Evidence of delayed nigrostriatal dysfunction in corticobasal syndrome: A SPECT follow-up study

ObjectiveTo demonstrate that degeneration of substantia nigra neurons may occur at later stages of disease in some patients with corticobasal syndrome (CBS) who evidenced preserved nigrostriatal pathway at a baseline FP-CIT SPECT study.BackgroundCurrent pathological criteria for the definite diagnosis of corticobasal degeneration consider substantia nigra cell loss as a mandatory finding. However, dopamine transporter SPECT imaging performed in a large cohort of CBS patients showed about 10% of normal scans.MethodsWe describe 4 patients with clinical diagnosis of CBS and normal FP-CIT SPECT at baseline whose tracer uptake resulted pathological at 1-year follow-up scan. Clinical assessment has been performed at the time of SPECT scan. A semi-quantitative approach was performed for striatal FP-CIT binding values.ResultsBaseline SPECT scans have been performed after 2.3 ± 1.5 years from onset. All CBS patients presented asymmetric rigid-akinetic parkinsonism (mean Hoehn-Yahr stage 2.5; UPDRS motor score 18) with poor levodopa response and ideo-motor limb apraxia. At follow-up, neurological examination revealed some additional features, including limb dystonia, language impairment, postural instability, ocular gaze impairment, alien limb. All patients showed pathological FP-CIT uptake at the SPECT performed 10–15 months apart from the baseline scan.ConclusionsOur longitudinal FP-CIT SPECT findings support in vivo the hypothesis that substantia nigra neuronal loss may occur at later stages in some patients with CBS, despite early extrapyramidal symptoms.     

Profound degeneration of wake-promoting neurons in Alzheimer's disease

IntroductionSleep-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.MethodsWe 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.ResultsThe 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.DiscussionWPNs 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.     

Tau and α-synuclein brainstem pathology in Alzheimer disease: relation with extrapyramidal signs

Extrapyramidal symptoms (EPS) in Alzheimer disease (AD) often increase with disease severity. Their neuropathological substrate is a matter of discussion. We investigated tau and alpha-synuclein (AS) pathologies in brainstem in AD patients with and without EPS. Among 160 elderly subjects with autopsy-proven AD (110 female, 50 male, aged 61-102, mean 84.1 +/- 8.3 SD years), 151 (94.4%) being demented, 35 (21.9%) had clinically reported EPS (rigidity, bradykinesia, gait impairment). Neuropathological examination included standardized classification of AD according to current criteria, and semiquantitative assessment of neuronal loss in substantia nigra (SN), locus coeruleus (LC), and of tau and AS lesions in brainstem, and, in addition, of cerebrovascular lesions. The prevalence of EPS was only slightly more frequent in higher Braak stages. Tau pathology in brainstem significantly increased with increasing Braak stages, while AS lesions did not. EPS correlated best with SN cell loss (P < 0.001) and much less with AS pathology in several brain areas (P < 0.05), except in medulla oblongata (P < 0.001). Although both pathologies in substantia nigra correlated with neuron loss (P < 0.001), nigral tau lesions, present in 88.5% of EPS positive cases (without AS lesions in 55.6%), did not correlate with EPS. Additional cerebrovascular changes apparently did not influence the development of EPS symptoms in fully developed AD. With other recent data, these results suggest that neuronal loss in SN, partly related to tau lesions, is a major pathological substrate of EPS in AD, but some cases with and without EPS may show no or only minimal nigral changes. However, often associated with nigral tau lesions and higher Braak stages, EPS in elderly patients may be a surrogate marker for severe neuritic AD pathology.     

Alzheimer's disease and corticobasal degeneration presenting as corticobasal syndrome

The aim of this article is to compare patients with Alzheimer's disease (AD) pathology and corticobasal degeneration pathology (CBD) presenting as corticobasal syndrome (CBS). Clinicopathologic series was used. Five patients with AD and 11 patients with CBD were clinically diagnosed with CBS. Patients with AD pathology had an earlier age of onset than patients with CBD pathology (58 vs. 68 years, P = 0.004), but the two groups had similar disease duration and core features of CBS. Tremors were only present in CBD cases (73%, P = 0.026), but myoclonus was more common in AD than CBD (80 vs. 18%, P = 0.036). Neuropsychological testing showed similar degrees of memory impairment and attentional deficits. ^99mTc‐HMPAO SPECT imaging demonstrated parietal hypoperfusion in AD patients and frontotemporal hypoperfusion in CBD patients. AD patients with clinical CBS have similar characteristics to CBD patients. Functional brain imaging may have greater utility than the clinical and neuropsychological features in differentiating AD presenting as CBS from CBD. © 2009 Movement Disorder Society     

Symmetric corticobasal degeneration (S-CBD)

BackgroundCorticobasal 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.ObjectiveTo 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.MethodsAll 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.ResultsFive 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.ConclusionsCBD 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.     

