Pick's Disease Presenting as Tremulous Parkinsonism with Limited Levodopa Response-A Rare Cause of Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease. OBJECTIVES: We would like to highlight a rare but important differential of corticobasal syndrome. METHODS: A 78-year-old female had a 4-year history of predominantly right-hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right-sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post-mortem. RESULTS: The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau-related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease. CONCLUSIONS: Pick's disease can rarely present with clinical features of corticobasal syndrome.

Relationships between PET and blood plasma biomarkers in corticobasal syndrome.

INTRODUCTION: Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS. METHODS: A cohort of eighteen CBS patients (8 amyloid beta [Aß]+; 10 Aß-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake. RESULTS: CBS Aß+ group showed a reduced Aß42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aß- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aß- from CBS Aß+ and showed positive associations with Aß and tau PET uptake. DISCUSSION: This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology. HIGHLIGHTS: Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aß)- from CBS Aß+. Plasma neurofilament light concentrations are elevated in CBS Aß- and Aß+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aß and tau positron emission tomography (PET) uptake. Aß42/40 ratio showed a negative correlation with Aß PET uptake.

Comparing classic-onset corticobasal syndrome to speech/language-onset corticobasal syndrome.

INTRODUCTION: Patients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS. METHODS: We conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy. RESULTS: Median age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS. CONCLUSION: Classic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course.

Hypertrophy of the inferior olivary nucleus in corticobasal degeneration: A neuropathological study.

AIMS: Corticobasal degeneration (CBD) is a rare neurodegenerative disorder. The status of the inferior olivary nucleus (ION) in CBD has been inadequately investigated. In this study, we conducted a pathological investigation of the ION in CBD. MATERIALS AND METHODS: We reviewed the data of Japanese patients with pathologically confirmed CBD who underwent consecutive autopsies between 1985 and 2020 at our institute. We retrospectively examined clinical data from medical records and clinicopathological conferences and semi-quantitatively assessed the ION, central tegmental tract, superior cerebellar peduncle, and dentate nucleus. RESULTS: Of the 32 patients included, 14 (43.8%) had hypertrophy of the ION (HION), of whom 6 showed laterality. In the 14 HION cases, with or without laterality, except in 1 unevaluable case, atrophy/myelin pallor of the central tegmental tract was observed on the same side as the hypertrophy. Ten patients with HION, with or without laterality, had atrophy/myelin pallor of the superior cerebellar peduncle on the contralateral side to the hypertrophy. CONCLUSION: The ION presents with hypertrophic changes in CBD. The lesion is a primary degeneration in CBD and is related to the degeneration of the Guillain-Mollaret triangle. This finding contributes to the elucidation of the specific pathological characteristics of CBD.

Neuropathologic Validation and Diagnostic Accuracy of Presynaptic Dopaminergic Imaging in the Diagnosis of Parkinsonism.

BACKGROUND AND OBJECTIVES: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.

Localizing apraxia in corticobasal syndrome: a morphometric MRI study.

Apraxia localization has relied on voxel-based, lesion-symptom mapping studies in left hemisphere stroke patients. Studies on the neural substrates of different manifestations of apraxia in neurodegenerative disorders are scarce. The primary aim of this study was to look into the neural substrates of different manifestations of apraxia in a cohort of corticobasal syndrome patients (CBS) by use of cortical thickness. Twenty-six CBS patients were included in this cross-sectional study. The Goldenberg apraxia test (GAT) was applied. 3D-T1-weighted images were analyzed via the automated recon-all Freesurfer version 6.0 pipeline. Vertex-based multivariate General Linear Model analysis was applied to correlate GAT scores with cortical thickness. Deficits in imitation of meaningless gestures correlated with bilateral superior parietal atrophy, extending to the angular and supramarginal gyri, particularly on the left. Finger imitation relied predominantly on superior parietal lobes, whereas the left angular and supramarginal gyri, in addition to superior parietal lobes, were critical for hand imitation. The widespread bilateral clusters of atrophy in CBS related to apraxia indicate different pathophysiological mechanisms mediating praxis in neurodegenerative disorders compared to vascular lesions, with implications both for our understanding of praxis and for the rehabilitation approaches of patients with apraxia.

