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Keith A Josephs - One of the best experts on this subject based on the ideXlab platform.
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Corticobasal Degeneration key emerging issues
Journal of Neurology, 2018Co-Authors: Keith A JosephsAbstract:Corticobasal Degeneration (CBD) was first described by Rebeiz et al. in 1967, and was called corticodentatonigral Degeneration with neuronal achromasia [1]. Since then, our knowledge of the clinical features and underlying tau pathology has grown tremendously. Clinical antemortem diagnosis of CBD pathology remains challenging and has led to the development of revised diagnostic criteria. As various clinical phenotypes may have CBD pathology, accurate prevalence studies are lacking. Recently, pooled prevalence of fronto-temporal lobar Degeneration, PSP and CBS was reported as 10.6 per 100,000 [2]. Although rare, CBD is an important disease to understand because it provides a model of a specific proteinopathy (tauopathy) and, therefore, opportunity to study pathophysiology of tauopathies and efficacy of tau-directed therapies. In the past few years, identification of tau specific ligands has advanced neuroimaging of tauopathies such as CBD and progressive supranuclear palsy. However, clinical prediction of CBD pathology remains challenging and an active are of research. In this review, we highlight key emerging issues in CBD pathophysiology, genetics and novel neuroimaging techniques with tau ligands.
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key emerging issues in progressive supranuclear palsy and Corticobasal Degeneration
Journal of Neurology, 2015Co-Authors: Keith A JosephsAbstract:It has been approximately 50 years since neurologists were introduced to the entities, “progressive supranuclear palsy” and “Corticobasal Degeneration”. Since the two seminal publications, there have been significant advancements in our understanding of these two neurodegenerative diseases, particularly the fact that both are associated with tau. Recent advances over the past 3 years that are notable to the field are discussed in this review that covers clinical diagnosis, pathological features, neuroimaging and CSF biomarkers, genetic associations and clinical trials related to progressive supranuclear palsy and Corticobasal Degeneration.
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neuropathological features of Corticobasal Degeneration presenting as Corticobasal syndrome or richardson syndrome
Brain, 2011Co-Authors: Naomi Kouri, Irene Litvan, Melissa E Murray, Anhar Hassan, Rosa Rademakers, Ryan J Uitti, Bradley F Boeve, Neill R Graffradford, Zbigniew K Wszolek, Keith A JosephsAbstract: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. * Abbreviations : CBD-CBS : Corticobasal Degeneration presenting as Corticobasal syndrome CBD-RS : Corticobasal Degeneration presenting as Richardson syndrome PSP-RS : progressive supranuclear pasly presenting as Richardson syndrome
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Neuropathological features of Corticobasal Degeneration presenting as Corticobasal syndrome or Richardson syndrome.
Brain : a journal of neurology, 2011Co-Authors: Naomi Kouri, Irene Litvan, Melissa E Murray, Anhar Hassan, Rosa Rademakers, Ryan J Uitti, Bradley F Boeve, Zbigniew K Wszolek, Neill R Graff-radford, Keith A JosephsAbstract: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.
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Corticobasal Degeneration a pathologically distinct 4r tauopathy
Nature Reviews Neurology, 2011Co-Authors: Naomi Kouri, Rosa Rademakers, Keith A Josephs, Jennifer L Whitwell, Dennis W DicksonAbstract:Corticobasal Degeneration is a rare, progressive neurodegenerative disorder with highly variable clinical presentation, and is difficult to identify in living patients. The classic clinical presentation of this disease—Corticobasal syndrome—often occurs in conjunction with other neurological diseases. Kouri et al. discuss the use of imaging and biomarkers to improve diagnosis, and examine the genomic data that should provide insights into novel pathways involved in the pathogenesis of tauopathy.
Irene Litvan - One of the best experts on this subject based on the ideXlab platform.