Dopamine D2 receptor SPECT in corticobasal syndrome and autopsy-confirmed corticobasal degeneration

BackgroundCorticobasal degeneration (CBD) is a rare neurodegenerative disorder characterized by tau-positive neuronal and glial lesions in the cortex and striatum with neuronal loss in cortical regions and in the substantia nigra. Striatal dopamine D2 receptor binding in autopsy-confirmed CBD has not been studied before.MethodsWe performed D2 receptor single photon emission computerized tomography using ¹²³I-IBZM in nine patients with a clinically diagnosed corticobasal syndrome (CBS) and on ten healthy controls. Two of the patients subsequently came to autopsy and were diagnosed with CBD.ResultsOverall striatal D2 receptor binding was preserved in 8/9 patients, but more asymmetric than in controls. Overall striatal binding in pathologically confirmed CBD was reduced in one case and normal in the other, and was lower contralateral to the clinically more affected side in both.ConclusionThis first study on D2 receptor imaging in autopsy-confirmed CBD demonstrates that loss of postsynaptic striatal neurons in CBD is a variable finding. Given the heterogeneity of our findings in pathology-confirmed cases, D2 receptor imaging seems to be of little practical value in the diagnostic workup of patients with CBS.     

Anatomical differences between CBS‐corticobasal degeneration and CBS‐Alzheimer's disease

We compare patterns of gray matter loss on MRI in subjects presenting as corticobasal syndrome (CBS) with Alzheimer disease pathology (CBS‐AD) to those presenting as CBS with corticobasal degeneration pathology (CBS‐CBD). Voxel‐based morphometry was used to compare patterns of gray matter loss in pathologically confirmed CBS‐AD subjects (n = 5) and CBS‐CBD subjects (n = 6) to a group of healthy controls (n = 20), and to each other. Atlas based parcellation using the automated anatomic labeling atlas was also utilized in a region‐of‐interest analysis to account for laterality. The CBS‐AD subjects were younger at the time of scan when compared with CBS‐CBD subjects (median: 60 years vs. 69; P = 0.04). After adjusting for age at time of MRI scan, the CBS‐AD subjects showed loss in posterior frontal, temporal, and superior and inferior parietal lobes, while CBS‐CBD showed more focal loss predominantly in the posterior frontal lobes when compared with controls. In both CBS‐AD and CBS‐CBD groups, there was basal ganglia volume loss, yet relative sparing of hippocampi. On direct comparisons between the two subject groups, CBS‐AD showed greater loss in both temporal and inferior parietal cortices than CBS‐CBD. No regions showed greater loss in the CBS‐CBD group compared to the CBS‐AD group. These findings persisted when laterality was taken into account. In subjects presenting with CBS, prominent temporoparietal, especially posterior temporal and inferior parietal, atrophy may be a clue to the presence of underlying AD pathology. © 2010 Movement Disorder Society     

Corticobasal degeneration with neither argyrophilic inclusions nor tau abnormalities: a new subgroup?

In corticobasal degeneration (CBD), cerebral cortical neuronal loss with achromasia and degeneration of the subcortical nuclei, particularly the substantia nigra, are common. Recent studies have suggested that the occurrence of argyrophilic nigral inclusions, resembling the neurofibrillary tangles found in progressive supranuclear palsy, and widespread tau abnormalities may be features of CBD. We studied brain tissues from two patients in whom CBD was suspected clinically. From the distribution of their cortical and subcortical lesions, the patients were diagnosed as having CBD. However, Gallyas/taupositive neuronal and glial structures were not found, which suggests there may be a subgroup of CBD with neither argyrophilic inclusions nor tau abnormalities.     

Corticobasal syndrome: recent advances and future directions

Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder described by Rebeiz et al. It is characterized by progressive, asymmetric, cortical (eg, apraxia, alien limb phenomena, cortical sensory loss, and myoclonus), and extrapyramidal (eg, rigidity, bradykinesia, dystonia, and tremor) dysfunction. However, CBD has many clinical phenotypes, and the features used for predicting CBD have low sensitivity. Therefore, the term corticobasal syndrome (CBS) has been used to characterize such clinical features, whereas the term CBD is used to refer to the pathological disorder. The most frequent causes of CBS are CBD, followed by Alzheimer's disease, progressive supranuclear palsy, frontotemporal lobar degeneration with TDP-43 pathology (sporadic and familial), Pick's disease, Lewy body disease, frontotemporal lobar degeneration with fused in sarcoma-positive inclusions, Creutzfeldt-Jakob disease, and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes. The topography of neurodegeneration dictates the clinical syndrome not according to the underlying pathology. Researchers have attempted to develop fluid biomarkers or imaging analysis for diagnosing CBS. The aim of this review was to highlight recent advances in CBS diagnosis and discuss future directions.     

