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Although the initial symptoms of corticobasal degeneration (CBD) are varied, psychiatric symptoms are uncommon. Here, we report the autopsy findings of a patient with early CBD who presented with hallucinations. A 68‐year‐old man developed memory loss and visions of bears and insects. Because of slow vertical eye movement, postural instability, and levodopa‐unresponsive parkinsonism, the patient initially was clinically diagnosed with progressive supranuclear palsy. He died of a urinary tract infection 11 months after the onset of the disease. Histopathological examination revealed neuronal loss and gliosis, which were severe in the substantia nigra and moderate in the globus pallidus and subthalamic nucleus. Astrocytic plaques were scattered throughout the amygdala and premotor cortex. The superficial cortical layers lacked ballooned neurons and spongiosis, and tau deposition was greater in glia than in neurons. The amygdala contained a moderate number of argyrophilic grains and pretangles. Western blot analysis showed a 37‐kDa band among the low‐molecular‐weight tau fragments. Because the CBD pathology was mild, we attributed the patient's visual hallucinations to the marked argyrophilic grain pathology. CBD can occur with psychiatric symptoms, including visual hallucinations, and argyrophilic grain pathology may be associated with psychiatric symptoms. [ABSTRACT FROM AUTHOR]

Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies. [ABSTRACT FROM AUTHOR]

Background: Early diagnosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) is important for clinical care and key to developing successful disease‐modifying agents. The patient‐dependent phases of decision‐making made before contact with a healthcare professional have been inadequately studied. Objectives: To evaluate the patient‐dependent phases of decision‐making from symptom onset, comparing this to clinician and/or health system delays within the overall diagnostic pathway. Methods: Using the Anderson General Model of Total Patient Delay and a mixed‐methods approach in participants with PSP/CBS and their caregivers recruited to the Scottish PSP and CBS cohort, we quantified and evaluated the determinants of "appraisal", "illness," and "behavioral" delay, comparing this to the clinician and/or health system delays ("treatment" delay) within the overall time from symptom onset to diagnosis. Results: The time from index symptom onset to diagnosis was 3.26 (interquartile range [IQR] = 2.42, 4.75) years in PSP and 2.58 (IQR = 1.69, 4.08) years in CBS. Patient appraisal delay was 24 (IQR = 6, 60) weeks in PSP and 8 (IQR = 5, 24) weeks in CBS, illness delay 0 (IQR = −14, 0) weeks in PSP and 0 (IQR = −4, 0) weeks in CBS, with little perceived behavioral delay. Determinants of delay included the non‐specificity of symptoms, normalization of symptoms within the context of age or normal physiological variability, and the extent of insight into new somatic symptoms. Conclusions: Although patient appraisal delay contributes to overall diagnostic delay in PSP/CBS, the greater proportion of overall diagnostic delay arises after contact with a healthcare professional (treatment delay). [ABSTRACT FROM AUTHOR]

Although many entities have been established within the broad spectrum of Parkinson disease (PD) and atypical parkinsonisms, they are often difficult to differentiate. To clarify the current clinical diagnostic conditions and problems in PD and atypical parkinsonisms, we analyzed volumes of the Annuals of the Pathological Autopsy Cases in Japan. Among 130 105 autopsies conducted from 2007 to 2016 throughout Japan, patients were included in the study if they had been either clinically or pathologically diagnosed with PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). Autopsy rates were 6.4% for clinically diagnosed PD, 34.1% for MSA, 16.3% for PSP, and 17.4% for CBD. The specificities and sensitivities of clinical diagnoses were 88.0% and 82.0% for PD, 95.2% and 86.0% for MSA, 82.7% and 73.2% for PSP, and 55.4% and 57.7% for CBD, respectively. Clinical diagnoses had relatively high accuracy, but low autopsy rates are of concern. Many patients with rarer disorders were clinically misdiagnosed with PD, a more common disorder. Autopsy rates, irrespective of specific disorders, should be increased to detect rare diseases. Increasing autopsy rates will increase the available clinical information regarding pathologically confirmed patients and contribute to more accurate clinical diagnoses. [ABSTRACT FROM AUTHOR]

The formation of amyloid filaments through templated seeding is believed to underlie the propagation of pathology in most human neurodegenerative diseases. A widely used model system to study this process is to seed amyloid filament formation in cultured cells using human brain extracts. Here, we report the electron cryo‐microscopy structures of tau filaments from undifferentiated seeded SH‐SY5Y cells that transiently expressed N‐terminally HA‐tagged 1N3R or 1N4R human tau, using brain extracts from individuals with Alzheimer's disease or corticobasal degeneration. Although the resulting filament structures differed from those of the brain seeds, some degrees of structural templating were observed. Studying templated seeding in cultured cells, and determining the structures of the resulting filaments, can thus provide insights into the cellular aspects underlying neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Although ~25% of sporadic CBD cases present with progressive supranuclear palsy-Richardson's syndrome (PSP-RS),[1] only one other case of microtubule-associated protein tau gene ( I MAPT i )- related CBD with a PSP-like phenotype has been reported.[2] We aim to highlight important issues regarding the classification of I MAPT i -associated tauopathies and the implications for clinical research. Keywords: MAPT; corticobasal degeneration; progressive supranuclear palsy; pathology EN MAPT corticobasal degeneration progressive supranuclear palsy pathology 691 694 4 04/18/23 20230401 NES 230401 Corticobasal degeneration (CBD) is a rare, 4-repeat (4R) tauopathy characterized by astrocytic plaque neuropathology. Histological examination revealed neuronal and glial 4R tau pathology, with frequent astrocytic plaques typical of CBD (Fig. CBD pathology was most prominent in the posterior frontal lobe, deep gray nuclei and tegmental regions of the brainstem. [Extracted from the article]