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neuropathological features of Corticobasal Degeneration presenting as Corticobasal syndrome or richardson syndrome
Brain, 2011Co-Authors: Naomi Kouri, Irene Litvan, Melissa E Murray, Anhar Hassan, Rosa Rademakers, Ryan J Uitti, Bradley F Boeve, Neill R Graffradford, Zbigniew K Wszolek, Keith A JosephsAbstract: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. * Abbreviations : CBD-CBS : Corticobasal Degeneration presenting as Corticobasal syndrome CBD-RS : Corticobasal Degeneration presenting as Richardson syndrome PSP-RS : progressive supranuclear pasly presenting as Richardson syndrome
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Neuropathological features of Corticobasal Degeneration presenting as Corticobasal syndrome or Richardson syndrome.
Brain : a journal of neurology, 2011Co-Authors: Naomi Kouri, Irene Litvan, Melissa E Murray, Anhar Hassan, Rosa Rademakers, Ryan J Uitti, Bradley F Boeve, Zbigniew K Wszolek, Neill R Graff-radford, Keith A JosephsAbstract: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.
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comparison of apraxia in Corticobasal Degeneration and progressive supranuclear palsy
Neurology, 2001Co-Authors: V Pharr, B Fantie, Bob Uttl, M Stark, Irene Litvan, Jordan GrafmanAbstract:Objective: To describe ideomotor apraxia in patients with Corticobasal Degeneration and those with progressive supranuclear palsy, two parkinsonian disorders that are often misdiagnosed due to the overlap in their clinical features, and to determine whether systematic apraxia testing is useful for differential diagnosis. Methods: Fourteen patients fulfilling National Institute of Neurological Disorders and Stroke–Society for Progressive Supranuclear Palsy clinical criteria for progressive supranuclear palsy, 13 patients fulfilling modified Lang criteria for Corticobasal Degeneration, and 12 normal healthy control subjects were given the Test of Oral and Limb Apraxia, which was scored according to the Florida Apraxia Battery for occurrence of various types of apraxic errors. Results: Both patients with progressive supranuclear palsy and Corticobasal Degeneration committed a greater number of apraxic errors than normal healthy control subjects on both transitive and intransitive tasks (p Conclusions: Patients with Corticobasal Degeneration show more severe ideomotor apraxia than patients with progressive supranuclear palsy, and systematic assessment of ideomotor apraxia facilitates the differential diagnosis between patients with progressive supranuclear palsy and those with Corticobasal Degeneration.
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Comparison of apraxia in Corticobasal Degeneration and progressive supranuclear palsy.
Neurology, 2001Co-Authors: V Pharr, B Fantie, Bob Uttl, M Stark, Irene Litvan, Jordan GrafmanAbstract:OBJECTIVE: To describe ideomotor apraxia in patients with Corticobasal Degeneration and those with progressive supranuclear palsy, two parkinsonian disorders that are often misdiagnosed due to the overlap in their clinical features, and to determine whether systematic apraxia testing is useful for differential diagnosis. METHODS: Fourteen patients fulfilling National Institute of Neurological Disorders and Stroke-Society for Progressive Supranuclear Palsy clinical criteria for progressive supranuclear palsy, 13 patients fulfilling modified Lang criteria for Corticobasal Degeneration, and 12 normal healthy control subjects were given the Test of Oral and Limb Apraxia, which was scored according to the Florida Apraxia Battery for occurrence of various types of apraxic errors. RESULTS: Both patients with progressive supranuclear palsy and Corticobasal Degeneration committed a greater number of apraxic errors than normal healthy control subjects on both transitive and intransitive tasks (p < 0.001 in both cases), but apraxia was much more severe in patients with Corticobasal Degeneration than progressive supranuclear palsy (p < 0.001). The index of apraxia severity, in combination with the assessment of the two key features of progressive supranuclear palsy (falls and vertical gaze palsy), correctly classified all patients. CONCLUSIONS: Patients with Corticobasal Degeneration show more severe ideomotor apraxia than patients with progressive supranuclear palsy, and systematic assessment of ideomotor apraxia facilitates the differential diagnosis between patients with progressive supranuclear palsy and those with Corticobasal Degeneration.
