia, and their cortical connections. Diffusion tensor imaging (DTI) is an MR imaging technique sensitive to gray and white matter microstructure integrity. This study was performed to determine whether DTI may demonstrate microstructural differences between PSP and CBD, particularly within the thalamus and its cortical connections. Nine patients with probable PSP, 11 with probable CBD, and 7 controls formed the study group. Apparent diffusion coefficient average (ADC(ave)) and fractional anisotropy (FA) values were measured in regions of interest positioned in the ventrolateral (motor), medial, anterior, and posterior regions of the thalami, basal ganglia, fronto-orbital white matter, cingulum, supplementary motor area (SMA), and precentral and postcentral gyri in patients and controls. In PSP, ADC(ave) values were increased in several areas: the thalamus, particularly in its anterior and medial nuclei; cingulum; motor area; and SMA. FA values were particularly decreased in the fronto-orbital white matter, anterior cingulum, and motor area. In CBD, ADC(ave) was increased in the motor thalamus, in the precentral and postcentral gyri, ipsilateral to the affected frontoparietal cortex, and in the bilateral SMA. FA was mainly decreased in the precentral gyrus and SMA, followed by the postcentral gyrus and cingulum. In patients with PSP, thalamic involvement was diffuse and prevalent in its anterior part, whereas in CBD involvement was asymmetric and confined to the motor thalamus. DTI may be useful in the differential diagnosis of these 2 parkinsonian disorders.

Corticobasal degeneration and Parkinson's disease assessed by HmPaO SPECT: The utility of factorial discriminant analysis

The diagnosis of corticobasal degeneration (CBD) is difficult despite the existence of some typical clinical features. Single photon emission computerized tomography (SPECT) in CBD presents an original pattern (with asymmetric hypoperfusion in pre- and retrorolandic regions) that could facilitate the differential diagnosis of CBD relative to the other degenerative parkinsonian syndromes. The objective of our study was to compare the regional cerebral blood flow measurements studied by SPECT in both CBD and Parkinson's disease (PD) using a multivariate procedure. Twenty-one patients with probable CBD and 20 patients with probable PD underwent brain (99m)Tc HmPaO SPECT. We used factorial discriminant analysis (FDA) to study the relative fixation of 26 regions of interest (ROIs) drawn on two transverse slices, together with the asymmetry indexes of 13 pairs of ROIs. FDA performed using the full set of parameters classified all the patients correctly. In order to classify the patients more easily, a predictive score using a selection of parameters was established. The most discriminating ROIs were the temporoinsular, temporoparietal, and frontal medial regions. We believe that this semiautomatic classification may be a precious tool for reinforcing the current clinical differential diagnosis of CBD and PD.

Limb apraxia in corticobasal degeneration and progressive supranuclear palsy

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) share pathologic features, and cortical and subcortical signs. Apraxia is frequently described in CBD and sometimes in PSP; however, it is difficult to distinguish ideomotor from limb-kinetic apraxia, and apraxia frequency is unclear. The authors set out to clarify the nature and frequency of apraxia in these diseases. The authors compared probable CBD and PSP patients, matched for motor disability, to healthy age-matched controls on cognitive tests and the De Renzi ideomotor apraxia test. Cognitive impairment was similar, but more CBD (70.8%) than PSP (36%) patients had apraxia. CBD patients committed more apraxic errors of awkwardness and were more compromised on simple gestures; PSP patients committed more sequence errors. While progressive supranuclear palsy (PSP) patients had ideomotor apraxia, the peculiar gesture compromise in corticobasal degeneration (CBD) suggests that limb-kinetic apraxia is dominant. In both illnesses, the movement production system of Roy and Square appears compromised: in CBD defective control of muscle activation seems likely, producing clumsy movements; in PSP, control of motor program activation appears defective, resulting in sequence errors and perseverations. The De Renzi test can reliably estimate apraxia frequency and may be used to distinguish limb-kinetic from ideomotor apraxia.

Imaging early-stage corticobasal degeneration with [99mTc]TRODAT-1 SPET.

