Corticobasal Syndrome Cases Research Articles

Evaluation of Cerebrospinal Fluid α-Synuclein Seed Amplification Assay in Progressive Supranuclear Palsy and Corticobasal Syndrome.

Seed amplification assay (SAA) testing has been developed as a biomarker for the diagnosis of α-synuclein-related neurodegenerative disorders. The objective of this study was to assess the rate of α-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) and to analyze clinical and pathological features of SAA-positive and -negative cases. A total of 96 cerebrospinal fluid samples from clinically diagnosed PSP (n = 59) and CBS (n = 37) cases were analyzed using α-synuclein SAA. Six of 59 (10.2%) PSP cases were α-synuclein SAA positive, including one case who was MSA-type positive. An exploratory analysis showed that PSP cases who were Parkinson's disease-type positive were older and had a shorter disease duration compared with SAA-negative cases. In contrast, 11 of 37 (29.7%) CBS cases were α-synuclein SAA positive, including two cases who were MSA-type positive. Our results suggest that α-synuclein seeds can be detected in PSP and CBS using a cerebrospinal fluid α-synuclein SAA, and in PSP this may impact on clinical course. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The prioritization of biomarkers in the diagnostic workup of motor tauopathy

AbstractMotor tauopathies represent a spectrum of degenerative, poorly levodopa‐responsive parkinsonisms unified by the pathological accumulation of hyperphosphorylated tau protein fragments in the brain. The principal entities, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are rare conditions (<10 per 100,000) and present with non‐amnestic cognitive impairment ‐ mostly involving frontal‐subcortical networks – in around 40% of patients at baseline. Additionally, the phenotypic PSP spectrum expresses with oculomotor dysfunction, falls and bulbar symptoms at varying degrees. On the other hand, CBD tauopathy is the most frequent aetiology underlying the corticobasal syndrome (CBS) that is a multifaceted disorder characterized by a markedly asymmetric Parkinsonism with apraxia and neocortical deficits. Paralleling the clinical symptoms, the distribution of functional and metabolic impairment specifically involves different brain regions in PSP and CBD. Hence, metabolism assessment by FDG‐positron emission tomography (PET) allows for accurate distinction of motor tauopathies from other parkinsonisms or one with another (AUC 0.80 and 0.92‐0.97, respectively). In this context, the European Intersociety Consensus Diagnostic Task Force recommends the use of FDG‐PET as the first‐level diagnostic biomarker to achieve early and accurate differential diagnosis of motor tauopathies. Afterwards, the assessment of CSF biomarkers of Alzheimer’s disease (AD) is advised to identify that minority of cases of CBS underpinned by an AD aetiology (10‐20%). With this sequence of biomarkers, the diagnostic workflow aims to an early identification of motor tauopathies and advocates in‐depth etiological investigation of CBS where access to AD‐specific drugs, when available, should be considered in a non‐negligible proportion of patients.

PET-based classification of corticobasal syndrome

IntroductionCorticobasal degeneration (CBD) is the most common neuropathological substrate for clinically diagnosed corticobasal syndrome (CBS), while identifying CBD pathology in living individuals has been challenging. This study aimed to examine the capability of positron emission tomography (PET) to detect CBD-type tau depositions and neuropathological classification of CBS. MethodsSixteen CBS cases diagnosed by Cambridge's criteria and 12 cognitively healthy controls (HCs) underwent PET scans with 11C-PiB, 11C-PBB3, and 18F-FDG, along with T1-weighted magnetic resonance imaging. Amyloid positivity was assessed by visual inspection of 11C-PiB retentions. Tau positivity was judged by quantitative comparisons of 11C-PBB3 binding to HCs. ResultsSixteen CBS cases consisted of two cases (13%) with amyloid and tau positivities indicative of Alzheimer's disease (AD) pathologies, 11 cases (69%) with amyloid negativity and tau positivity, and three cases (19%) with amyloid and tau negativities. Amyloid(−), tau(+) CBS cases showed increased retentions of 11C-PBB3 in the frontoparietal areas, basal ganglia, and midbrain, and reduced metabolism in the precentral gyrus and thalamus relative to HCs. The enhanced tau probe retentions in the frontal gray and white matters partially overlapped with metabolic deficits and atrophy and correlated with Clinical Dementia Rating scores. ConclusionsPET-based classification of CBS was in accordance with previous neuropathological reports on the prevalences of AD, non-AD tauopathies, and others in CBS. The current work suggests that 11C-PBB3-PET may assist the biological classification of CBS and understanding of links between CBD-type tau depositions and neuronal deteriorations leading to cognitive declines.

