Corticobasal Degeneration Pathology Research Articles

Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology

AbstractBackgroundProsopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.MethodA 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. V T values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.ResultAtrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.ConclusionAlthough prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology

AbstractBackgroundProsopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.MethodA 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. VT values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.ResultAtrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.ConclusionAlthough prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

Improving the early diagnosis of corticobasal syndrome: a large clinico-pathological study

BackgroundCorticobasal syndrome is associated with a heterogeneous spectrum of pathologies, with low predictive value for Corticobasal degeneration (CBD) pathology. Here, we validate the Armstrong criteria and interrogate clinical features to improve accurate diagnosis ante-mortem.MethodsWe applied Armstrong criteria to all archived cases with a clinical diagnosis of CBS or CBS- overlap syndrome over disease course. Clinical and radiological features were compared by pathologi- cal substrate.Results105 of 123 patients met diagnostic criteria for either Probable or Possible CBS/CBD of whom 38 (36%) had CBD and 79 (75%) had 4-repeat tauopathies (4RT). 3 years from onset, 8/22(36%) of those with Probable CBD and 19/48(40%) Possible CBD had pathology-confirmed CBD, whilst 11/35 (31%) were ‘Armstrong-negative”. Over disease course, PPV for CBD was similar (36%). Criteria were better at predicting 4RT, 82% and 75% within 3 years of onset and over disease course, respectively. Addition of specific language or behavioural abnormalities did not improve PPV. 46% patients met MDS PSP/CBS criteria over disease course, with 92% PPV for 4RT. No individual clinical feature was found to singularly predict underlying pathology.ConclusionThe Armstrong criteria have low predictive value for CBD both in early disease and over disease course. However, it has >80% prediction of 4RT. A combination of more specific biomarkers are required to improve diagnosis.d.lux@ucl.ac.uk

Traumatic brain injury and age at onset of cognitive decline in corticobasal degeneration, corticobasal syndrome, and progressive supranuclear palsy

AbstractBackgroundTraumatic brain injury (TBI) has been repeatedly shown to be a risk factor for several neurodegenerative diseases. However, no studies have yet examined TBI as a risk factor for corticobasal degeneration (CBD) or corticobasal syndrome (CBS), and few have examined progressive supranuclear palsy (PSP) in relation to TBI.MethodThis is a retrospective observational study using the National Alzheimer’s Coordinating Centers (NACC) database. TBI status was assessed based on self‐reported history. Clinicians estimate was used for determining age at onset (AAO) of cognitive decline and autopsy examination was used for neuropathological diagnosis of CBD and PSP. The most recent assessment of participants was used as of June 2018, including participant visits which occurred between 2005 and 2018. The NACC dataset includes a total of 38,249 participants. 101 (14 TBI+) participants were included with clinical (antemortem) diagnoses of PSP and 137 (16 TBI+) with CBS. 2,743 autopsy samples were also included, including 120 (14 TBI+), 58 (7 TBI+), and 11 (1 TBI+) with neuropathological (autopsy) diagnoses of PSP, CBD, or both, respectively. 181 (21 TBI+) of the participants with autopsy diagnosed PSP or CBD had antemortem cognitive decline.ResultTBI is associated with a significant 4‐year earlier AAO of cognitive decline among participants with an antemortem diagnosis of CBS and a 6‐year earlier AAO in participants with autopsy diagnosed PSP. Additionally, TBI among participants with autopsy diagnosed CBD without concomitant Alzheimer’s disease (AD) neuropathology was associated with a 7‐year earlier AAO of cognitive decline (p=.066). History of TBI was not significantly associated with the prevalence of PSP and/or CBD pathology postmortem.ConclusionThis is the first report linking TBI with an earlier onset of cognitive decline in CBS and in neuropathologically defined PSP.

Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice.