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four‐repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late‐onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n = 7; age at onset: 41–75 years), depressive disorder (n = 1; 49 years), bipolar disorder (n = 2; 32 and 37 years) and somatoform disorder (n = 1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non‐AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non‐AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS‐PSP neuropathological criteria. No case had high‐level Alzheimer's disease pathology, Lewy body disease or limbic‐predominant age‐related TDP‐43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late‐onset psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Globular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non‐globular glial 4‐repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Methods: For this case–control study the Mayo Clinic brain banks were queried for all cases with an autopsy‐confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR‐parkinsonism index, midbrain volume, and white matter hyperintensities.18F‐Fluorodeoxyglucose‐, 11C Pittsburg compound‐, and 18F‐flortaucipir‐positron emission tomography scans were reviewed. Results: Twelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p = 0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p = 0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson‐plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR‐parkinsonism index, and larger midbrain volumes. Conclusions: Female sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT. [ABSTRACT FROM AUTHOR]

The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The pathological diagnostic procedure begins by assessing the macroscopic findings to evaluate the degenerative lesions in brains with the naked eye. Usually, degenerative lesions show variable atrophy and brownish discoloration in accordance with disease‐specific profiles. These macroscopic appearances support neuropathologists in identifying the relevant regions for microscopic examination. The neuropathological diagnosis of parkinsonism is based on regional distribution and fundamental proteinopathies in neurons and glia cells. LBD and MSA are synucleinopathies, and PSP and CBD are tauopathies. Among them, glial‐predominant proteinopathy (MSA, PSP, and CBD) may play a significant role in volume reduction. Therefore, macroscopic inspection provides the appropriate direction for assessment. The disease duration, the severity of lesions, and mixed pathologies make the validation of macroscopic observations more complicated. In this review, we outline the macroscopic diagnostic clues in LBD, MSA, PSP, and CBD that could help with pathological refinement. [ABSTRACT FROM AUTHOR]

A 57‐year‐old man presented with dynamic aphasia with evolving agrammatism and anomia. Additionally, he exhibited emerging atypical parkinsonism and features of behavioral variant frontotemporal dementia. Insights pertinent to this complex clinical presentation are discussed. [ABSTRACT FROM AUTHOR]

The tauopathies are a heterogeneous group of neurodegenerative disorders in which the prevailing underlying disease process is intracellular deposition of abnormal misfolded tau protein. Diseases often categorized as tauopathies include progressive supranuclear palsy, chronic traumatic encephalopathy, corticobasal degeneration, and frontotemporal lobar degeneration. Tauopathies can be classified through clinical assessment, imaging findings, histologic validation, or molecular biomarkers tied to the underlying disease mechanism. Many tauopathies vary in their clinical presentation and overlap substantially in presentation, making clinical diagnosis of a specific primary tauopathy difficult. Anatomic imaging findings are also rarely specific to a single tauopathy, and when present may not manifest until well after the point at which therapy may be most impactful. Molecular biomarkers hold the most promise for patient care and form a platform upon which emerging diagnostic and therapeutic applications could be developed. One of the most exciting developments utilizing these molecular biomarkers for assessment of tau deposition within the brain is tau‐PET imaging utilizing novel ligands that specifically target tau protein. This review will discuss the background, significance, and clinical presentation of each tauopathy with additional attention to the pathologic mechanisms at the protein level. The imaging characteristics will be outlined with select examples of emerging imaging techniques. Finally, current treatment options and emerging therapies will be discussed. This is by no means a comprehensive review of the literature but is instead intended for the practicing radiologist as an overview of a rapidly evolving topic. [ABSTRACT FROM AUTHOR]

Background: High‐quality prevalence studies are important in estimating the burden of disease in a population, thus informing priority setting, resource allocation, delivery, and use of health services. Objectives: This study was undertaken to systematically review the methods and results of previous prevalence studies of progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) and make recommendations for future studies. Methods: A total of 2 authors independently identified original articles that described the prevalence of PSP or CBS using several comprehensive and overlapping search strategies, assessed study quality, and extracted relevant data. Descriptive and pooled analyses were performed as appropriate. Results: A total of 16 studies were identified in PSP and 9 studies in CBS, with highly heterogeneous methods of case definition, identification, and verification in identified studies. Few studies were deemed of necessary quality or methodological homogeneity to justify a full meta‐analysis. In addition, few studies reported age‐ and sex‐stratified results. The best 3 prevalence studies in PSP gave a pooled rate of 7.1 per 100,000 per year, whereas the pooled rate in 2 CBS studies was roughly 3 times lower at 2.3 per 100,000 per year. Based on crude rates, there was little evidence to suggest clear sex differences in the prevalence of PSP or CBS or that the prevalence of PSP had increased over time, but some evidence to suggest that prevalence may increase with increasing age. Conclusion: Given the paucity of prevalence studies in PSP and CBS, further high‐quality prevalence studies are necessary. [ABSTRACT FROM AUTHOR]

MAPT gene, corticobasal degeneration, progressive supranuclear palsy, corticobasal syndrome, frontotemporal lobar degeneration Keywords: MAPT gene; corticobasal degeneration; progressive supranuclear palsy; corticobasal syndrome; frontotemporal lobar degeneration EN MAPT gene corticobasal degeneration progressive supranuclear palsy corticobasal syndrome frontotemporal lobar degeneration 716 718 3 04/18/23 20230401 NES 230401 Mutations in the microtubule-associated protein tau gene ( I MAPT i ) are associated with heterogeneous clinical and pathological manifestations, and their pathogenicity is based on two different mechanisms: missense and splicing mutations, leading to aggregates of insoluble filaments of tau.[1] This letter describes the phenotype of a patient carrying the rare variant I MAPT i p.V363I mutation and explores the clinical presentation through multimodal imaging biomarkers. Expanding MAPT p.V363I Mutation Phenotype: An Overlapping of PSP-CBS and Posterior Cortical Atrophy. [Extracted from the article]