Corticobasal syndrome as a phenotype of various neurodegenerative disorders: a case series

Corticobasal syndrome (CBS) is a variant of atypical parkinsonism. The underlying cause may be corticobasal degeneration or other proteinopathies, which can be verified only after studying specific biomarkers. The disease aetiology in CBS needs to be established to determine the disease prognosis. It can also affect the choice of pathogenetic treatment due to the differences in the molecular pathogenesis of proteinopathies that cause neurodegenerative processes. Four clinical cases of CBS are presented: in patients with four-repeat tauopathy, Alzheimer's disease, frontotemporal dementia and CreutzfeldtJakob disease. Examples are provided of the clinical, genetic and biochemical biomarkers available for differential diagnosis of CBS.

Non‐fluent/agrammatic variant of primary progressive aphasia with progressive supranuclear palsy

AbstractBackgroundNon‐fluent/agrammatic variante of primary progressive aphasia (nfvPPA) is a neurodegenerative disorder characterized by speech production impairment (1). The overlap of nfvPPA and progressive supranuclear palsy (PSP) and corticobasal syndrome cases have been reported (2). As nfvPPA progresses, a parkinsonian disorder often co‐occurs (3). There are different kinds of language impairment including articulatory deficits, agrammatism, reduced speech rate, and anomia (1). Here we present a Peruvian woman with nfvPPA with single‐photon emission computed tomography (SPECT) and parkinsonian syndrome.MethodWe describe a 73‐year‐old woman with progressive speech production impairment and parkinsonian syndrome. She completed standard neurological, neuropsychological, and speech‐language evaluations, as well as brain MRI and SPECT scan.ResultThe patient is a right‐handed woman with 16 years of education. No family history of dementia, parkinsonism or motor neuron disease was reported. At age 71, she presented progressive difficulty in speaking, anomia and verbal hesitancy; but she can understand conversations, send and read text messages. She also had depressive symptoms. MRI showed mild left frontal and perisylvian > right atrophy (fig 1).By age 73, she developed a prominent reduction in spontaneous speech, mild difficulties in reading and writing, occasional paraphasia, less empathy, dietary change, moria and, mild parkinsonism (she expresses less emotion, tremor, slowly walk and falls). Her episodic memory starts to decline thereafter.On examination, she had mild‐moderate telegraphic speech, imitation behavior, mild facial masking, bradykinesia and mild postural instability but no abnormal extraocular movement. Speech‐language assessment showed non‐fluent aphasia and apraxia of speech. Impaired comprehension of syntactically complex sentences. Naming was mildly impaired. Syntactic errors were present. Executive function was also impaired, but visuoperceptual skills were preserved.Serological analyses were unrevealing. Brain SPECT scan showed left frontal and perisylvian > right cortical hypoperfusion (fig 2).ConclusionWe report a Peruvian case of an elderly woman presenting with a 3‐year history of nfvPPA features and PSP. Her SPECT scan showed left frontal and perisylvian > right cortical hypoperfusion. Consider early evaluating motor function in nfvPPA patients in light of the possibility of CBS or PSP overlap.