The aggregation of abnormally phosphorylated tau protein in neurons and glia is a neuropathological hallmark of several neurodegenerative disorders, collectively known as tauopathies. They are further subclassified based on the preferential pathological aggregation of three carboxyl-terminal repeat domains (3R) and/or 4R tau. Corticobasal degeneration (CBD) is a rare neurodegenerative disorder classified as a 4R tauopathy. In the present study, we extend analysis of CBD-tau cell-type specific pathology transmission with 3R and 4R tau isoform distinguishable changes. We use a humanized tau (hTau) mouse line, which overexpress all six human tau isoforms in a murine tau knockout background and perform intrastriatal inoculation of control and CBD-tau enriched human brain homogenate. We show that CBD-tau causes hyperphosphorylation of tau at Ser202 predominantly in oligodendrocytes. Next, we demonstrate the spread of tau pathology from striatum to the overlaying corpus callosum and further to the contralateral side. Finally, we demonstrate that the almost exclusive oligodendrocyte-based transmission of hyperphosphorylated tau is reflected in the endogenous 4R tau isoform expression and corresponds to subclassification of CBD as a 4R tauopathy. Additionally, we identify functional changes in oligodendrocytes reflected by myelin basic protein abnormalities upon CBD-tau inoculation. These changes are not observed in murine tau knockout mice lacking both human and murine tau. Our study presents not only in vivo tau isoform–driven region- and cell-specific tau pathology, but also underlines that tau pathology seeding and transmission might be oligodendrocyte-based. These results, which need to be extended to more cases, give new insights into why tauopathies might vary greatly in both histopathological and neuroanatomical patterns.

18F-AV-1451 positron emission tomography in neuropathological substrates of corticobasal syndrome.

Multiple neuropathological processes can manifest in life as a corticobasal syndrome. We sought to relate retention of the tau-PET tracer 18F-AV-1451 and structural magnetic resonance measures of regional atrophy to clinical features in clinically diagnosed and neuropathologically confirmed cases of corticobasal syndrome and to determine whether these vary with the underlying neuropathological changes. In this observational, cross-sectional study, 11 subjects (eight female and three male, median age 72 years) with corticobasal syndrome underwent structural MRI, tau-PET with 18F-AV-1451, amyloid-PET with 11C-Pittsburgh compound B, detailed clinical examinations and neuropsychological testing. Of the 11, three had evidence of high amyloid burden consistent with Alzheimer's disease while eight did not. Neuropathological evaluations were acquired in six cases. Mixed effects general linear models were used to compare 18F-AV-1451 retention and atrophy in amyloid-negative corticobasal syndrome cases to 32 age-matched healthy control subjects and to relate cortical and subcortical 18F-AV-1451 retention and atrophy to clinical features. Subjects without amyloid, including three with pathologically confirmed corticobasal degeneration, showed greater regional 18F-AV-1451 retention and associated regional atrophy in areas commonly associated with corticobasal degeneration pathology than healthy control subjects [retention was higher compared to healthy controls (P = 0.0011), driven especially by the precentral gyrus (P = 0.011) and pallidum (P < 0.0001), and greater atrophy was seen in subjects compared to control subjects (P = 0.0004)]. Both 18F-AV-1451 retention and atrophy were greater in the clinically more affected hemisphere [on average, retention was 0.173 standardized uptake value ratio units higher on the more affected side (95% confidence interval, CI 0.11-0.24, P < 0.0001), and volume was 0.719 lower on the more affected side (95% CI 0.35-1.08, P = 0.0001)]. 18F-AV-1451 retention was greater in subcortical than in cortical regions, P < 0.0001. In contrast to these findings, subjects with amyloid-positive corticobasal syndrome, including two neuropathologically confirmed cases of Alzheimer's disease, demonstrated greater and more widespread 18F-AV-1451 retention and regional atrophy than observed in the amyloid-negative cases. There was thalamic 18F-AV-1451 retention but minimal cortical and basal ganglia uptake in a single corticobasal syndrome subject without neuropathological evidence of tau pathology, likely representing non-specific signal. Asymmetric cortical and basal ganglia 18F-AV-1451 retention consonant with the clinical manifestations characterize corticobasal syndrome due to corticobasal degeneration, whereas the cortical retention in cases associated with Alzheimer's disease is greater and more diffuse.