Background: Normal pressure hydrocephalus (NPH) manifests as gait instability, cognitive impairment, and urinary incontinence. This clinical triad of NPH sometimes occurs with ventriculomegaly in patients with neurodegenerative disease. Patients with pathologically verified neurodegenerative diseases, such as progressive supranuclear palsy (PSP), have received antemortem diagnoses of NPH. Objectives: This study presents clinical and pathological features of a patient with pathologically verified corticobasal degeneration (CBD) coexisting with clinically shunt‐responsive NPH. Methods: We performed clinical, radiological, and pathological evaluations in a patient with CBD whose antemortem diagnosis was PSP Richardson's syndrome (PSP‐RS) coexisting with shunt‐responsive NPH. Results: A 59‐year‐old woman developed bradykinesia and gait instability and then frequent falls, urinary incontinence, and supranuclear vertical gaze palsy followed. At 63 years of age, her gait disturbance and urinary incontinence had deteriorated rapidly, and cognitive impairment was disclosed. There were typical findings of NPH with ventriculomegaly and disproportionately enlarged subarachnoid space hydrocephalus as well as a 2‐layer appearance with decreased and increased cerebral blood perfusion. Shunt placement ameliorated gait instability for more than 1 year and improved radiological indicators of NPH. However, atrophy of the midbrain progressed with time after transient increases in size. Although the antemortem diagnosis was probable PSP‐RS, pathological evaluation verified CBD. There were severe discontinuities of the ependymal lining of the lateral ventricles and subependymal rarefaction and gliosis with tau‐positive deposition. Conclusions: Shunt surgery could ameliorate NPH symptoms in patients with 4‐repeat tauopathies. Careful assessments of clinical findings are necessary to predict the benefits of shunts as a therapeutic option for patients with neurodegenerative diseases coexisting with NPH. [ABSTRACT FROM AUTHOR]

Introduction: Primary tauopathies are neurological disorders in which tau protein deposition is the predominant pathological feature. Alzheimer's disease is a secondary tauopathy with tau forming hyperphosphorylated insoluble aggregates. Tau pathology can propagate from region to region in the brain, while alterations in tau processing may impair tau physiological functions. Methods: We reviewed literature on tau biology and anti‐tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. Results: The past 15 years have seen >30 drugs interfering with tau aggregation, processing, and accumulation reaching the clinic. Initial results with tau aggregation inhibitors and anti‐tau monoclonal antibodies have not shown clinical efficacy. Discussion: The reasons for these clinical failures are unclear but could be linked to the clearing of physiological forms of tau by non‐specific drugs. Research is now concentrating efforts on developing reliable translational animal models and selective compounds targeting specific tau epitopes, neurotoxic tau aggregates, and post‐translational tau modifications. [ABSTRACT FROM AUTHOR]

Aims: Neuronal and glial inclusions comprising transactive response DNA‐binding protein of 43 kDa (TDP‐43) have been identified in the brains of patients with corticobasal degeneration (CBD), and a possible correlation between the presence of these inclusions and clinical phenotypes has been speculated. However, the significance of TDP‐43 pathology in the pathomechanism of CBD has remained unclear. Here, we investigated the topographical relationship between TDP‐43 inclusions and neuronal loss in CBD. Methods: We estimated semi‐quantitatively neuronal loss and TDP‐43 pathology in the form of neuronal cytoplasmic inclusions (NCIs), astrocytic inclusions (AIs), oligodendroglial cytoplasmic inclusions (GCIs), and dystrophic neurites in 22 CNS regions in 10 patients with CBD. Then, the degree of correlation between the severity of neuronal loss and the quantity of each type of TDP‐43 inclusion was assessed. We also investigated tau pathology in a similar manner. Results: TDP‐43 pathology was evident in nine patients. The putamen and globus pallidus were the regions most frequently affected (80%). NCIs were the most prominent form, and their quantity was significantly correlated with the severity of neuronal loss in more than half of the regions examined. The quantities of TDP‐43 NCIs and tau NCIs were correlated in only a few regions. The number of regions where the quantities of TDP‐43 AIs and GCIs were correlated with the severity of neuronal loss was apparently small in comparison with that of NCIs. Conclusions: TDP‐43 alterations in neurons, not closely associated with tau pathology, may be involved in the pathomechanism underlying neuronal loss in CBD. There was a significant topographical correlation between neuronal cytoplasmic aggregation of TDP‐43 and neuronal loss in CBD, suggesting that TDP‐43 protein aberration might be associated with neuronal degeneration in CBD. There was no close correlation between the burden of TDP‐43 and that of tau in neurons. [ABSTRACT FROM AUTHOR]

Neuropathological diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) requires interpretation of tau morphology based on extensive brain sampling. Here we report subcortical tau burden is sufficient to distinguish PSP and CBD, regardless of the tau morphology. The tau pallido‐claustral ratio is a promising diagnostic indicator for PSP and CBD. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to develop a deep learning‐based model for differentiating tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD), based on tau‐immunostained digital slide images. Methods: We trained the YOLOv3 object detection algorithm to detect five tau lesion types: neuronal inclusions, neuritic plaques, tufted astrocytes, astrocytic plaques and coiled bodies. We used 2522 digital slide images of CP13‐immunostained slides of the motor cortex from 10 cases each of AD, PSP and CBD for training. Data augmentation was performed to increase the size of the training dataset. We next constructed random forest classifiers using the quantitative burdens of each tau lesion from motor cortex, caudate nucleus and superior frontal gyrus, ascertained from the object detection model. We split 120 cases (32 AD, 36 PSP, 31 CBD and 21 PiD) into training (90 cases) and test (30 cases) sets to train random forest classifiers. Results: The resultant random forest classifier achieved an average test score of 0.97, indicating that 29 out of 30 cases were correctly diagnosed. A validation study using hold‐out datasets of CP13‐ and AT8‐stained slides from 50 cases (10 AD, 17 PSP, 13 CBD and 10 PiD) showed >92% (without data augmentation) and >95% (with data augmentation) diagnostic accuracy in both CP13‐ and AT8‐stained slides. Conclusion: Our diagnostic model trained with CP13 also works for AT8; therefore, our diagnostic tool can be potentially used by other investigators and may assist medical decision‐making in neuropathological diagnoses of tauopathies. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to clarify the different topographical distribution of tau pathology between progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and establish a machine learning‐based decision tree classifier. Methods: Paraffin‐embedded sections of the temporal cortex, motor cortex, caudate nucleus, globus pallidus, subthalamic nucleus, substantia nigra, red nucleus, and midbrain tectum from 1020 PSP and 199 CBD cases were assessed by phospho‐tau immunohistochemistry. The severity of tau lesions (i.e., neurofibrillary tangle, coiled body, tufted astrocyte or astrocytic plaque, and tau threads) was semi‐quantitatively scored in each region. Hierarchical cluster analysis was performed using tau pathology scores. A decision tree classifier was made with tau pathology scores using 914 cases. Cross‐validation was done using 305 cases. An additional ten cases were used for a validation study. Results: Cluster analysis displayed two distinct clusters; the first cluster included only CBD, and the other cluster included all PSP and six CBD cases. We built a decision tree, which used only seven decision nodes. The scores of tau threads in the caudate nucleus were the most decisive factor for predicting CBD. In a cross‐validation, 302 out of 305 cases were correctly diagnosed. In the pilot validation study, three investigators made a correct diagnosis in all cases using the decision tree. Conclusion: Regardless of the morphology of astrocytic tau lesions, semi‐quantitative tau pathology scores in select brain regions are sufficient to distinguish PSP and CBD. The decision tree simplifies neuropathologic differential diagnosis of PSP and CBD. [ABSTRACT FROM AUTHOR]

Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD. [ABSTRACT FROM AUTHOR]

We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right‐sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild‐to‐moderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tau‐immunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentato‐olivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation. [ABSTRACT FROM AUTHOR]

Corticobasal degeneration, seizures, parkinsonism, metabolic disease, hypoparathyroidism Keywords: Corticobasal degeneration; seizures; parkinsonism; metabolic disease; hypoparathyroidism EN Corticobasal degeneration seizures parkinsonism metabolic disease hypoparathyroidism 600 603 4 05/04/21 20210501 NES 210501 The clinical presentation of Hypoparathyroidism is variable and is considered as a great masquerader with systemic and neurological symptoms.1,2 We present a potential reversible disorder from wheel chair dependency to normal lifestyle, in a patient with 25-year history of long-standing seizures, and 6 years history of atypical parkinsonism in the form of corticobasal syndrome phenotype. [Extracted from the article]

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder. Keywords: corticobasal degeneration; hallucinations; REM sleep behavior disorder EN corticobasal degeneration hallucinations REM sleep behavior disorder 383 385 3 04/05/22 20220401 NES 220401 In autopsy series of patients with parkinsonism, the presence of rapid eye movement sleep behavior disorder (RBD) or visual hallucinations (VH) has a greater than 90% specificity for -synuclein pathology.1,2 Accordingly, these clinical features are often useful when considering the differential diagnosis of atypical parkinsonsim. Corticobasal syndrome with visual hallucinations and probable REM-sleep behavior disorder: an autopsied case report of a patient with CBD and LBD pathology. [Extracted from the article]

Background: Despite initial underreporting of language dysfunctions in corticobasal syndrome (CBS), aphasia is now recognized as a frequent feature of this disease. Aphasia in CBS seems clinically overlying to a non‐fluent/agrammatic primary progressive aphasia (nfaPPA), which is also a clinical phenotype associated with corticobasal degeneration (CBD) pathology. However, the clinical features of aphasia in CBS still remain poorly delineated, resulting in misjudgements in the differential diagnosis from a PPA presentation of the disease. Aims: To investigate the language disorders of this syndrome, also through a systematic examination of recoding skills (reading, written spelling and repetition) and articulatory disturbances, which have been rarely examined in previous studies. Methods & Procedures: We present a clinical and neuropsychological descriptive study of the language impairments in a case series of 12 aphasic patients with a clinical diagnosis of CBS. Language assessment was conducted by means of the Esame NeuroPsicologico dell'Afasia, a comprehensive Italian battery for language functions, the Token Test, and the Apraxia of Speech Rating Scale. Outcomes & Results: The language profile of the patients showed a severe expressive language disorder, characterized by non‐fluent speech, apraxia of speech (AoS) with predominant stuttering‐like dysfluencies, spatial/apraxic agraphia, lack of word‐finding and defective sentence repetition. Severe limb apraxia, visual–spatial deficit and alien hand syndrome were also present. Neuroimaging showed bilateral left asymmetric atrophies and hypometabolism in the frontal premotor, parietal posterior and temporal areas. Conclusions & Implications: These findings suggest that aphasia in CBS might present as a 'mixed PPA', instead of an nfaPPA as previously stated, showing a combination of features of the nfa and logopenic variants of the PPA, associated with AoS, stuttering and agraphia, which might be additional important cognitive markers for the clinical diagnosis of CBS and discriminating features of an nfaPPA presentation of a CBD. These results might also suggest specific intervention areas in the rehabilitation of patients with CBS. What this paper addsWhat is already known on the subjectLanguage disorders in CBS patients usually present clinically overlying to an nfaPPA, which is also a clinical phenotype associated with CBD pathology, according to recent diagnostic criteria. However, the clinical features of aphasia in CBS still remain poorly delineated, and this raises difficulties and misjudgements for clinicians in the differential diagnosis from a PPA presentation of the disease.What this paper adds to existing knowledgeThis study shows that the language profile of our CBS patients was characterized by severe expressive language disorders, with non‐fluent speech, apraxia of speech (AoS) with predominant stuttering‐like dysfluencies, spatial/apraxic agraphia, lack of word‐finding, and defective sentence repetition. These findings suggest that aphasia in CBS might present as a 'mixed PPA', rather than an nfaPPA as previously stated, showing a combination of features of the nfa and logopenic variants of the PPA associated with AoS, stuttering and agraphia.What are the potential or actual clinical implications of this work?These results suggest that AoS, stuttering and agraphia might be important additional cognitive markers for the clinical diagnosis of CBS, and discriminating features of an nfaPPA presentation of a CBD. The language disorders exhibited in the present study might also support speech and language therapists in targeting specific intervention areas in the rehabilitation of patients with CBS. [ABSTRACT FROM AUTHOR]