Intracortical diffusion tensor imaging signature of microstructural changes in frontotemporal lobar degeneration

BackgroundFrontotemporal lobar degeneration (FTLD) is a neuropathological construct with multiple clinical presentations, including the behavioural variant of frontotemporal dementia (bvFTD), primary progressive aphasia—both non-fluent variant (nfvPPA) and semantic variant (svPPA)—progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), characterised by the deposition of abnormal tau protein in the brain. A major challenge for treating FTLD is early diagnosis and accurate discrimination among different syndromes. The main goal here was to investigate the cortical architecture of FTLD syndromes using cortical diffusion tensor imaging (DTI) analysis and to test its power to discriminate between different clinical presentations.MethodsA total of 271 individuals were included in the study: 87 healthy subjects (HS), 31 semantic variant primary progressive aphasia (svPPA), 37 behavioural variant (bvFTD), 30 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), 47 PSP Richardson’s syndrome (PSP-RS) and 39 CBS cases. 3T MRI T1-weighted images and DTI scans were analysed to extract three cortical DTI derived measures (AngleR, PerpPD and ParlPD) and mean diffusivity (MD), as well as standard volumetric measurements. Whole brain and regional data were extracted. Linear discriminant analysis was used to assess the group discrimination capability of volumetric and DTI measures to differentiate the FTLD syndromes. In addition, in order to further investigate differential diagnosis in CBS and PSP-RS, a subgroup of subjects with autopsy confirmation in the training cohort was used to select features which were then tested in the test cohort.Three different challenges were explored: a binary classification (controls vs all patients), a multiclass classification (HS vs bvFTD vs svPPA vs nfvPPA vs CBS vs PSP-RS) and an additional binary classification to differentiate CBS and PSP-RS using features selected in an autopsy confirmed subcohort.ResultsLinear discriminant analysis revealed that PerpPD was the best feature to distinguish between controls and all patients (ACC 86%). PerpPD regional values were able to classify correctly the different FTLD syndromes with an accuracy of 85.6%. The PerpPD and volumetric values selected to differentiate CBS and PSP-RS patients showed a classification accuracy of 85.2%.Conclusions(I) PerpPD achieved the highest classification power for differentiating healthy controls and FTLD syndromes and FTLD syndromes among themselves. (II) PerpPD regional values could provide an additional marker to differentiate FTD, PSP-RS and CBS.

Dual-Phase β-Amyloid PET Captures Neuronal Injury and Amyloidosis in Corticobasal Syndrome.

Objectives: In recent years several 18F-labeled amyloid PET (Aβ-PET) tracers have been developed and have obtained clinical approval. There is evidence that Aβ-PET perfusion can provide surrogate information about neuronal injury in neurodegenerative diseases when compared to conventional blood flow and glucose metabolism assessment. However, this paradigm has not yet been tested in neurodegenerative disorders with cortical and subcortical affection. Therefore, we investigated the performance of early acquisition 18F-flutemetamol Aβ-PET in comparison to 18F-fluorodeoxyglucose (FDG)-PET in corticobasal syndrome (CBS).Methods: Subjects with clinically possible or probable CBS were recruited within the prospective Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer’s Disease (ActiGliA) observational study and all CBS cases with an available FDG-PET prior to Aβ-PET were selected. Aβ-PET was acquired 0–10 min p.i. (early-phase) and 90–110 min p.i. (late-phase) whereas FDG-PET was recorded statically from 30 to 50 min p.i. Semiquantitative regional values and asymmetry indices (AI) were compared between early-phase Aβ-PET and FDG-PET. Visual assessments of hypoperfusion and hypometabolism were compared between both methods. Late-phase Aβ-PET was evaluated visually for assessment of Aβ-positivity.Results: Among 20 evaluated patients with CBS, 5 were Aβ-positive. Early-phase Aβ-PET and FDG-PET SUVr correlated highly in cortical (mean R = 0.86, range 0.77–0.92) and subcortical brain regions (mean R = 0.84, range 0.79–0.90). Strong asymmetry was observed in FDG-PET for the motor cortex (mean |AI| = 2.9%), the parietal cortex (mean |AI| = 2.9%), and the thalamus (mean |AI| = 5.5%), correlating well with AI of early-phase Aβ-PET (mean R = 0.87, range 0.62–0.98). Visual assessments of hypoperfusion and hypometabolism were highly congruent.Conclusion: Early-phase Aβ-PET facilitates assessment of neuronal injury in CBS for cortical and subcortical areas. Known asymmetries in CBS are captured by this method, enabling assessment of Aβ-status and neuronal injury with a single radiation exposure at a single visit.

