Corticobasal Degeneration Cases Research Articles

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

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.

Acalculia in Autopsy-Proven Corticobasal Degeneration

Corticobasal degeneration (CBD) is a neurodegenerative condition presenting with an asymmetric extrapyramidal disorder, cortical sensory loss, and apraxia. While the original case descriptions mentioned acalculia,1 few studies have investigated this,2,3 and reports of acalculia in autopsy-proven CBD are very rare. We detail 2 autopsy-defined CBD cases with acalculia to emphasize that CBD compromises cognitive functioning due to disease that includes parietal cortex. ### Case 1. A 72-year-old right-handed woman with hypertension and hypothyroidism was evaluated for progressive cognitive and motor difficulties over 3 years. She first noted writing difficulty. Her right hand began performing involuntary, semi-purposeful movements. She required increasing assistance dressing and cutting food. She misjudged spatial relationships while driving and cooking. She had several falls. Examination revealed Mini-Mental State Examination (MMSE) score of 27. She had ideomotor apraxia, slowed writing, and difficulty copying geometric designs. Number knowledge was impaired, including miscounting “X” marks on a paper and erring during oral and written calculations (e.g., given “9 + 12,” she responded “20”). Memory, digit span, reading, comprehension, and speech were intact. She had axial rigidity and decreased right arm swing, but no other involuntary movements. Neuropsychological evaluation ( z scores relative to 25 demographically matched controls) revealed deficits on spatial tasks (e.g., geometric figure copy z = −7.74), mild executive dysfunction (e.g., animal category naming fluency z = −1.90), and preserved language (e.g., Boston Naming test z = −0.86) and memory (delayed recall of a 10-word list z = 0.02). MRI showed parietal atrophy. Over the next 18 months, ideomotor apraxia worsened, and she …

Corticobasal syndrome: a field of uncertainty

Over the last 20 years the nomenclature, the different clinical and neuropathological subtypes and thus the classification of corticobasal syndrome have changed considerably. The clinical diagnosis of corticobasal syndrome and its different subtypes is still difficult with low predictive values when the pathological diagnosis as the gold standard is applied. This is the major handicap in the field of corticobasal syndrome for all clinical MRI, functional MRI and PET studies as well as treatment trials (all the latter had been negative). Further, there is no general agreement on the nomenclature and the subtypes of corticobasal syndrome. Clinically, it is characterised by a slow onset and progressive asymmetric cortical and extrapyramidal dysfunction. The different subtypes of corticobasal syndrome (CBS) can be classified based on different pathologies as follows: corticobasal degeneration (CBS–CBD), progressive supranuclear palsy (CBS–PSP), Alzheimer’s disease (CBS–AD) and frontotemporal lobe degeneration (FTLD) with ubiquitin-only immunoreactive inclusions mainly showing immunoreactivity to the TAR DNA-binding protein of 43 kDa (CBS–TDP) (for references see Whitwell et al. 2010). This month’s Journal Club will focus on three recently published articles on corticobasal syndrome. In the first, a very carefully performed clinicopathological re-evaluation, all the archival cases in the Queen Square Brain Bank over a 20-year period with either the clinical diagnosis of corticobasal syndrome or the pathological diagnosis of corticobasal degeneration were re-evaluated. It is important to note that the sensitivity and the predictive positive value were remarkably low even in this highly qualified centre. This is something one should always bear in mind in any study on non-pathologically proven cases of corticobasal degeneration. In the second study, the patterns of atrophy on imaging were correlated with the histopathological diagnosis and different subtypes of corticobasal syndrome. It is important to note that all cases were proven histopathologically. Therefore, this study is of diagnostic value for the discrimination of the different subtypes of corticobasal syndrome. In the third study, the cholinergic deficits in different areas of the brain were examined in a PET study in patients with corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia. These cases, however, were not autopsy-proven and thus the results must be interpreted with caution.