[Cortico-basal syndrome and cortico-basal degeneration: From the clinical diagnosis to the lesional substrate for an adapted care]. / Le syndrome cortico-basal et la dégénérescence cortico-basale : du diagnostic clinique au substrat lésionnel pour une prise en charge adaptée.

Cortico-basal degeneration is a relatively uncommon cause of degenerative parkinsonism in the elderly. From a clinical point of view, it manifests as a cortico-basal syndrome (CBS), featuring a highly asymmetrical akinetic-rigid syndrome, dystonia, myoclonus and cognitive-behavioral impairment with predominant apraxia. Other clinical phenotypes are possible, including variants with mainly language or behavioral impairment, or with axial, symmetrical parkinsonism resembling progressive supranuclear palsy (PSP). Current diagnostic criteria take into account the heterogeneity of clinical presentations. However, a diagnosis of certainty can only be reached by a pathological study, with the evidence of TAU-positive intraneuronal inclusions. Indeed SCB may be underpinned by other lesional substrates, ranging from frontotemporal degeneration to Alzheimer's disease. Symptom management must be early, multidisciplinary and adapted to the progression of the disorder. The identification of the pathological substrate is an essential prerequisite for pathophysiological therapeutic trials.

Differential Synaptic Loss in ß-Amyloid Positive Versus ß-Amyloid Negative Corticobasal Syndrome.

BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evaluating the Effect of Alzheimer's Disease-Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy.

OBJECTIVES: To evaluate the effect of Alzheimer's disease (AD) -related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). METHODS: Data from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained from the 4-R-Tauopathy Neuroimaging Initiative 1 and 2, the Alzheimer's Disease Neuroimaging Initiative, and a local cohort from the Toronto Western Hospital. Patients with CBS and PSP were divided into AD-positive (CBS/PSP-AD) and AD-negative (CBS/PSP-noAD) groups based on fluid biomarkers and amyloid PET scans. Cognitive, motor, and depression scores; AD fluid biomarkers (cerebrospinal p-tau, t-tau, and amyloid-beta, and plasma ptau-217); and neuroimaging data (amyloid PET, MRI and fMRI) were collected. Clinical features, whole-brain gray matter volume and functional networks connectivity were compared across groups. RESULTS: Data were analyzed from 87 CBS/PSP-noAD and 23 CBS/PSP-AD, 18 AD, and 30 healthy controls. CBS/PSP-noAD showed worse performance in comparison to CBS/PSP-AD in the PSPRS [mean(SD): 34.8(15.8) vs 23.3(11.6)] and the UPDRS scores [mean(SD): 34.2(17.0) vs 21.8(13.3)]. CBS/PSP-AD demonstrated atrophy in AD signature areas and brainstem, while CBS/PSP-noAD patients displayed atrophy in frontal and temporal areas, globus pallidus, and brainstem compared to healthy controls. The default mode network showed greatest disconnection in CBS/PSP-AD compared with CBS/PSP-no AD and controls. The thalamic network connectivity was most affected in CBS/PSP-noAD. INTERPRETATION: AD biomarker positivity may modulate the clinical presentation of CBS/PSP, with evidence of distinctive structural and functional brain changes associated with the AD pathology/co-pathology. ANN NEUROL 2024;96:99-109.

Age-Related Pathology in Corticobasal Degeneration.

Elderly human brains are vulnerable to multiple proteinopathies, although each protein has a different transmission pathway. Tau-immunoreactive astrocytes are well-known in elderly brains. In contrast, astrocytic plaques, a hallmark in corticobasal degeneration (CBD), rarely occur in aging and neurodegenerative disease other than CBD. To elucidate the clinicopathological correlation of aging-related pathology in CBD, we examined 21 pathologically proven CBD cases in our institute (12 males and 9 females, with a mean age of death 70.6 years). All CBD cases showed grains and neurofibrillary tangles (NFTs). Fifteen cases (71.4%) showed beta-amyloid deposition such as senile plaques or cerebral amyloid angiopathy. Three cases (14.3%) had Lewy body pathology. One case was classified as amygdala-predominant Lewy body disease, although no cases met the pathological criteria for Alzheimer's disease. Five cases (23.8%) displayed Limbic-predominant and age-related TDP-43 encephalopathy (LATE). NFTs, grains, and TDP-43-positive neuronal inclusions were widely distributed throughout the limbic system of CBD patients, but their densities were low. CBD might a have similar cell vulnerability and transmission pathway to that of multiple proteinopathy in aging brains.