The Significance of Vascular Pathogenesis in the Examination of Corticobasal Syndrome

Corticobasal syndrome (CBS) is a clinical entity, classified as an atypical Parkinsonism, characterized by both motor and higher cortical dysfunctions. The clinical manifestation of CBS is associated with several pathologies, among which corticobasal degeneration (CBD) is the most common. The aim of our study was to elaborate on the possible vascular pathogenesis of CBS and consider types of vascular lesions in these cases. Several cases of vascular CBS are described in the literature. The majority of presented patients were affected by internal carotid artery (ICA) stenosis and ischemic strokes; few cases were associated with vascular malformations or autoimmune diseases. Vascular CBS is preceded by an abrupt onset. The clinical manifestation does not significantly differ with non-vascular CBS. Patients with vascular CBS are usually elderly; often with coexistent hypertension, dyslipidemia and diabetes mellitus. Inferring from our observations, cerebral hypoperfusion can play a significant role in neuropathological changes in neurodegenerative diseases. To the best of our knowledge paper is the first comprehensive review of vascular CBS and we are positive that our observations show that further research concerning the vascular pathogenesis of tauopathy atypical Parkinsonism is required.

Unravelling Genetic Factors Underlying Corticobasal Syndrome: A Systematic Review.

Corticobasal syndrome (CBS) is an atypical parkinsonian presentation characterized by heterogeneous clinical features and different underlying neuropathology. Most CBS cases are sporadic; nevertheless, reports of families and isolated individuals with genetically determined CBS have been reported. In this systematic review, we analyze the demographical, clinical, radiological, and anatomopathological features of genetically confirmed cases of CBS. A systematic search was performed using the PubMed, EMBASE, and Cochrane Library databases, included all publications in English from 1 January 1999 through 1 August 2020. We found forty publications with fifty-eight eligible cases. A second search for publications dealing with genetic risk factors for CBS led to the review of eight additional articles. GRN was the most common gene involved in CBS, representing 28 out of 58 cases, followed by MAPT, C9ORF72, and PRNP. A set of symptoms was shown to be significantly more common in GRN-CBS patients, including visuospatial impairment, behavioral changes, aphasia, and language alterations. In addition, specific demographical, clinical, biochemical, and radiological features may suggest mutations in other genes. We suggest a diagnostic algorithm to help in identifying potential genetic cases of CBS in order to improve the diagnostic accuracy and to better understand the still poorly defined underlying pathogenetic process.

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied. To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD. This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019. Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures. A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05). These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.

MAPT p.V363I mutation

ObjectivePatients with corticobasal syndrome (CBS) present with heterogeneous clinical features, including asymmetric parkinsonism, dyspraxia, aphasia, and cognitive impairment; to better understand the genetic etiology of this rare disease, we undertook a genetic analysis of microtubule-associated protein tau (MAPT).MethodsWe performed a genetic evaluation of MAPT mutations in 826 neurologically healthy controls and 173 cases with CBS using the Illumina NeuroChip genotyping array.ResultsWe identified 2 patients with CBS heterozygous for a rare mutation in MAPT (p.V363I) that is located in the highly conserved microtubule-binding domain. One patient was pathologically confirmed and demonstrated extensive 4-repeat-tau-positive thread pathology, achromatic neurons, and astrocytic plaques consistent with corticobasal degeneration (CBD).ConclusionsWe report 2 CBS cases carrying the rare p.V363I MAPT mutation, one of which was pathologically confirmed as CBD. Our findings support the notion that this rare coding change is pathogenic.