Does corticobasal degeneration exist? A clinicopathological re-evaluation

The pathological findings of corticobasal degeneration are associated with several distinct clinical syndromes, and the corticobasal syndrome has been linked with a number of diverse pathologies. We have reviewed all the archival cases in the Queen Square Brain Bank for Neurological Disorders over a 20-year period with either a clinical diagnosis of corticobasal syndrome or pathological diagnosis of corticobasal degeneration in an attempt to identify the main diagnostic pitfalls. Of 19 pathologically confirmed corticobasal degeneration cases, only five had been diagnosed correctly in life (sensitivity=26.3%) and four of these had received an alternative earlier diagnosis. All five of these had a unilateral presentation, clumsy useless limb, limb apraxia and myoclonus, four had cortical sensory impairment and focal limb dystonia and three had an alien limb. Eight cases of corticobasal degeneration had been clinically diagnosed as progressive supranuclear palsy, all of whom had vertical supranuclear palsy and seven had falls within the first 2 years. On the other hand, of 21 cases with a clinical diagnosis of corticobasal syndrome, only five had corticobasal degeneration pathology, giving a positive predictive value of 23.8%; six others had progressive supranuclear palsy pathology, five had Alzheimer's disease and the remaining five had other non-tau pathologies. Corticobasal degeneration can present very commonly with a clinical picture closely resembling classical progressive supranuclear palsy or Richardson's syndrome, and we propose the term corticobasal degeneration-Richardson's syndrome for this subgroup. Cases of corticobasal degeneration-Richardson's syndrome have delayed onset of vertical supranuclear gaze palsy (>3 years after onset of first symptom) and the infrequent occurrence of predominant downgaze abnormalities, both of which can be helpful pointers to their underlying corticobasal degeneration pathology. Fourty-two per cent of corticobasal degeneration cases presented clinically with a progressive supranuclear palsy phenotype and 29% of cases with corticobasal syndrome had underlying progressive supranuclear palsy pathology. In contrast, in the Queen Square Brain Bank archival collection, corticobasal syndrome is a rare clinical presentation of progressive supranuclear palsy occurring in only 6 of the 179 pathologically diagnosed progressive supranuclear palsy cases (3%). Despite these diagnostic difficulties we conclude that corticobasal degeneration is a discrete clinicopathological entity but with a broader clinical spectrum than was originally proposed.

Symmetric corticobasal degeneration (S-CBD)

Background Corticobasal degeneration (CBD) is a neurodegenerative disease characterized pathologically by neuronal loss, gliosis and tau deposition in neocortex, basal ganglia and brainstem. Typical clinical presentation is known as corticobasal syndrome (CBS) and involves the core features of progressive asymmetric rigidity and apraxia, accompanied by other signs of cortical and extrapyramidal dysfunction. Asymmetry is also emphasized on neuroimaging. Objective To describe a series of cases of CBD with symmetric clinical features and to compare clinical and imaging features of these symmetric CBD cases (S-CBD) to typical cases of CBS with CBD pathology. Methods All cases of pathologically confirmed CBD from the Mayo Clinic Rochester database were identified. Clinical records were reviewed and quantitative volumetric analysis of symmetric atrophy on head MRI using atlas based parcellation was performed. Subjects were classified as S-CBD if no differences had been observed between right- and left-sided cortical or extrapyramidal signs or symptoms. S-CBD cases were compared to 10 randomly selected typical CBS cases. Results Five cases (2 female) met criteria for S-CBD. None had limb dystonia, myoclonus, apraxia or alien limb phenomena. S-CBD cases had significantly less asymmetric atrophy when compared with CBS cases ( p = 0.009); they were also younger at onset (median 61 versus 66 years, p < 0.05) and death (67 versus 73 years, p < 0.05). Family history was present in 40% of S-CBD cases. Conclusions CBD can have a symmetric presentation, clinically and radiologically, in which typical features of CBS, such as limb apraxia, myoclonus, dystonia and alien limb phenomenon, may be absent.

Glucocerebrosidase mutations p.L444P and p.N370S are not associated with multisystem atrophy, progressive supranuclear palsy and corticobasal degeneration in Polish patients