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language disturbances in Corticobasal Degeneration
Neurology, 2000Co-Authors: Carol Frattali, Jordan Grafman, Nicholas J. Patronas, F Makhlouf, Irene LitvanAbstract:Article abstract To characterize the language deficits in Corticobasal Degeneration (CBD) and their relation to neuroradiologic findings, the authors administered a standardized battery of neurobehavioral tests and performed MRI studies on 15 patients with CBD. Eight patients (53%) had classifiable aphasias, including anomic, Broca’s and transcortical motor aphasias. The aphasias were associated primarily with left frontal and parietal cortical damage and subcortical white matter and corpus callosum abnormalities. Our findings demonstrate that language disturbances in CBD are more frequent than previously considered.
David G Munoz - One of the best experts on this subject based on the ideXlab platform.
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Relationship between frontotemporal dementia and Corticobasal Degeneration/progressive supranuclear palsy.
Dementia and Geriatric Cognitive Disorders, 2004Co-Authors: Andrew Kertesz, David G MunozAbstract:Progressive supranuclear palsy (PSP) and Corticobasal Degeneration (CBD) were described as separate entities, but prior to that an extrapyramidal variety of Pick’s disease was recognized. Subsequently
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relationship between frontotemporal dementia and Corticobasal Degeneration progressive supranuclear palsy
Dementia and Geriatric Cognitive Disorders, 2004Co-Authors: Andrew Kertesz, David G MunozAbstract:Progressive supranuclear palsy (PSP) and Corticobasal Degeneration (CBD) were described as separate entities, but prior to that an extrapyramidal variety of Pick’s disease was recognized. Subsequently
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the Corticobasal Degeneration syndrome overlaps progressive aphasia and frontotemporal dementia
Neurology, 2000Co-Authors: Andrew Kertesz, P Martinezlage, Wilda Davidson, David G MunozAbstract:Objective: To provide evidence for the hypothesis that the Corticobasal Degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex. Background: Corticobasal Degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted. Methods: Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records. Results: All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex. Conclusions: There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as “heterogenous.”
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Corticobasal Degeneration shares a common genetic background with progressive supranuclear palsy
Annals of Neurology, 2000Co-Authors: Emilio Di Maria, Massimo Tabaton, Tiziana Vigo, Giovanni Abbruzzese, Emilia Bellone, Catia Donati, Emma Frasson, Roberta Marchese, Pasquale Montagna, David G MunozAbstract:Corticobasal Degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that Corticobasal Degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background.
Andrew Kertesz - One of the best experts on this subject based on the ideXlab platform.
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Corticobasal Degeneration and progressive aphasia
Neurology, 2006Co-Authors: Paul Mcmonagle, Mervin Blair, Andrew KerteszAbstract:Objective: To describe language impairment in the Corticobasal Degeneration syndrome (CBDS) presenting as either a cognitive or motor disorder, to compare the evolution of aphasia in CBDS with primary progressive aphasia (PPA), and to examine whether the side of maximal cerebral atrophy or akinesia reflects the severity of aphasia. Methods: We divided 40 patients with CBDS according to motor or cognitive onsets and conducted detailed language assessments with the Western Aphasia Battery (WAB). We analyzed scores according to the side of atrophy and motor rigidity. Longitudinal performance over three annual assessments was compared against matched patients with PPA and Alzheimer disease. Results: Language at baseline was more impaired in cognitive than motor-onset CBDS but there was no correlation between the side of atrophy or motor impairment and the WAB. Serial assessment (n = 19) showed a similar evolution of aphasia in cognitive-onset CBDS and PPA and delayed aphasia in motor-onset CBDS. Conclusion: Aphasia is common in the Corticobasal Degeneration syndrome but there is little correlation with the laterality of clinical deficits. Cognitive-onset Corticobasal Degeneration syndrome and primary progressive aphasia are similar such that their aphasia appears identical.
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relationship between frontotemporal dementia and Corticobasal Degeneration progressive supranuclear palsy
Dementia and Geriatric Cognitive Disorders, 2004Co-Authors: Andrew Kertesz, David G MunozAbstract:Progressive supranuclear palsy (PSP) and Corticobasal Degeneration (CBD) were described as separate entities, but prior to that an extrapyramidal variety of Pick’s disease was recognized. Subsequently
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Relationship between frontotemporal dementia and Corticobasal Degeneration/progressive supranuclear palsy.