SQSTM1 Pro392Leu presenting as a corticobasal syndrome with progressive nonfluent aphasia.

Corticobasal syndrome is generally considered to be a sporadic condition. There are familial and isolated genetic cases, associated with GRN, MAPT, c9orf72 or PNRP variants. Some reports implicate other genes: LRRK2, CHMP2B, GBA, CYP27A1, PSEN1, APP, TARDBP and TBK1. Here, we report a case of a patient carrying a SQSTM1 Pro392Leu variant. We report a 57-year-old right-handed-woman with a history of progressive speech impairment, marked right side rigidity and bradykinesia, with rest tremor and stimulus sensitive myoclonus. She had predominantly right-sided apraxia. She had right side agraphestesia and astereognosis. MRI showed asymmetrical left frontotemporoparietal atrophy. DaTSCAN showed predominantly left involvement, PiB-PET was negative. CSF NfL was of 9356.5pg/mL. She carried a heterozygous variant P392L in SQSTM1. This case report expands the spectrum of phenotypes associated with SQSTM1 pathogenic variants. It also expands the list of genes associated with corticobasal syndrome, supporting the involvement of the ubiquitin-proteasome system in this condition.

Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights.

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.

Nucleus Basalis of Meynert Degeneration Predicts Cognitive Decline in Corticobasal Syndrome.

BACKGROUND: Cognitive changes are common in corticobasal syndrome (CBS) and significantly impact quality of life and caregiver burden. However, relatively few studies have investigated the neural substrates of cognitive changes in CBS, and reliable predictors of cognitive impairment are currently lacking. The nucleus basalis of Meynert (NbM), which serves as the primary source of cortical cholinergic innervation, has been functionally associated with cognition. This study aimed to explore whether patients with CBS exhibit reduced NbM volumes compared with healthy control participants and whether NbM degeneration can serve as a predictor of cognitive impairment in patients with CBS. METHODS: In this study, we investigated in vivo volumetric changes of the NbM in 38 patients with CBS and 84 healthy control participants. Next, we assessed whether gray matter degeneration of the NbM evaluated at baseline could predict cognitive impairment during a 12-month follow-up period in patients with CBS. All volumetric analyses were performed using 3T T1-weighted images obtained from the 4-Repeat Tauopathy Neuroimaging Initiative. RESULTS: Patients with CBS displayed significantly lower NbM volumes than control participants (p < .001). Structural damage of the NbM also predicted the development of cognitive impairment in patients with CBS as assessed by longitudinal measurements of the Clinical Dementia Rating Sum of Boxes (p < .001) and Mini-Mental State Examination (p = .035). CONCLUSIONS: Our findings suggest that NbM atrophy may represent a promising noninvasive in vivo marker of cognitive decline in CBS and provide new insights into the neural mechanisms that underlie cognitive impairment in CBS.

The enigma of depression in corticobasal degeneration, a frequent but poorly understood co-morbidity.

Depression is one of the most frequent neuropsychiatric symptoms in corticobasal degeneration (CBD), a rare, sporadic, and late-onset progressive neurodegenerative disorder of unknown etiology. It is clinically characterized by a levodopa-poorly responsible akinetic-rigid syndrome, apraxia, limb dystonia, cognitive, mood, behavioral, and language disorders. This 4-repeat (4R) tauopathy is morphologically featured by asymmetric frontoparietal atrophy, neuronal loss, and gliosis in cortex and subcortex including substantia nigra, ballooned/achromatic neurons with filamentous 4R tau aggregates in cortex and striatum, widespread thread-like structures, pathognomonic "astroglial plaques", "tufted astrocytes", and numerous "coiled bodies" (in astrocytes and oligodendroglia) in cerebral white matter. CBD is non-specific, as pathologically proven cases include several clinical phenotypes. Pubmed and Google Scholar were systematically analyzed until October 2023, with focus on the prevalence, clinical manifestation, neuroimaging data, and treatment options of depression in CBD. Its prevalence is about 30-40% which is more frequent than in most other atypical parkinsonian syndromes. Depression usually does not correlate with motor and other clinical parameters, suggesting different pathophysiological mechanisms. Asymmetric atrophy and hypometabolism of frontoparietal cortical areas are associated with disruption of fronto-subcortical circuits, nigrostriatal dopaminergic, and cholinergic deficiency. Since no specific neuroimaging, neuropathological, or biomarker studies of depression in CBD are available, its pathobiological mechanisms and pathogenesis are poorly understood. Antidepressive therapy may be useful, but is often poorly tolerated. Depression in CBD, like in other parkinsonian syndromes, may be related to multi-regional patterns of cerebral disturbances and complex pathogenic mechanisms that deserve further elucidation as a basis for early diagnosis and adequate treatment to improve the quality of life in this fatal disease.

Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With ß-Amyloid-Negative CBS.

BACKGROUND AND OBJECTIVES: Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in ß-amyloid (Aß)-negative CBS. METHODS: We included patients with clinically diagnosed Aß-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). RESULTS: Overall, 21 patients with Aß-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. DISCUSSION: [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aß-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

Corticobasal degeneration with visual hallucination as an initial symptom: A case report.

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.

Clinical and MRI characterization of apraxic syndrome in corticobasal degeneration: A single-case study.

Objective: To identify the cortical and subcortical distribution of atrophy and the disorganization of white matter bundles underlying the apraxic disorders in a patient with corticobasal degeneration (CBD). Method: Patient underwent appropriate neuropsychological tasks aimed at identifying the nature of the apraxic disorder and morphometric structural MRI with whole-brain voxel-wise analysis. Results: Progressive limbkinetic apraxia (LKA) with onset in the right upper limb with subsequent extension to the limbs, trunk, orofacial district, and eye movements was documented, associated with element of ideomotor apraxia (IMA). The MRI study showed grey matter atrophy extending to much of the frontal cortex bilaterally, including the precentral cortex, and into the inferior parietal regions. Caudate and putamen were involved on the left. Significant clusters of white matter atrophy were found in the bilateral superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF) and corpus callosum (CC). Sensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were normal. Conclusion: Previous observations in CBD indicate lack of inhibitory control from the sensory to the primary motor cortex with dysfunctional frontoparietal and cortico-motoneuron projections. Our neuroimaging data are partially consistent with these observations suggesting that the apraxic disorder in our patient might be produced by the disconnection of the primary motor cortex from the parietal areas that prevents selection and control of muscle movements, in the presence of preserved cortico-motoneuron as demonstrated by normal PEM. Apraxic disorders in CBD are high-level deficits of movement control that spare the motoneuron.

Left and right corticobasal syndrome: comparison of cognitive profiles between metabolic imaging - matched groups.

BACKGROUND: Corticobasal syndrome (CBS) is typically asymmetric. Case reports suggest that left-hemisphere CBS (lhCBS) is associated with major language impairment, and right-hemisphere CBS (rhCBS) is associated with major visuospatial deficits, but no group study has ever verified these observations. In our study, we enrolled 49 patients with CBS, classified them as lhCBS or rhCBS based on asymmetry of hypometabolism on brain FDG-PET and compared their cognitive and behavioural profiles. METHODS: We defined asymmetry of hypometabolism upon visual inspection of qualitative PET images and confirmed it through paired comparison of left- and right-hemisphere FDG uptake values. The two groups were also matched for severity of hypometabolism within the more affected and more preserved hemispheres, to unravel differences in the cognitive profiles ascribable specifically to each hemisphere's functional specializations. All patients were assessed for memory, language, executive and visuospatial deficits, apraxia, neglect, dyscalculia, agraphia and behavioural disturbances. RESULTS: LhCBS (n. 26) and rhCBS (n. 23) patients did not differ for demographics, disease duration and severity of global cognitive impairment. The two cognitive profiles were largely overlapping, with two exceptions: Digit span forward was poorer in lhCBS, and visual neglect was more frequent in rhCBS. CONCLUSIONS: After balancing out patients for hemispheric hypometabolism, we did not confirm worse language or visuospatial deficits in, respectively, lhCBS and rhCBS. However, verbal short-term memory was more impaired in lhCBS, and spatial attention was more impaired in rhCBS. Both of these functions reflect the functional specialization of the left and right fronto-parietal pathways, i.e. of the main loci of neurodegeneration in CBS.