The aim of this study was to investigate the nigrostriatal dopaminergic function in patients with corticobasal degeneration (CBD) using [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2']oxo-[1R-(exo-exo)]-[99mTc]technetium ([99mTc]TRODAT-1) brain single-photon emission tomography (SPET). Five patients with probable CBD, 10 age- and duration-matched patients with idiopathic Parkinson's disease (IPD) and 10 age-matched healthy volunteers completed the SPET study. The images were obtained 4 h after intravenous injection of 925 MBq of [99mTc]TRODAT-1. Using a magnetic resonance imaging atlas of the striatum, the ratios of specific striatal binding to non-specific occipital binding were calculated. Clinical analysis showed that the CBD patients obtained significantly higher scores on the Unified Parkinson's Disease Rating Scale and a significantly worse score for activities of daily living. In the CBD and IPD groups, striatum-occipital/occipital, caudate nucleus-occipital/occipital and putamen-occipital/occipital ratios decreased significantly relative to those of healthy subjects. No statistical difference could be found between the CBD and IPD groups for these ratios, although relatively even, decreased uptakes in the caudate nucleus and putamen were found in the CBD group. On further analysis of the index of binding reduction, the differences between the caudate nucleus and putamen were significantly lower in the CBD group than in the IPD group. The striatal uptake of [99mTc]TRODAT-1 showed a distinct asymmetry in both the CBD and IPD patients. From this study, it can be concluded that early-stage CBD patients have a worse performance and more difficulties with daily activities than IPD patients. CBD patients demonstrated essentially similar patterns of [99mTc]TRODAT-1 binding as those with IPD. However, there was relatively more homogeneous involvement of the caudate nucleus and putamen in the CBD patients. This provides information about the differences between these patients in the early stages.

神経変性疾患（パーキンソン症候群を中心に）

Among the diseases causing parkinsonism, drug-induced parkinsonism is important because physicians often use anti-dopaminergic drugs such as benzamides for gastrointestinal disorders. In 28 patients with drug-induced parkinsonism, 13 (47%) showed persistent parkinsonism even 6 months after the cessation of the causative drugs. This means anti-dopaminergic drugs may bring subclinical parkinsonism to the clinical level especially in the elderly. Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy including striatonigral degeneration were recognized in 2003 as specific diseases by the National Health Insurance of Japan. The diagnostic criteria of PSP (the modification of NINDS-SPSP criteria) made by the study group of the Ministry of Health, Welfare and Labour (MHWL) of Japan has demonstrated that their sensitivity was 83% and specificity 97% in "probable PSP". Patients with CBD were surveyed among the main neurologic institutions in Japan using the provisional diagnostic criteria There were 151 patients with "probable CBD" and 13 with "definite CBD". Based on these data, the number of patients with PSP and CBD in 2001 was estimated as 6,400 (5.03 per 100,000) and 2,500 (1.93 per 100,000), respectively, in Japan. Neuroprotective drugs hold hope for the treatment of neurodegenerative diseases. Although many agents were reported to be neuroprotective for Parkinson's disease from in vitro studies, pramipexole, a dopamine agonist, is the only one with good clinical evidence based on neuroimaging. Other dopamine agonists as well as various nerve trophic factors may also have the same effects, though further confirmatory studies are necessary.

Magnetic resonance imaging-based volumetry differentiates progressive supranuclear palsy from corticobasal degeneration

Because there are no biological markers for the clinical diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), we established a mathematical model based on three-dimensional magnetic resonance (MR) imaging to differentiate between these parkinsonian disorders. Using MR imaging-based volumetry we studied the pattern of atrophic changes in patients with probable, possible or definite PSP ( n = 33) or CBD ( n = 18). Patients were compared with 22 controls with similar age. To establish a mathematical model that would allow for differentiation of PSP, CBD and controls we performed a discriminant analysis. We found a significant reduction in average brain, brainstem, midbrain and frontal gray matter volumes in patients with PSP, whereas patients with CBD showed atrophy of parietal cortex and corpus callosum. With the exception of reduced midbrain volumes in PSP, the measured volumes of anatomical structures showed an extensive overlap with the normal range on an individual basis. Using only post mortem confirmed cases of PSP ( n = 8) and CBD ( n = 7) as well as all controls, the volumes of midbrain, parietal white matter, temporal gray matter, brainstem, frontal white matter and pons were identified to separate best between groups and were used to construct a model with two canonical variables. This model allowed to correctly predict the diagnosis in 95% of controls as well as in 76% of all PSP and 83% of all CBD patients. Similar results were obtained only when patients with a possible and probable diagnosis of PSP and CBD, who were not involved in the development of the discriminant analysis, were classified. 3D-MR imaging-based volumetry may help to differentiate PSP from CBD ante mortem.