Dementia and Geriatric Cognitive Disorders, 2004Co-Authors: Andrew Kertesz, David G MunozAbstract:Progressive supranuclear palsy (PSP) and Corticobasal Degeneration (CBD) were described as separate entities, but prior to that an extrapyramidal variety of Pick’s disease was recognized. Subsequently
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the Corticobasal Degeneration syndrome overlaps progressive aphasia and frontotemporal dementia
Neurology, 2000Co-Authors: Andrew Kertesz, P Martinezlage, Wilda Davidson, David G MunozAbstract:Objective: To provide evidence for the hypothesis that the Corticobasal Degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex. Background: Corticobasal Degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted. Methods: Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records. Results: All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex. Conclusions: There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as “heterogenous.”
Helen Ling - One of the best experts on this subject based on the ideXlab platform.
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Does Corticobasal Degeneration exist? A clinicopathological re-evaluation.
Brain : a journal of neurology, 2020Co-Authors: Helen Ling, Janice L Holton, Tamas Revesz, Luke A Massey, David R Williams, Dominic C Paviour, Sean S O'sullivan, Andrew J. LeesAbstract: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.
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Fulminant Corticobasal Degeneration: a distinct variant with predominant neuronal tau aggregates.
Acta Neuropathologica, 2020Co-Authors: Helen Ling, Karen Davey, Ellen Gelpi, Zane Jaunmuktane, Edwin Jabbari, Roberto Simone, Lea R'bibo, S Brandner, Matthew EllisAbstract:Corticobasal Degeneration typically progresses gradually over 5–7 years from onset till death. Fulminant Corticobasal Degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed Corticobasal Degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), Corticobasal syndrome (N = 2) and Richardson’s syndrome (N = 2). We also studied four Corticobasal Degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched Corticobasal Degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p
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fulminant Corticobasal Degeneration a distinct variant with predominant neuronal tau aggregates
Acta Neuropathologica, 2020Co-Authors: Helen Ling, Karen Davey, Ellen Gelpi, Zane Jaunmuktane, Edwin Jabbari, Roberto Simone, S Brandner, Lea Rbibo, Matthew EllisAbstract:Corticobasal Degeneration typically progresses gradually over 5–7 years from onset till death. Fulminant Corticobasal Degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed Corticobasal Degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), Corticobasal syndrome (N = 2) and Richardson’s syndrome (N = 2). We also studied four Corticobasal Degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched Corticobasal Degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic Corticobasal Degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of Corticobasal Degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.
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astrogliopathy predominates the earliest stage of Corticobasal Degeneration pathology
Brain, 2016Co-Authors: Helen Ling, Gabor G Kovacs, Jean Paul Vonsattel, Karen Davey, John Hardy, Huw R Morris, Thomas T Warner, Janice L Holton, Tamas ReveszAbstract:See Kobylecki and Mann (doi:[10.1093/aww267][1]) for a scientific commentary on this article . Animal models have shown that tau seeding and propagation are strain- and neural network-specific. The study of preclinical cases is valuable to gain insights into early pathological features of Corticobasal Degeneration and its progression. Three preclinical Corticobasal Degeneration cases and six age-matched end-stage Corticobasal Degeneration cases were included in this study. Tau immunohistochemistry performed in 20 brain regions and quantitative assessment of regional tau load using image analysis were performed. Semi-quantitative grading of tau-positive cellular lesions and neuronal loss in the frontal, parietal and temporal cortices, striatum, substantia nigra and subthalamic nucleus were assessed. All preclinical cases were clinically asymptomatic but had widespread tau lesions in the typically affected regions in Corticobasal Degeneration and the pathognomonic astrocytic plaques were the most prominent lesion type in the anterior frontal and striatal regions. Mean total tau load (sum of all regional tau