Progressive aphasia, apraxia of speech and agraphia in corticobasal degeneration: A 12-case series clinical and neuropsychological descriptive study.

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

Individual Brain Metabolic Signatures in Corticobasal Syndrome.

Corticobasal syndrome (CBS) is the usual clinical presentation of patients with corticobasal degeneration pathology. Nevertheless, there are CBS individuals with postmortem neuropathology typical of Alzheimer's disease (AD). In this study, we aim to detect FDG-PET metabolic signatures at the single-subject level in a CBS sample, also evaluated with cerebrospinal fluid (CSF) markers for AD pathology. 21 patients (68.9±6.4 years; MMSE score = 21.7±6.3) fulfilling current criteria for CBS were enrolled. All underwent a clinical-neuropsychological assessment and an instrumental evaluation for biomarkers of neurodegeneration, amyloid and tau pathology (i.e., FDG-PET imaging and CSF Aβ42 and tau levels) at close intervals. CBS subjects were classified according to the presence or absence of CSF markers of AD pathology (i.e., low Aβ42 and high phosphorylated tau levels). Optimized voxel-based SPM procedures provided FDG-PET metabolic patterns at the single-subject and group levels. Eight CBS had an AD-like CSF profile (CBS-AD), while thirteen were negative (CBS-noAD). The two subgroups did not differ in demographic characteristics or global cognitive impairment. FDG-PET SPM t-maps identified different metabolic signatures. Namely, all CBS-AD patients showed the typical AD-like hypometabolic pattern involving posterior cingulate cortex, precuneus and temporo-parietal cortex, whereas CBS-noAD cases showed bilateral hypometabolism in fronto-insular cortex and basal ganglia that is typical of the frontotemporal lobar degeneration spectrum. These results strongly suggest the inclusion of FDG-PET imaging in the diagnostic algorithm of individuals with CBS clinical phenotype in order to early identify functional metabolic signatures due to different neuropathological substrates, thus improving the diagnostic accuracy.

Clinicopathologic subtype of Alzheimer's disease presenting as corticobasal syndrome

IntroductionThe corticobasal syndrome (CBS) is associated with several neuropathologic disorders, including corticobasal degeneration and Alzheimer's disease (AD). MethodIn this report, we studied 43 AD patients with CBS (AD-CBS) and compared them with 42 AD patients with typical amnestic syndrome (AD-AS), as well as 15 cases of corticobasal degeneration and CBS pathology. ResultsUnlike AD-AS, AD-CBS had prominent motor problems, including limb apraxia (90%), myoclonus (81%), and gait disorders (70%). Alien limb phenomenon was reported in 26% and cortical sensory loss in 14%. Language problems were also more frequent in AD-CBS, and memory impairment was less frequent. AD-CBS had more tau pathology in perirolandic cortices but less in superior temporal cortex than AD-AS. In addition, AD-CBS had greater neuronal loss in the substantia nigra. DiscussionAD-CBS is a clinicopathological subtype of AD with an atypical distribution of Alzheimer-type tau pathology. Greater neuronal loss in the substantia nigra may contribute to Parkinsonism which is not a feature of typical AD.

Corticobasal degeneration.

Corticobasal degeneration (CBD) is a rare neurodegenerative disease characterized by the predominance of pathological 4 repeat tau deposition in various cell types and anatomical regions. Corticobasal syndrome (CBS) is one of the clinical phenotypes associated with CBD pathology, manifesting as a progressive asymmetric akinetic-rigid, poorly levodopa-responsive parkinsonism, with cerebral cortical dysfunction. CBD can manifest as several clinical phenotypes, and similarly, CBS can also have a pathologic diagnosis other than CBD. This chapter discusses the clinical manifestations of pathologically confirmed CBD cases, the current diagnostic criteria, as well as the pathologic and neuroimaging findings of CBD/CBS. At present, therapeutic options for CBD remain symptomatic. Further research is needed to improve the clinical diagnosis of CBD, as well as studies on disease-modifying therapies for this relentlessly progressive neurodegenerative disorder.

Corticobasal degeneration: key emerging issues.