Background: Corticobasal degeneration (CBD) can present with various clinical phenotypes including Richardson's syndrome (RS). Although neuropathological examination can differentiate CBD and progressive supranuclear palsy (PSP) pathologies, no clinical or imaging findings can differentiate CBD from other pathologies when a patient presents with a variant type of CBD. As these various phenotypes are associated with non‐CBD pathologies, clinical diagnostic accuracy can be low for such patients. Objectives: To present clinical features of two cases with symptom progression in line with PSP‐RS, who were diagnosed with CBD based on neuropathological examination. Methods: Baseline, follow up examinations, and detailed neuropathological examinations of two CBD cases presenting and progressing in line with probable PSP‐RS are demonstrated. Results: The two cases clinically diagnosed as probable PSP‐RS were shown to have CBD upon neuropathological examination, which is the gold standard for diagnosis of both PSP and CBD. Conclusions: These cases emphasize the importance of neuropathology for the definite diagnosis, and stress the need for distinctive markers to increase the reliability of clinical diagnosis before death. View Supplementary Video 1 View Supplementary Video 2 [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that show parkinsonism as their main symptom. Both PSP and CBD are sporadic tauopathies associated with hyperphosphorylated four‐repeat tau aggregation in neurons and glial cells. The characteristic pathologies of PSP are midbrain atrophy and the appearance of tufted astrocytes and globose‐type neurofibrillary tangles. PSP shows severe degeneration in the globus pallidus, substantia nigra, subthalamic nucleus, and cerebellar dentate nuclei. Conversely, the characteristic pathologies of CBD are cortical atrophy and the appearance of astrocytic plaques and argyrophilic threads. CBD is associated with severe degeneration in the cerebral white matter, substantia nigra, and globus pallidus. Clinical symptoms depend on the topographical distribution and severity of degeneration rather than on the type of aggregated protein or inclusions. PSP and CBD present clinically differential diagnostic difficulties because of their overlapping pathological distributions. [ABSTRACT FROM AUTHOR]

Background: The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category "probable 4-repeat (4R)-tauopathy" for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration.Objectives: To validate the accuracy of these clinical criteria for "probable 4R-tauopathy" to predict underlying 4R-tauopathy pathology.Methods: Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies).Results: We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of "probable 4R-tauopathy" was 10% and 99% in the first year and 59% and 88% at final record.Conclusions: The new diagnostic category "probable 4R-tauopathy" showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction: Sleep‐wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake‐promoting neurons (WPNs) remains unclear. Methods: We performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease‐specific controls. Results: The three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter‐synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. Discussion: WPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep‐wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP. [ABSTRACT FROM AUTHOR]

Corticobasal syndrome (CBS) is clinically characterised by a wide range of motor, cognitive, and behavioural features but remains challenging to diagnose accurately. Despite recent evidence supporting the presence of social cognition and emotion processing disturbances, few studies have explored the nature of empathic ability in CBS. This study aimed to (a) investigate the extent to which cognitive and affective dimensions of empathy are affected in CBS and (b) to determine the impact of such changes on carer burden. Empathic capacity was assessed in 29 CBS patients and 28 matched healthy controls. We employed the Interpersonal Reactivity Index (IRI), an instrument measuring: (a) perspective taking, (b) fantasy, (c) empathic concern, and (d) personal distress. A significant change in both perspective taking and empathic concern was observed in CBS following disease onset. Furthermore, affective empathy deficits in CBS patients predicted higher levels of carer burden. Disturbances in both cognitive and affective empathy are present in CBS and lead to increased levels of carer burden. [ABSTRACT FROM AUTHOR]

Only 25% to 56% of patients with CBD pathology are correctly diagnosed antemortem.1 Further, in one autopsy study, only 7 of 13 patients presenting with CBS had CBD at postmortem.2 One imaging modality used for diagnosis is dopamine transporter (DaT) imaging, which usually demonstrate loss of dopaminergic innervation to the striatum, occasionally with severe lateralization.3 Here, we present a case with probable CBD who had received a DaT-single-photon emission computed tomography (SPECT) 9 years before diagnosis, as part of establishing a normal DaT-SPECT reference data set. Keywords: corticobasal degeneration; dopamine transporter imaging; atypical parkinsonism EN corticobasal degeneration dopamine transporter imaging atypical parkinsonism 607 609 3 05/04/21 20210501 NES 210501 Little is known about the early stages of corticobasal degeneration (CBD), which presents itself in a variety of syndromes of which the most common presentation is referred to as corticobasal syndrome (CBS). During analysis of the DaT-SPECT, the patient was identified as 1 of the healthy controls who had volunteered to serve as normal reference material 9 years earlier (Fig. [Extracted from the article]

Background and purpose: Cognitively stimulating life experiences and activities are deemed to moderate the clinical impact of brain damage progressively building a neural and cognitive reserve (CR). CR has been studied extensively in various neurodegenerative disorders, but not in corticobasal degeneration (CBD). Methods: Using Statistical Parametric Mapping 8, years of education, as a determinant of CR, was correlated with tracer uptake on positron emission tomography with 18F‐fluorodeoxyglucose, as a marker of neurodegeneration, in 35 patients with various phenotypes of CBD, including a cognitive–motor composite score or symptoms duration as covariates for controlling disease stage. Results: A cluster of relative hypometabolism was found associated with higher education in the left inferior regions of pre‐ and post‐rolandic gyri and insula, which represent typical loci of neurodegeneration in CBD regardless of clinical presentation. Conclusions: The present findings extend to CBD the evidence gathered in other neurodegenerative disorders that a higher CR has a protective effect against the clinical manifestations of brain degeneration. [ABSTRACT FROM AUTHOR]