The Role of Dual-Phase 18 F-FP-CIT PET to Early Diagnosis of Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegeneration characterized by asymmetric parkinsonism, dystonia, myoclonus, and apraxia. In the early stage, CBS presents with asymmetric parkinsonism and cortical symptoms (apraxia and alien hand), and neuroimaging finding is often vague, making early clinical differentiation from idiopathic Parkinson disease (IPD) challenging. This study was performed to delineate the specific patterns of cortical hypoperfusion, dopamine transporter (DAT) uptake using dual-phase FP-CIT PET in discriminating between CBS and IPD at early stage. PATIENTS AND METHODS: The study enrolled clinically diagnosed CBS (n = 11) and IPD (n = 22) patients (age and sex matched). All participants underwent dual-phase 18 F-FP-CIT PET, and regional SUV ratio (SUVR) was obtained by semiquantitative analysis. The early perfusion imaging and DAT imaging were compared between groups. RESULTS: The regional SUVRs (early phase) of the frontal lobe, thalamus, cingulate, and caudate were significantly lower in patients with CBS, whereas the SUVR of occipital lobe was lower in the IPD group. The CBS group exhibited more prominent asymmetry than the IPD group, particularly in the perirolandic area, superior frontal gyrus, and anterior parietal lobe in early phase PET. Striatal DAT uptake (delayed phase) revealed that the caudate showed lower SUVR and prominent asymmetry in the CBS group, and the caudate-to-putamen ratio (CP ratio) was significantly lower in CBS patients ( P < 0.001). Among the parameters (early and delayed), the CP ratio in DAT exhibited the most powerful discriminative power from receiver operating characteristic curve comparison (area under curve = 0.983). CONCLUSIONS: This study demonstrated that the dual-phase FP-CIT PET is useful in differentiating CBS and IPD in the early stage of the disease, and a lower CP ratio of DAT imaging is highly informative for distinguishing between corticobasal degeneration and IPD.

Probable 4-Repeat Tauopathy Criteria Predict Brain Amyloid Negativity, Distinct Clinical Features, and FDG-PET/MRI Neurodegeneneration Patterns in Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome (CBS) is associated with diverse underlying pathologies, including the four-repeat (4R)-tauopathies. The Movement Disorders Society (MDS) criteria for progressive supranuclear palsy (PSP) proposed the novel category "probable 4R-tauopathy" to address the phenotypic overlap between PSP and corticobasal degeneration (CBD). OBJECTIVES: To investigate the clinical ability of the MDS-PSP criteria for probable 4R-tauopathy in predicting a negative amyloid-PET in CBS. Additionally, this study aims to explore CBS patients classified as 4R-tauopathy concerning their clinical features and neuroimaging degeneration patterns. METHODS: Thirty-two patients with probable CBS were prospectively evaluated and split into those who fulfilled or did not fulfill the 4R-tauopathy criteria (CBS-4RT+ vs. CBS-4RT-). All patients underwent positron emission tomographies (PET) with [18 F]fluorodeoxyglucose and [11 C]Pittsburgh Compound-B (PIB) on a hybrid PET-MRI scanner to perform multimodal quantitative comparisons with a control group. RESULTS: Eleven patients were clinically classified as CBS-4RT+, and only one had a positive PIB-PET. The CBS-4RT+ classification had 92% specificity, 52% sensitivity, and 69% accuracy in predicting a negative PIB-PET. The CBS-4RT+ group presented with dysarthria and perseveration more often than the CBS-4RT- group. Moreover, the CBS-4RT+ group showed a prominent frontal hypometabolism extending to the supplementary motor area and striatum, and brain atrophy at the anterior cingulate and bilateral striata. CONCLUSIONS: The 4R-tauopathy criteria were highly specific in predicting a negative amyloid-PET in CBS. Patients classified as 4R-tauopathy presented distinct clinical aspects, as well as brain metabolism and atrophy patterns previously associated with tauopathies.