Alzheimer's disease: Report of two autopsy cases with a clinical diagnosis of corticobasal degeneration

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Corticobasal degeneration (CBD) is a rare neurodegenerative disease affecting adults, being characterized clinically by a combination of extrapyramidal signs and focal cortical syndromes. In both diseases, tau deposits are a characteristic neuropathological feature. We report two new patients with autopsy‐proven AD, in whom clinical diagnoses of CBD were made during life. The ages of the patients at onset were 52 and 67 years, and the disease durations were 9 and 15 years, respectively. At autopsy, both cases exhibited marked cortical atrophy with evident neuronal loss in the convex areas of the frontal and parietal lobes. Immunohistochemically, AT8‐positive neurofibrillary tangles (NFTs) and Aβ‐positive senile plaques (SPs) were widespread and abundant in the cerebral cortex (Alzheimer pathology stage VI/C of Braak and Braak), leading us to the final pathological diagnosis of AD. No tau lesions suggestive of CBD were observed, and the deep gray matter areas, including the substantia nigra, were unremarkable (exceptionally, only mild neuronal loss was noted in the putamen in case 2). These findings further strengthen the idea that in AD, neurodegeneration with tau and Aβ deposits may begin in the fronto‐parietal neocortical areas, which are often preferentially affected in CBD, earlier than, or as early as the medial temporal lobe, and that extrapyramidal signs, such as rigidity and tremor, can occur in the absence of neuronal loss in the basal ganglia and substantia nigra.     

Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity

Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.     

Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome.

The objective of this study is to better define the pathological characteristics of pathologically proven progressive supranuclear palsy (PSP) presenting with the corticobasal syndrome (CBS). PSP is characterized by early falls, vertical supranuclear ophthalmoplegia, and axial rigidity, whereas asymmetric limb features, including rigidity, bradykinesia, apraxia, alien limb phenomena, and cortical sensory loss are characteristic of CBS. We investigated clinicopathological characteristics of 5 cases of PSP that presented with CBS (CBS-PSP). Comprehensive pathological analysis was undertaken to determine the presence of concomitant pathological processes as well as quantitative tau burden in cortical regions of CBS-PSP, compared with 8 typical PSP cases (Typ-PSP). The clinical features in the CBS-PSP cases included asymmetrical features, apraxia, alien limb phenomena, and progressive aphasia. All cases had Parkinsonism, and vertical supranuclear ophthalmoplegia was noted in all but 1 case of CBS-PSP. Secondary neuropathological diagnoses included argyrophilic grain disease (AGD) in 1 of the 8 cases of Typ-PSP, whereas Alzheimer's disease (AD), Lewy body disease, AGD, and vascular disease was found in 3 cases of CBS-PSP. Image analysis of cortical tau burden performed in 8 Typ-PSP and 3 CBS-PSP cases revealed a significant increased tau burden in mid-frontal and inferior-parietal cortices in the CBS-PSP cases. This study demonstrates that when PSP presents as CBS, it is most likely due to either a concurrent cortical pathology from a secondary process such as AD or from the primary pathology of PSP extending into cortical areas that are primarily and commonly affected in CBD.     

From Progressive Nonfluent Aphasia to Corticobasal Syndrome: A Case Report of Corticobasal Degeneration

In a previous report, we presented longitudinal clinical, cognitive and anatomical data of a right-handed woman, whose clinical picture evolved from progressive nonfluent aphasia with apraxia of speech to corticobasal syndrome (CBS) in the last stage of the disease. The patient died at age 57 and pathological examination revealed severe atrophy in the left frontal operculum and left premotor area. On histological examination, there was diffuse tau-positive pathology in gray and white cortical hemispheric gray and white matter, basal ganglia and substantia nigra, compatible with corticobasal degeneration (CBD). This case demonstrates the clinical overlap between frontotemporal lobar degeneration and CBD. In this case, early motor speech impairment predicted earlier and more accurately than CBS the presence of underlying tau-pathology and CBD.     