Recent works showed that tool use can be impaired in stroke patients because of either planning or technical reasoning deficits, but these two hypotheses have not yet been compared in the field of neurodegenerative diseases. The aim of this study was to address the relationships between real tool use, mechanical problem‐solving, and planning skills in patients with Alzheimer's disease (AD, n = 32), semantic dementia (SD, n = 16), and corticobasal syndrome (CBS, n = 9). Patients were asked to select and use ten common tools, to solve three mechanical problems, and to complete the Tower of London test. Motor function and episodic memory were controlled using the Purdue Pegboard Test and the BEC96 questionnaire, respectively. A data‐transformation method was applied to avoid ceiling effects, and single‐case analysis was performed based on raw scores and completion time. All groups demonstrated either impaired or slowed tool use. Planning deficits were found only in the AD group. Mechanical problem‐solving deficits were observed only in the AD and CBS groups. Performance in the Tower of London test was the best predictor of tool use skills in the AD group, suggesting these patients had general rather than mechanical problem‐solving deficits. Episodic memory seemed to play little role in performance. Motor dysfunction tended to be associated with tool use skills in CBS patients, while tool use disorders are interpreted as a consequence of the semantic loss in SD in line with previous works. These findings may encourage caregivers to set up disease‐centred interventions. [ABSTRACT FROM AUTHOR]

Background and purpose Atypical Parkinsonian disorders ( APD) frequently overlap in clinical presentations, making the differential diagnosis challenging in the early stages. The present study aimed to evaluate the accuracy of the [18F]fluoro-deoxy-glucose positron emission tomography Statistical Parametric Mapping ( SPM) optimized procedure in supporting the early and differential diagnosis of APD. Methods Seventy patients with possible APD were retrospectively included from a large clinical cohort. The included patients underwent [18F]fluoro-deoxy-glucose positron emission tomography within 3 months of the first clinical assessment and a diagnostic follow-up. An optimized SPM voxel-wise procedure was used to produce t-maps of brain hypometabolism in single subjects, which were classified by experts blinded to any clinical information. We compared the accuracy of both the first clinical diagnosis and the SPM t-map classifications with the diagnosis at follow-up as the reference standard. Results At first diagnosis , 60% of patients were classified as possible APD (progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy) and about 40% as APD with uncertain diagnosis, providing 52% sensitivity, 97% specificity and 86% accuracy with respect to the reference standard. SPM t-map classification showed 98% sensitivity, 99% specificity and 99% accuracy, and a significant agreement with the diagnosis at follow-up ( P < 0.001). Conclusions The SPM t-map classification at entry predicted the second diagnosis at follow-up. This indicates its significantly superior role for an early identification of APD subtypes, particularly in cases of uncertain diagnosis. The use of a metabolic biomarker at entry in the instrumental work-up of APD may shorten the diagnostic time, producing benefits for treatment options and support to the patients. [ABSTRACT FROM AUTHOR]

Introduction Corticobasal syndrome (CBS) resulting from genetic Alzheimer's disease (AD) has been described only once. Whether familial CBS-AD is a distinct clinical entity with its own imaging signature remains unknown. Methods Four individuals with CBS from two families underwent detailed assessment. For two individuals, regional atrophy and hypoperfusion were compared to autopsy-confirmed typical late-onset AD and corticobasal degeneration, as well as genetically proven PSEN1 cases with an amnestic presentation. Results One family harbored a novel mutation in PSEN1 :p.Phe283Leu. MRI demonstrated severe parietal, perirolandic, and temporal atrophy, with relative sparing of frontal and ipsilateral hippocampal regions. Autopsy confirmed pure AD pathology. The other family harbored a known PSEN1 mutation:p.Gly378Val. Discussion This report confirms familial CBS-AD as a distinct clinical entity, with a parietal-perirolandic-temporal atrophy signature. It illustrates the clinical heterogeneity that can occur despite a shared genetic cause and underscores the need for biomarkers such as amyloid imaging during life. [ABSTRACT FROM AUTHOR]

Aims The manner in which pathological lesions of corticobasal degeneration ( CBD) progress remains poorly understood. Because the pathology of early disease stages may be fundamental for elucidating a border between clinical and preclinical states of CBD, the present study aimed to detect preclinical or early clinical CBD cases by examining a series of forensic autopsy cases. Methods A series of 887 brains from medicolegal autopsies was examined. Immunohistochemistry for tau ( AT8, 3, and 4-repeat-tau) and Gallyas- Braak was applied for diagnosis. Neuropathological diagnosis of CBD followed criteria updated in 2002 by a working group. Results Three autopsy cases (0.34%) were identified that fulfilled CBD pathological criteria. Two cases were preclinical or very early clinical cases without brain atrophy; the other case had exhibited a 5-year history of advanced frontotemporal dementia. Significant microscopic differences between the subclinical and clinical cases included occurrence of neuronal loss with spongiosis and gliosis, as well as a difference in degree of tau pathology in the superficial layer of the neocortical areas and white matter. Anatomical hierarchy of tau pathology in the brain was not evident, but asymmetric neocortical tau pathology that might influence the clinical phenotype was found in preclinical and early clinical cases. Conclusions The results revealed the pathological features of subclinical and early clinical CBD cases. Comparison with clinical CBD cases showed that neuronal loss, cortical atrophy and volume reduction of white matter may be involved in the occurrence of clinical symptoms of CBD. Additionally, immunohistochemistry is essential for detecting preclinical CBD cases, regardless of case selection. [ABSTRACT FROM AUTHOR]

The patient was a 72-year-old Japanese woman. At the age of 57, she started having difficulty performing daily work and developed agraphia. She also exhibited restlessness and loss of interest, and began to speak less. Thereafter, stereotypical behavior, gait disturbance and dysphagia were noted. CT scan demonstrated left-dominant frontal and temporal lobe atrophy. She died at the age of 72, about 16 years after the onset of symptoms. Neuropathologically, the brain weighed 867 g, and showed remarkable cerebral atrophy with degeneration of the white matter, predominantly in the left dorsal frontal lobe and anterior temporal lobe. Microscopically, severe neuronal loss and gliosis with rarefaction were found in the cerebral cortex, and severe destruction of myelin and axons was observed in the cerebral white matter. Moderate neuronal loss with gliosis was also found in the pallidum and substantia nigra. Gallyas- Braak staining and tau immunostaining revealed pretangle neurons, NFTs, ballooned neurons and astrocytic plaques in the cerebral cortex, subcortical nuclei and brainstem, and argyrophilic threads and coiled bodies in the subcortical white matter. Tau isoform-specific immunostaining revealed that most tau-immunoreactive structures were positive for 4-repeat (4 R) tau, but some of the NFTs were positive for 3-repeat (3 R) tau in the cerebral neocortex. Immunoblotting demonstrated an accumulation of 4 R tau in the cerebral cortex and subcortical white matter. The patient was pathologically diagnosed as having corticobasal degeneration. Her long survival course likely accounts for the severe white matter degeneration and accumulation of 3 R tau in NFTs. [ABSTRACT FROM AUTHOR]

Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, formerly called also as neurofibrillary tangle-only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance. [ABSTRACT FROM AUTHOR]

Tufted astrocytes ( TAs) in progressive supranuclear palsy ( PSP) and astrocytic plaques ( APs) in corticobasal degeneration ( CBD) have been regarded as the pathological hallmarks of major sporadic 4-repeat tauopathies. To better define the astrocytic inclusions in PSP and CBD and to outline the pathological features of each disease, we reviewed 95 PSP cases and 30 CBD cases that were confirmed at autopsy. TAs exhibit a radial arrangement of thin, long, branching accumulated tau protein from the cytoplasm to the proximal processes of astrocytes. APs show a corona-like arrangement of tau aggregates in the distal portions of astrocytic processes and are composed of fuzzy, short processes. Immunoelectron microscopic examination using quantum dot nanocrystals revealed filamentous tau accumulation of APs located in the immediate vicinity of the synaptic structures, which suggested synaptic dysfunction by APs. The pathological subtypes of PSP and CBD have been proposed to ensure that the clinical phenotypes are in accordance with the pathological distribution and degenerative changes. The pathological features of PSP are divided into 3 representative subtypes: typical PSP type, pallido-nigro-luysian type ( PNL type), and CBD-like type. CBD is divided into three pathological subtypes: typical CBD type, basal ganglia- predominant type, and PSP-like type. TAs are found exclusively in PSP, while APs are exclusive to CBD, regardless of the pathological subtypes, although some morphological variations exist, especially with regard to TAs. The overlap of the pathological distribution of PSP and CBD makes their clinical diagnosis complicated, although the presence of TAs and APs differentiate these two diseases. The characteristics of tau accumulation in both neurons and glia suggest a different underlying mechanism with regard to the sites of tau aggregation and fibril formation between PSP and CBD: proximal-dominant aggregation of TAs and formation of filamentous NFTs in PSP in contrast to the distal-dominant aggregation of APs and formation of less filamentous pretangles in CBD. [ABSTRACT FROM AUTHOR]

Pretangles are cytoplasmic tau immunoreactivity in neurons without apparent formation of fibrillary structures. In Alzheimer disease, such tau deposition is considered to represent a premature state prior to fibril formation ( AD-pretangles), later to form neurofibrillary tangles and finally ghost tangles. This morphological evolution from pretangles to ghost tangles is in parallel with their profile shift from four repeat ( 4R) tau-positive pretangles to three repeat ( 3R) tau-positive ghost tangles with both positive neurofibrillary tangles in between. This complementary shift of tau profile from 4R to 3R suggests that these tau epitopes are represented interchangeably along tangle evolution. Similar tau immunoreactivity without fibril formation is also observed in corticobasal degeneration ( CBD-pretangles). CBD-pretangles and AD-pretangles share: (i) selective 4R tau immunoreactivity without involvement of 3R tau; and (ii) argyrophilia with Gallyas silver impregnation. However, CBD-pretangles neither evolve into ghost tangles nor exhibit 3R tau immunoreactivity even at the advanced stage. Because electron microscopic studies on these pretangles are quite limited, it remains to be clarified whether such differences in later evolution are related to their primary ultrastructures, potentially distinct between AD and CBD. As double staining for 3R and 4R tau clarified complementary shift from 4R to 3R tau along evolution from pretangles to ghost tangles, double immunoelectron microscopy, if possible, may clarify similar profile shifts in relation to each tau fibril at the ultrastructural dimension. This will provide a unique viewpoint on how molecular (epitope) representations are related to pathogenesis of fibrillary components. [ABSTRACT FROM AUTHOR]

Background Clinical presentations of pathologically confirmed corticobasal degeneration ( CBD) vary, and the heterogeneity makes its clinical diagnosis difficult, especially when a patient lacks any motor disturbance in the early stage. Methods We compared clinical and pathological features of four pathologically confirmed CBD cases that initially developed non-motor symptoms, including behavioural and psychiatric symptoms but without motor disturbance ( CBD- NM), and five CBD cases that initially developed parkinsonism and/or falls ( CBD- M). The age range at death for the CBD- NM and CBD- M subjects (58-85 years vs 45-67 years) and the range of disease duration (2-18 years vs 2-6 years) did not significantly differ between the groups. Results Prominent symptoms in the early stage of CBD- NM cases included self-centred behaviours such as frontotemporal dementia ( n = 1), apathy with and without auditory hallucination ( n = 2), and aggressive behaviours with delusion and visual hallucination ( n = 1). Among the four CBD- NM cases, only one developed asymmetric motor disturbance, and two could walk without support throughout the course. Final clinical diagnoses of the CBD- NM cases were frontotemporal dementia ( n = 2), senile psychosis with delirium ( n = 1), and schizophrenia ( n = 1). Neuronal loss was significantly less severe in the subthalamic nucleus and substantia nigra in the CBD- NM cases than in the CBD- M cases. The severity of tau pathology in all regions examined was comparable in the two groups. Conclusion CBD cases that initially develop psychiatric and behavioural changes without motor symptoms may have less severe degenerative changes in the subthalamic nucleus and substantia nigra, and some CBD cases can lack motor disturbance not only in the early stage but also in the last stage of the course. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