In vivo retention of 18F-AV-1451 in corticobasal syndrome.

Objective:To study the usefulness of 18F-AV-1451 PET in patients with corticobasal syndrome (CBS).Methods:We recruited 8 patients with CBS, 17 controls, 31 patients with Alzheimer disease (AD), and 11 patients with progressive supranuclear palsy (PSP) from the Swedish BioFINDER study. All patients underwent clinical assessment, 18F-AV-1451 PET, MRI, and quantification of β-amyloid pathology. A subset of participants also underwent 18F-FDG-PET.Results:In the 8 patients with CBS, 6 had imaging findings compatible with the corticobasal degeneration pathology and 2 with typical AD pathology. In the 6 patients with CBS without typical AD pathology, there were substantial retentions of 18F-AV-1451 in the motor cortex, corticospinal tract, and basal ganglia contralateral to the most affected body side. These patients could be clearly distinguished from patients with AD dementia or PSP using 18F-AV-1451. However, cortical atrophy was more widespread than the cortical retention of 18F-AV1451 in these CBS cases, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results are in sharp contrast to AD dementia, where 18F-AV-1451 retention was more widespread than cortical atrophy, and correlated well with cortical thickness and hypometabolism.Conclusions:Patients with CBS without typical AD pathology exhibited AV-1451 retention in the motor cortex, corticospinal tract, and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD dementia or PSP. However, cortical atrophy measured with MRI and decreased 18F-fluorodeoxyglucose uptake were more widespread than 18F-AV-1451 uptake and probably represent earlier, yet less specific, markers of CBS.Classification of evidence:This study provides Class III evidence that 18F-AV-1451 PET distinguishes between CBS and AD or PSP.

Mutation analysis of C9orf72 in patients with corticobasal syndrome

Corticobasal syndrome (CBS) is a neurodegenerative disease characterized by progressive asymmetrical rigidity and apraxia, cortical sensory loss, myoclonus, dystonia, and cognitive impairment. CBS is usually sporadic and associated with tau pathology but there are reports of TDP-43 pathology. We screened 39 CBS cases to determine if any of the cases could be explained by a G4C2-repeat expansion in a noncoding region of C9orf72 gene, the most common genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. One patient with CBS had a large (>50 repeats) expansion in C9orf72. Our case features a 63-year-old right-handed woman who developed mild apathy 9 years before presentation, which progressed to include behavioral symptoms, oral stereotypies, significant language impairment, parkinsonism and apraxia. A magnetic resonance imaging acquired at age 60 years, that is, 6 years after disease onset revealed significant asymmetric left > right frontotemporal atrophy, including orbitofrontal and parietal areas. Her father developed a behavioral syndrome and died at an early age. This case highlights the importance of genetic screening for C9orf72 in patients with CBS.

Clinical Profile of PiB-Positive Corticobasal Syndrome

BackgroundCorticobasal syndrome (CBS) is a multifaceted neurodegenerative disorder characterized by a combination of motor and cognitive deficits. Several different pathological entities, including Alzheimer’s pathology, have been described in association with CBS. The present study aimed to establish clinical, neuropsychological, and neuroimaging features that could be useful in the distinction of CBS due to AD pathology from other CBS cases in life based on [11C] Pittsburgh Compound B positron emission tomography (PiB-PET) status.MethodsPatients with CBS were prospectively recruited from a specialized cognitive disorders clinic. All patients underwent detailed clinical and neuropsychological assessment, with structural imaging using voxel-based analysis of magnetic resonance imaging. Alzheimer’s pathology was detected using PiB-PET imaging, and PiB-positive and PiB-negative groups were compared.ResultsFourteen CBS patients meeting defined criteria were included (7 male, 7 female; mean age 66.1+/−6.9 years; median symptom duration was 35.5+/−22.6 months) and compared to 20 matched control subjects. Of the 14 patients, 4 were PiB-positive and 10 PiB-negative. There were no significant differences between PiB-positive and PiB-negative CBS patients in age, gender, education, symptom duration, or motor features. PiB-positive patients had greater visuospatial deficits, a higher rate of sentence repetition impairment, and more functional decline. Voxel-based morphometry analyses demonstrated extensive peri-insular and post-central atrophy in both groups, but PiB-positive patients had atrophy that extended to include the posterior part of the left superior temporal gyrus.ConclusionsVisuospatial function, aspects of language, and the pattern of cerebral atrophy may be useful in distinguishing patients with CBS due to underlying AD pathology.