From progressive nonfluent aphasia to corticobasal syndrome: a case report of corticobasal degeneration

In a previous report, we presented longitudinal clinical, cognitive and anatomical data of a right-handed woman, whose clinical picture evolved from progressive nonfluent aphasia with apraxia of speech to corticobasal syndrome (CBS) in the last stage of the disease. The patient died at age 57 and pathological examination revealed severe atrophy in the left frontal operculum and left premotor area. On histological examination, there was diffuse tau-positive pathology in gray and white cortical hemispheric gray and white matter, basal ganglia and substantia nigra, compatible with corticobasal degeneration (CBD). This case demonstrates the clinical overlap between frontotemporal lobar degeneration and CBD. In this case, early motor speech impairment predicted earlier and more accurately than CBS the presence of underlying tau-pathology and CBD.     

The many faces of corticobasal degeneration

Corticobasal degeneration (CBD) has characteristic neuropathological features, but is a clinically heterogeneous disorder. It can present with various clinical syndromes. The corticobasal syndrome (CBS) is the best recognized and over the course of the illness may be the most common manifestation. Dementia, progressive non-fluent aphasia, speech apraxia, progressive supranuclear palsy (PSP)-like syndrome and posterior cortical atrophy syndrome are other presentations of CBD. The CBS is not specific for the pathology of CBD. Patients presenting as CBS have CBD as the underlying pathology in about 55% of the cases, PSP pathology in 20%, Pick's disease in 7%, and non tau pathology in the remaining. CBS is a sensitive clinical phenotype for tau pathology. Patients with CBS could potentially be candidates for therapies aiming to modify tau biochemistry.     

Cerebrospinal fluid biomarker profiling in corticobasal degeneration: Application of the AT(N) and other classification systems

IntroductionTotal tau (τT), phosphorylated tau (τP-181) and amyloid beta (Aβ42) are cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). There is no consensus on the interpretation criteria of these biomarkers. The aim of this study was to apply three different sets of criteria for CSF AD biomarker interpretation in a cohort of corticobasal degeneration (CBD) patients.MethodSForty patients fulfilling diagnostic criteria for “probable CBD” were included. The AT(N), BIOMARKAPD/ABSI and the τP-181/Aβ42 ratio criteria were applied.ResultsThe AT(N) criteria categorized 50% of “probable CBD” patients as AD, and 62.5% as harboring amyloid pathology. The BIOMARKAPD/ABSI and τP- 181/Aβ42 criteria categorized ~40% of “probable CBD” patients as AD.DiscussionUse of different interpretation criteria for CSF AD biomarkers produces diverse results. AD pathology is common in patients fulfilling “probable” CBD criteria. CBD diagnostic criteria may have suboptimal positive predictive value. A consensus regarding interpretation criteria of CSF AD biomarkers is pivotal.     

Corticobasal degeneration: a pathologically distinct 4R tauopathy

Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5(th) to 7(th) decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient. The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau. CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient's clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques. The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy. Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome. Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.     

Ubiquitin-positive achromatic neurons in corticobasal degeneration

A 66-year-old woman presented with an alien limb syndrome without dementia. The course of her illness was unremitting and at autopsy 6 years later her diagnosis was confirmed as corticobasal degeneration without Alzheimer-type pathology. Although the presence of ballooned achromatic cortical neurons and cell loss from the substantia nigra distinguishes such patients, the site and density of achromatic neurons has not previously been quantified. We show that immunohistochemistry for the cell stress protein ubiquitin selectively stains these achromatic neurons, whereas they do not stain for abnormally phosphorylated tau protein. Phosphorylated neurofilament antibodies recognise both ballooned and non-ballooned neurons. In this case, high densities of ubiquitin-positive ballooned neurons were found in frontal cortical regions with the highest densities in layers V and VI of the anterior cingulate cortex. In addition, high densities of ubiquitin-positive ballooned neurons were found in the insular cortex, claustrum and amygdala. These results confirm past reports of frontal pathology, but show that there is also considerable pathology in insular and parahippocampal cortical regions and some subcortical regions. Our findings suggest that the distribution and staining characteristics of ballooned neurons in corticobasal degeneration may help to differentiate these cases pathologically, while the absence of dementia appears to be an important clinical criterion.     

Brainstem Pathologies Correlate With Depression and Psychosis in Parkinson's Disease

BackgroundThe pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus.MethodsThe brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants’ history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation.ResultsOf the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ² = 7.1, p = 0.008, df = 1) and depression (χ² = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5–6.4, χ² = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3–5.0, χ² = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra.ConclusionThese results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.     

Sporadic corticobasal syndrome due to FTLD-TDP

Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.