ABSTRACT An understanding of the anatomic distributions of major neurodegenerative disease lesions is important to appreciate the differential clinical profiles of these disorders and to serve as neuropathological standards for emerging molecular neuroimaging methods. To address these issues, here we present a comparative survey of the topographical distribution of the defining molecular neuropathological lesions among 10 neurodegenerative diseases from a large and uniformly assessed brain collection. Ratings of pathological severity in 16 brain regions from 671 cases with diverse neurodegenerative diseases are summarized and analyzed. These include: 1) amyloid-β and tau lesions in Alzheimer's disease; 2) tau lesions in three other tauopathies including Pick's disease, progressive supranuclear palsy and corticobasal degeneration; 3) α-synuclein inclusion ratings in four synucleinopathies including Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, and multiple system atrophy; and 4) TDP-43 lesions in two TDP-43 proteinopathies, including frontotemporal lobar degeneration associated with TDP-43 and amyotrophic lateral sclerosis. The data presented graphically and topographically confirm and extend previous pathological anatomic descriptions and statistical comparisons highlight the lesion distributions that either overlap or distinguish the diseases in each molecular disease category. J. Comp. Neurol. 521:4339-4355, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Recently, a number of genetic parkinsonian conditions have been recognized that share some features with the clinical syndromes of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA), the classic phenotypic templates of atypical parkinsonism. For example, patients with progranulin, dynactin, or ATP13A gene mutations may have vertical supranuclear gaze palsy. This has made differential diagnosis difficult for practitioners. In this review, our goal is to make clinicians aware of these genetic disorders and provide clinical clues and syndromic associations, as well as investigative features, that may help in diagnosing these disorders. The correct identification of these patients has important clinical, therapeutic, and research implications. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Recently, a hexanucleotide ( GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis ( FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration ( OPCD), atypical Parkinsonian syndrome ( APS) and a corticobasal syndrome ( CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene. [ABSTRACT FROM AUTHOR]

Abstract: Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer''s disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies. [Copyright &y& Elsevier]

Background: Multiple pathologies may underlie corticobasal syndrome (CBS), including Alzheimer's disease (AD). Dopamine transporter density imaging with Ioflupane 123 I SPECT (DaTscan) may be normal in CBS. No studies to date have examined the relationship between DaTscan status and underlying pathology in CBS., Objectives: The main objective of the study was to test whether a normal DaTscan in CBS patients is indicative of an underlying AD pathology, as determined by cerebrospinal fluid (CSF) biomarkers., Methods: Eighteen CBS patients were included. They were divided into patients with an AD and a non-AD disease pathology, based on their cerebrospinal fluid biochemical profile. A typical AD CSF profile was defined as an increase in total and phosphorylated at threonine 181 tau protein in addition to a decrease in amyloid-beta with 42 amino acids. DaTscan data were compared in these two groups., Results: Eight of the 18 CBS patients (44%) had a normal DaTscan. Seven of the 18 CBS patients (39%) had an AD cerebrospinal fluid biochemical profile. Two of seven CBS patients with AD biomarker profile had abnormal DaTscans. Three of 11 CBS patients with a non-AD biomarker profile had normal DaTscans. A normal DaTscan was indicative of AD pathology with suboptimal (~70%) sensitivity and specificity. Semi-quantitative DaTscan analysis did not differentiate between AD from non-AD CSF biomarker profile in CBS., Conclusion: A normal DaTscan is indicative of AD in CBS, but the sensitivity and specificity of DaTscan as an in vivo marker of AD pathology is suboptimal., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background The progressive supranuclear palsy syndrome ( PSPS) and corticobasal syndrome ( CBS) are associated with relatively specific patterns of atrophy; the former predominantly involving the brainstem, the latter frontoparietal regions. However, it has become apparent that there are subjects that meet criteria for PSPS and CBS. We refer to subjects with this presentation as Hybrids. The hybrid presentation is not rare, yet there are no studies that have assessed the neuroanatomical correlates of the hybrid syndrome to explain its occurrence. Method In this study of 41 subjects and controls, we utilized the technique of voxel-based morphometry to assess both gray and white matter volume loss in six prospectively recruited Hybrids that underwent 3.0 T volumetric head magnetic resonance image scanning to determine the neuroanatomical correlates of the syndrome. We compared patterns of atrophy in three prospectively recruited groups: the Hybrid group ( n = 6), a PSPS group ( n = 10), and CBS group ( n = 5). All 21 subjects had completed the same standardized batteries assessing cognition, and motor, behavioral, executive, oculomotor and limb praxis function. Results The Hybrid group showed imaging features of both PSPS and CBS, with volume loss observed in the brainstem (superior cerebellar peduncle) and cortex (medial and lateral premotor, prefrontal and motor cortex). As expected, typical patterns of loss were observed in PSPS and CBS. Conclusions These findings explain the neuroanatomical basis of the overlapping presenting signs and symptoms of PSPS and CBS, in Hybrids. [ABSTRACT FROM AUTHOR]

Dystonia is considered one of the classical features of corticobasal degeneration and is reported in up to 83% in clinical, not pathologically confirmed, series. Here, we aimed to establish the frequency and the clinical characteristics of dystonia in CBD by reviewing the literature on 404 pathologically proven cases. Further, we aimed to identify the frequency and characteristics of dystonia in all described phenotypes with CBD pathology. Dystonia was present in only 37.5% of the 296 cases with adequate information. The majority of the cases with dystonia presented with a corticobasal syndrome, and dystonia occurred in the first 2 years from disease onset, affecting the upper limb. In cases with dystonia that presented with a 'dementia' phenotype, dystonia tended to appear later in the disease course and to more affect the cervical region and the face. With regard to the distribution of the phenotypes, fifty-four percent of 374 cases presented as corticobasal syndrome, 15% as frontotemporal dementia, and 10.7% as progressive supranuclear palsy. Dystonia and myoclonus were present in about half of all cases with corticobasal syndrome, implying that these features may not be as frequent in corticobasal syndrome as are akinetic-rigid syndrome and apraxia (100% and 86.3%, respectively). Dystonia and myoclonus almost co-occurred in our analysis, suggesting a possible association. In conclusion, despite dystonia being an inclusion criterion in all sets of clinical criteria for corticobasal degeneration, this was present in only one third of the pathologically proven cases presented here. More accurate characterization of dystonia in corticobasal degeneration would be of importance for clinical diagnosis and development of treatment strategies. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]