load) of end-stage Corticobasal Degeneration cases were nine times greater than that of the preclinical cases ( P = 0.04) and less tau load was found in all regions of the preclinical cases. An anterior-to-posterior tau load ratio in the frontal cortex in preclinical cases was 12-fold greater than in end-stage Corticobasal Degeneration cases. Relatively greater tau burden in the anterior frontal cortex, striatum and subthalamic nucleus suggests the striatal afferent connection to the dorsolateral prefrontal cortex and basal ganglia circuitry are the earliest neural network connections affected by Corticobasal Degeneration-related tau pathology. Differential distribution of the tau pathology to selective cortical regions in these preclinical cases implies phenotypic presentation may be predetermined at a very early stage of the disease process. Neuronal loss of the substantia nigra was either absent or very mild in the preclinical cases and was moderate to severe in end-stage Corticobasal Degeneration cases ( P < 0.05). Our findings suggest that a threshold of pathological burden in the ‘right’ anatomical regions needs to be reached before the onset of clinical symptoms. The early prominence of the astrocytic plaques in relation to sparse neuronal lesions leads one to speculate that Corticobasal Degeneration may begin as an astrogliopathy at a very early disease stage but neuronal lesions gradually take over as the predominant lesion type in advanced disease. * Abbreviations : CBD : Corticobasal Degeneration, CBS = Corticobasal syndrome FTD : frontotemporal dementia PSP : progressive supranuclear palsy RS : Richardson syndrome [1]: /lookup/doi/10.1093/brain/aww267
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Astrogliopathy predominates the earliest stage of Corticobasal Degeneration pathology.
Brain : a journal of neurology, 2016Co-Authors: Helen Ling, Gabor G Kovacs, Jean Paul Vonsattel, Karen Davey, John Hardy, Huw R Morris, Thomas T Warner, Janice L Holton, Tamas ReveszAbstract:SEE KOBYLECKI AND MANN DOI101093/AWW267 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Animal models have shown that tau seeding and propagation are strain- and neural network-specific. The study of preclinical cases is valuable to gain insights into early pathological features of Corticobasal Degeneration and its progression. Three preclinical Corticobasal Degeneration cases and six age-matched end-stage Corticobasal Degeneration cases were included in this study. Tau immunohistochemistry performed in 20 brain regions and quantitative assessment of regional tau load using image analysis were performed. Semi-quantitative grading of tau-positive cellular lesions and neuronal loss in the frontal, parietal and temporal cortices, striatum, substantia nigra and subthalamic nucleus were assessed. All preclinical cases were clinically asymptomatic but had widespread tau lesions in the typically affected regions in Corticobasal Degeneration and the pathognomonic astrocytic plaques were the most prominent lesion type in the anterior frontal and striatal regions. Mean total tau load (sum of all regional tau load) of end-stage Corticobasal Degeneration cases were nine times greater than that of the preclinical cases (P = 0.04) and less tau load was found in all regions of the preclinical cases. An anterior-to-posterior tau load ratio in the frontal cortex in preclinical cases was 12-fold greater than in end-stage Corticobasal Degeneration cases. Relatively greater tau burden in the anterior frontal cortex, striatum and subthalamic nucleus suggests the striatal afferent connection to the dorsolateral prefrontal cortex and basal ganglia circuitry are the earliest neural network connections affected by Corticobasal Degeneration-related tau pathology. Differential distribution of the tau pathology to selective cortical regions in these preclinical cases implies phenotypic presentation may be predetermined at a very early stage of the disease process. Neuronal loss of the substantia nigra was either absent or very mild in the preclinical cases and was moderate to severe in end-stage Corticobasal Degeneration cases (P < 0.05). Our findings suggest that a threshold of pathological burden in the 'right' anatomical regions needs to be reached before the onset of clinical symptoms. The early prominence of the astrocytic plaques in relation to sparse neuronal lesions leads one to speculate that Corticobasal Degeneration may begin as an astrogliopathy at a very early disease stage but neuronal lesions gradually take over as the predominant lesion type in advanced disease.