Recently, mutations in the GBA gene coding for lysosomal beta-glucocerebrosidase have been found as a risk factor for Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) [1–3]. These mutations seem to participate in the formation of Lewy bodies. PD and DLB have been classified as synucleinopathies; the third most common synucleinopathy are multisystem atrophies (MSA), which may share with PD and DLB at least part of the molecular pathogenesis. The incidence of mutations in the GBA gene in PD patients is variable and related to different populations studied, methods of DNA testing (sequencing versus looking for the most common mutations only), and different control groups. Lewy bodies were also found in some patients with tauopathies like Progressive Supranuclear Palsy (PSP) and corticobasal degeneration (CBD) [4–6]. Thus lysosomal dysfunction caused by GBA mutations may alter or disrupt the processing of the alphaor beta-synuclein [4]. To identify mutations in the GBA gene, genomic DNA was extracted from the white blood cells by standard techniques. A screening for mutations, p.L444P and p.N370S was performed in a group of 66 MSA patients (MSA-P = 34) and (MSA-C = 31), 34 PSP patients and in five cases of CBD. The patients were diagnosed at two movement disordered centers according to clinical criteria and the level of diagnosis (possible and probable) is shown in Table 1. PCR-RFLP methods were used as described earlier. Our results were compared to incidence of GBA mutations in other European populations and in PD/DLB patients [1–3]. None of the examined mutations in the GBA gene has been found in our cohort of patients with MSA, PSP and CBD. Although a limited number of our patients, and a less sensitive technique than direct sequencing [7], cannot completely rule out the possibility of increased frequency of p.L444P and p.N370S mutations in the beta-glucocerebrosidase gene (GBA), it seems rather unlikely that the incidence of these particular GBA mutations in MSA and PSP are compatible to their frequency in PD (about 4%) and DLB (from 4 to 23%), as reported in the literature [2, 8]. As yet, a total number of the published patients with MSA tested for GBA mutations are below the level of sensitivity because the incidence of the heterozygote state for the above mutations in European populations, excluding Scandinavia, is about 0.3%. Our results are also in agreement with those of neuropathologically confirmed MSA patients, published recently [9]. These results may indicate that PD and (DLB) have another pathway in formation of Lewy bodies than has MSA [10]. We also didn’t see differences between parkinsonian and cerebellar type of MSA. Moreover, we didn’t identify any GBA mutations in PSP and CBD patients. Z. Jamrozik (&) H. Kwiecinski Department of Neurology, Medical University of Warsaw, Warsaw, Poland e-mail: zjamrozik@amwaw.edu.pl

Degeneration in Different Parkinsonian Syndromes Relates to Astrocyte Type and Astrocyte Protein Expression

The reactive changes in different types of astrocytes were analyzed in parkinsonian syndromes in order to identify common reactions and their relationship to disease severity. Immunohistochemistry was used on formalin-fixed, paraffin-embedded sections from the putamen, pons, and substantia nigra from 13 Parkinson disease (PD), 29 multiple-system atrophy (MSA), 34 progressive supranuclear palsy (PSP), 10 corticobasal degeneration(CBD), and 13 control cases. Classic reactive astrocytes were observed in MSA, PSP, and CBD, but not PD cases; the extent of reactivity correlated with indices of neurodegeneration and disease stage. Approximately 40% to 45% of subcortical astrocytes in PD and PSP accumulated alpha-synuclein and phospho-tau, respectively; subcortical astrocytes in MSA and CBD cases did not accumulate these proteins. Protoplasmic astrocytes were identified from fibrous astrocytes by their expression of parkin coregulated gene and apolipoprotein D, and accumulated abnormal proteins in PD, PSP, and CBD, but not MSA. The increased reactivity of parkin coregulated gene-immunoreactive protoplasmic astrocytes correlated with parkin expression in PSP and CBD. Nonreactive protoplasmic astrocytes were observed in PD and MSA cases; in PD, they accumulated alpha-synuclein, suggesting that the attenuated response might be due to an increase in the level of alpha-synuclein. These heterogeneous astroglial responses in PD, MSA, PSP, and CBD indicate distinct underlying pathogenic mechanisms in each disorder.

Unintentional silver intoxication following self-medication: an unusual case of corticobasal degeneration

Silver toxicity is a rare condition. The most notable feature is a grey-blue discoloration of the skin, argyria, although harmful effects on the liver and kidney may be seen in severe cases. Neurological symptoms are an unusual consequence of silver toxicity. So far no effective treatment has been described for this metal overdose. We report the case of a 75-year-old man who had a history of self-medication with colloidal silver and presented with myoclonic seizures.