Symmetric corticobasal degeneration (S-CBD)

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

Apraxia in progressive nonfluent aphasia

The clinical and neuroanatomical correlates of specific apraxias in neurodegenerative disease are not well understood. Here we addressed this issue in progressive nonfluent aphasia (PNFA), a canonical subtype of frontotemporal lobar degeneration that has been consistently associated with apraxia of speech (AOS) and in some cases orofacial apraxia, limb apraxia and/or parkinsonism. Sixteen patients with PNFA according to current consensus criteria were studied. Three patients had a corticobasal syndrome (CBS) and two a progressive supranuclear palsy (PSP) syndrome. Speech, orofacial and limb praxis functions were assessed using the Apraxia Battery for Adults-2 and a voxel-based morphometry (VBM) analysis was conducted on brain MRI scans from the patient cohort in order to identify neuroanatomical correlates. All patients had AOS based on reduced diadochokinetic rate, 69% of cases had an abnormal orofacial apraxia score and 44% of cases (including the three CBS cases and one case with PSP) had an abnormal limb apraxia score. Severity of orofacial apraxia (but not AOS or limb apraxia) correlated with estimated clinical disease duration. The VBM analysis identified distinct neuroanatomical bases for each form of apraxia: the severity of AOS correlated with left posterior inferior frontal lobe atrophy; orofacial apraxia with left middle frontal, premotor and supplementary motor cortical atrophy; and limb apraxia with left inferior parietal lobe atrophy. Our findings show that apraxia of various kinds can be a clinical issue in PNFA and demonstrate that specific apraxias are clinically and anatomically dissociable within this population of patients.

Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide

Mutations in the progranulin gene ( PGRN) are a major cause of frontotemporal lobar degeneration (FTLD). Herein we estimated the contribution of the PGRN Leu271LeufsX10 mutation to FTLD and related disorders in the Brescia cohort. The PGRN Leu271LeufsX10 mutation was found in 31% of corticobasal syndrome (CBS), 29% of frontotemporal dementia with motorneuron disease (FTD-MND), 15% of behavioral variant frontotemporal dementia (FTD), 9.5% of primary progressive aphasia (PPA), 2% dementia with Lewy bodies and 0% of progressive supranuclear palsy and multiple system atrophy cases. The prevalence strongly increased in familial forms (75% CBS, 50% FTD-MND, 27% FTD, 18% PPA): in our cohort this mutation is a major disease determinant for FTLD-related disorders with a prominent motor component. MAPT haplotype was demonstrated to be a disease modifier in PGRN Leu271LeufsX10 carriers: in H1H2 subjects the disease onset was earlier than in H2H2 individuals. Sequencing of the whole PGRN gene disclosed a previously described mutation (c.2T > C, Met1X) and three novel ones (c.709-3; c.1011delG, His340ThrfsX21; c.1021C > T, Gln341X) in single families. In the Brescia cohort, while MAPT mutations have low prevalence, mutations in PGRN were shown in 28% of familial FTLD and 75% of familial CBS cases. The PGRN Leu271LeufsX10 mutation becomes one of the most common mutations worldwide, since it was identified in 38 patients belonging to 27 unrelated families.