Excitatory amino acid transporter 2 associates with phosphorylated tau and is localized in neurofibrillary tangles of tauopathic brains

Phosphorylated tau (p-tau) is the principal component of neurofibrillary tangles, a pathological hallmark, and likely plays a neurotoxic role in tauopathies including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We subjected brains from autopsy cases of AD, PSP, and CBD to a variety of immunohistochemical, immunoblotting, and pull-down assays. In this study, we show that excitatory amino acid transporter 2 (EAAT2) preferentially interacted with phosphorylated tau and was localized in neurofibrillary tangles in the brains of such patients. These results strongly indicate that EAAT2 acts in tauopathy-related neurodegeneration, and abnormalities in glutamate transport play an important role in the pathogenesis of tauopathies. Structured summary MINT- 7148349, MINT- 7148361: TAU (uniprotkb: P10636) physically interacts (MI: 0914) with EAAT2 (uniprotkb: P43004) by pull-down (MI: 0096) MINT- 7148372, MINT- 7148384: TAU (uniprotkb: P10636) physically interacts (MI: 0914) with EAAT2 (uniprotkb: P43004) by anti bait coimmunoprecipitation (MI: 0006)

An association study of common variation at the MAPT locus with late‐onset Alzheimer's disease

The MAPT gene that encodes Tau is located on chromosome 17q21, in a region, which has evolved to form two major haplotypes, H1 and H2. There is strong evidence that the H1 haplotype, and a sub-haplotype (H1C), are overrepresented and associated with increased risk for the sporadic tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Both PSP and CBD cases display Tau pathology similar to Late-Onset Alzheimer's Disease (LOAD). However, numerous association studies investigating the genetic involvement of MAPT in LOAD have generated conflicting results. Here we have used a large LOAD case-control sample to genotype SNPs that have been shown to define H1/H2 status and intra-H1 variability. Single marker association analyses found no evidence that any of the SNPs are associated with risk of LOAD. When gender and APOE4 status were taken into account we observed suggestive association for SNP rs242557 (P = 0.02). Stratification of the sample revealed association with rs242557 only in APOE4 positive individuals (P = 0.01 recessive model), however this result would not survive multiple correction. There was no significant difference in H1/H2 haplotype distribution between cases and controls. We also tested the association of specific sub-haplotypes on the H1 background and likewise results were negative. No effect was observed on disease age of onset for any of the markers studied. In summary, we find no evidence for allelic or haplotypic association, with SNPs in the MAPT gene and LOAD. SNP rs242557 is nominally significant in the APOE4 positive individuals. None of the SNPs studied modified AAO for LOAD.

Role of the Tau Gene Region Chromosome Inversion in Progressive Supranuclear Palsy, Corticobasal Degeneration, and Related Disorders

An inverted region on chromosome 17 has been previously linked to many Pick complex diseases. Due to the inversion, an exact causal locus has been difficult to identify, but the microtubule-associated protein tau gene is a likely candidate gene for its involvement in these diseases with tau inclusion. To search for variants that confer susceptibility to 4 tauopathies and clinically related disorders. Genomewide association study. University research laboratory. A total of 231 samples were genotyped from an unrelated white population of patients with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia, and frontotemporal dementia with amyotrophy. Unaffected individuals from the same population were used as controls. The results from an inverted region of chromosome 17 that contains the MAPT gene. Genotypes of cases and controls were compared using a Fisher exact test on a marker-by-marker basis. Haplotypes were determined by visually inspecting genotypes. Comparing any particular disease and controls, the association was constant across the inverted chromosome segment. Significant associations were seen for PSP and PSP combined with CBD. Of the 2 haplotypes seen in the region, H1 was overrepresented in PSP and CBD cases compared with controls. As expected, the markers are highly correlated and the association is seen across the entire region, which makes it difficult to narrow down a disease-causing variant or even a possible candidate gene. However, considering the pathologic abnormalities of these diseases and the involvement of tau mutations seen in familial forms, the MAPT gene represents the most likely cause driving the association.

Concomitant TAR-DNA-Binding Protein 43 Pathology Is Present in Alzheimer Disease and Corticobasal Degeneration but Not in Other Tauopathies

Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.

Neuropsychiatric Features in 36 Pathologically Confirmed Cases of Corticobasal Degeneration

Neuropsychiatric Features in 36 Pathologically Confirmed Cases of Corticobasal Degeneration

Neuropsychiatric Features in 36 Pathologically Confirmed Cases of Corticobasal Degeneration

The authors investigated neuropsychiatric features in 36 pathologically confirmed cases of corticobasal syndrome. Depression, compulsive behavior, and frontal lobe-type behavioral alterations were noted in eight patients (22%). No patient experienced visual hallucinations. If confirmed by a prospective study, the absence of visual hallucinations may help to distinguish corticobasal syndrome from other parkinsonian syndromes.

Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases?

New findings relating to the clinical, genetic and molecular bases of neurodegenerative disorders have led to a shift away from traditional nomenclatures of clinical syndromes. Historically, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were classified on the basis of distinct clinical and pathological features. In recent years, however, advances in molecular and genetic research have led clinicians to suggest that the similar etiologies of the three disorders warrant their amalgamation into a single disorder with three subtypes. In this Review, we consider the utility and validity of combining FTLD, CBD and PSP. The earliest reports of these disorders demonstrate their distinctiveness, whereas recent findings challenge traditional nomenclatures by showing etiological overlap. For example, tau inclusions have been confirmed in patients with CBD and those with PSP, and in some patients with FTLD, implying that all three disorders are 'tauopathies'. Furthermore, most patients with progressive nonfluent aphasia, a subtype of FTLD, show PSP or CBD post-mortem. Even tau-related cases of FTLD, CBD and PSP are distinguishable on the basis of other criteria, however, and many FTLD cases do not show tau pathology. We argue, therefore, that FTLD, CBD and PSP should be considered as pathologically similar but distinct syndromes. New research criteria for CBD and PSP should note that progressive nonfluent aphasia is often a precursor of these conditions.

Relation of hippocampal phospho-SAPK/JNK granules in Alzheimer’s disease and tauopathies to granulovacuolar degeneration bodies

Protein misfolding is a distinguishing feature of a number of neurodegenerative diseases. Accumulation of misfolded protein often results in cellular lesions, the location of lesions correlating with the nature of symptoms. Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD) and Pick's Disease (PiD) all present with pathological lesions containing hyperphosphorylated filamentous tau protein; however, the location and type of lesion varies. In addition, granulovacuolar degeneration (GVD) bodies have been reported within hippocampal pyramidal neurons in AD, PSP, CBD and PiD tissue. GVDs are defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles. We have previously reported that the phosphorylated form of stress-activated protein kinase/c-Jun N-terminal kinase (p-SAPK/JNK) accumulates in granules within hippocampal pyramidal cell bodies in AD tissue at the time that hyperphosphorylated tau begins to aggregate into early-stage NFTs. We now report that p-SAPK/JNK granules are found within the hippocampal CA1 region of PSP, CBD and PiD cases as well and that these granules are likely GVD bodies. Quantitatively, p-SAPK/JNK granules and GVDs are found in comparable numbers of CA1 cells. Within cells, p-SAPK/JNK granules are distributed throughout the cytoplasm in a manner similar to the distribution of GVDs and a subset of granules co-localize with GVD markers. Ultrastructurally, p-SAPK/JNK granules are located in large cytoplasmic vacuoles, thereby fitting the definition of a GVD body. With the implication of granular p-SAPK/JNK as a marker of GVDs, our study strongly suggests that a heterogeneous group of proteins form GVDs. The mechanism of GVD formation is therefore an interesting one, and is likely separate and distinct from the mechanism of tau inclusion formation.

Clinical and Pathologic Evidence of Corticobasal Degeneration and Progressive Supranuclear Palsy in Familial Tauopathy

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are neurodegenerative tauopathies. Sporadic and familial cases of PSP and CBD have been noted, but both have not been reported in a single family. To describe the clinical, oculomotor, balance, functional imaging, histopathologic, and genetic studies in a family with CBD and PSP. A report of the clinical and pathological features in a familial tauopathy. University of Minnesota. Patients We evaluated 2 siblings and clinically assessed 20 additional family members. Demonstration of salient features in deceased and living family members. Histopathologically confirmed CBD in one sibling and PSP in another deceased sibling were demonstrated; both had clinical features of corticobasal syndrome. In addition, 3 siblings had probable PSP by clinical criteria. Genetic studies of 4 affected family members demonstrated the H1/H1 haplotype but did not reveal pathogenic tau mutations. The family history revealed consanguinity. This is the first report, to our knowledge, of CBD and PSP in 2 individuals in a single family who presented with corticobasal syndrome and had other affected siblings with clinical PSP. Despite clinical and pathologic heterogeneity, a unifying genetic etiology appears likely in this familial tauopathy.

Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or alpha-synuclein. In AD, beta-amyloid (Abeta)-associated caspase activation and cleavage of tau at Asp421 (DeltaTau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether DeltaTau accumulates in other diseases not characterized by extracellular Abeta accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied DeltaTau accumulation in DLB cases associated with intracellular alpha-synuclein. DeltaTau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of DeltaTau may represent a common pathway associated with abnormal accumulation of intracellular tau or alpha-synuclein and may be relatively less dependent on the extracellular accumulation of Abeta in non-AD dementias.

Corticobasal Degeneration Substantiated by Imaging Studies

TO THE EDITOR: Corticobasal degeneration (CBD) is a slowly progressive disorder, characterized by initially unilateral akinesia, rigidity, apraxia, cortical sensory impairment, postural instability, and the alien hand syndrome. 1 Mathuranath PS Xuereb JH Bak T et al. Corticobasal ganglionic degeneration and/or frontotemporal dementia?. J Neurol Neurosurg Psychiatry. 2000; 68: 304-312 Google Scholar , 2 Graham NL Bak TH Hodges JR Corticobasal degeneration as a cognitive disorder. Mov Disord. 2003; 18: 1224-1232 Google Scholar , 3 Doran M du Plessis DG Enevoldson TP et al. Pathological heterogeneity of clinically diagnosed corticobasal degeneration. J Neurol Sci. 2003; 216: 127-134 Google Scholar The diagnosis can be challenging, given the variable presentations that reflect which brain region is affected first. Neuropathology is said to provide a definitive diagnosis, with neuronal achromasia and cortical atrophy of the frontoparietal region. 1 Mathuranath PS Xuereb JH Bak T et al. Corticobasal ganglionic degeneration and/or frontotemporal dementia?. J Neurol Neurosurg Psychiatry. 2000; 68: 304-312 Google Scholar , 3 Doran M du Plessis DG Enevoldson TP et al. Pathological heterogeneity of clinically diagnosed corticobasal degeneration. J Neurol Sci. 2003; 216: 127-134 Google Scholar SPECT can show asymmetrical parietal hypoperfusion, 2 Graham NL Bak TH Hodges JR Corticobasal degeneration as a cognitive disorder. Mov Disord. 2003; 18: 1224-1232 Google Scholar , 4 Slawek J Lass P Derejko M et al. Cerebral blood flow SPECT may be helpful in establishing the diagnosis of progressive supranuclear palsy and corticobasal degeneration. Nuclear Medicine Review Central Eastern Europe. 2001; 4: 73-76 Google Scholar , 5 Zhang L Murata Y Ishida R et al. Differentiating between progressive supranuclear palsy and corticobasal degeneration by brain perfusion SPECT. Nucl Med Commun. 2001; 22: 767-772 Google Scholar and focal atrophy can be seen on MRI. 6 Yekhlef F Ballan G Macia F et al. Routine MRI for the differential diagnosis of Parkinson's disease, MSA, PSP, and CBD. J Neural Transm. 2003; 110: 151-169 Google Scholar We describe a case of CBD in which the patient presented with few and mild symptoms, and where, over time, imaging studies were helpful diagnostic adjuncts.

Discrepancy between clinical and pathological diagnoses of CBD and PSP

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are often clinically confused with each other. Moreover, the discrepancy between clinical and pathological diagnoses of CBD and PSP are still controversial. We report here two atypical cases of PSP and CBD. A 73-year old woman was admitted with right hand rigidity, limb kinetic apraxia and cortical sensory loss. Brain atrophy, hypoperfusion and hypometabolism predominantly in the left frontoparietal lobes indicated CBD clinically. Pathological studies revealed neuronal loss and spongy change without ballooned neurons (BN) in the cerebral cortex. Modified Gallyas-Braak (G-B) staining revealed neurofibrillary tangles (NFTs) and tufted astrocytes, indicating pathological diagnosis of PSP. A 75-year-old man admitted with vertical gaze palsy, neck dystonia, parkinsonism and dementia. Atrophy of the frontal lobes and tegmentum of the midbrain and symmetrical frontal hypoperfusion in SPECT indicated PSP. However, neuronal loss and BN in the frontal lobes and clusters of astrocytic plaques indicated CBD pathologically. The G-B staining was useful for differentiating between CBD and PSP, but our atypical cases bring up a new issue about differential diagnosis of CBD and PSP.