Corticobasal degeneration (CBD) was first described by Rebeiz et al. in 1967, and was called corticodentatonigral degeneration with neuronal achromasia [1]. Since then, our knowledge of the clinical features and underlying tau pathology has grown tremendously. Clinical antemortem diagnosis of CBD pathology remains challenging and has led to the development of revised diagnostic criteria. As various clinical phenotypes may have CBD pathology, accurate prevalence studies are lacking. Recently, pooled prevalence of fronto-temporal lobar degeneration, PSP and CBS was reported as 10.6 per 100,000 [2]. Although rare, CBD is an important disease to understand because it provides a model of a specific proteinopathy (tauopathy) and, therefore, opportunity to study pathophysiology of tauopathies and efficacy of tau-directed therapies. In the past few years, identification of tau specific ligands has advanced neuroimaging of tauopathies such as CBD and progressive supranuclear palsy. However, clinical prediction of CBD pathology remains challenging and an active are of research. In this review, we highlight key emerging issues in CBD pathophysiology, genetics and novel neuroimaging techniques with tau ligands.

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.

Presymptomatic anterior frontal involvement in corticobasal degeneration.

This scientific commentary refers to ‘Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology’ by Ling et al. (doi:10.1093/brain/aww256) . One of the biggest challenges in the development of treatment for neurodegenerative disorders is being able to spot the earliest signs of disease, given that the underlying pathological changes may commence many years before clinical features develop. While models of pathological staging and spread have been established for common neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, the pattern of presymptomatic spread of rarer conditions, such as the neurodegenerative tauopathy corticobasal degeneration (CBD), is less well characterized. In this issue of Brain , Ling et al. (2016) demonstrate early CBD pathology in three asymptomatic cases. The authors propose, by comparison with late-stage disease, that astroglial pathology dominates at this early stage, with an anterior–posterior gradient of pathological change in the frontal lobe during disease progression. The Braak staging system used in Alzheimer’s disease (Braak et al. , 2006) depicts a spread of tau pathology from medial temporal lobe structures to neocortical regions with disease progression. Similarly, current concepts of Parkinson’s disease indicate initial Lewy body pathology in the dorsal motor nucleus of the vagus and olfactory bulb, spreading to the midbrain and thereafter to neocortical structures (Braak et al. , 2003). Several factors have been crucial to the development of these staging systems. First, both conditions are relatively common, and the existence of monogenic inherited forms has allowed more accurate study of disease mechanisms and progression. Second, the identification of ‘presymptomatic’ features such as mild cognitive impairment, hyposmia and REM sleep behaviour disorder has enabled better understanding of disease evolution. Third, techniques such as amyloid-β PET imaging and the use of CSF biomarkers have permitted identification of early or presymptomatic disease. Indeed, in the case of Alzheimer’s disease, the …

Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology

SEE KOBYLECKI AND MANN DOI101093/AWW267 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Animal models have shown that tau seeding and propagation are strain- and neural network-specific. The study of preclinical cases is valuable to gain insights into early pathological features of corticobasal degeneration and its progression. Three preclinical corticobasal degeneration cases and six age-matched end-stage corticobasal degeneration cases were included in this study. Tau immunohistochemistry performed in 20 brain regions and quantitative assessment of regional tau load using image analysis were performed. Semi-quantitative grading of tau-positive cellular lesions and neuronal loss in the frontal, parietal and temporal cortices, striatum, substantia nigra and subthalamic nucleus were assessed. All preclinical cases were clinically asymptomatic but had widespread tau lesions in the typically affected regions in corticobasal degeneration and the pathognomonic astrocytic plaques were the most prominent lesion type in the anterior frontal and striatal regions. Mean total tau load (sum of all regional tau load) of end-stage corticobasal degeneration cases were nine times greater than that of the preclinical cases (P = 0.04) and less tau load was found in all regions of the preclinical cases. An anterior-to-posterior tau load ratio in the frontal cortex in preclinical cases was 12-fold greater than in end-stage corticobasal degeneration cases. Relatively greater tau burden in the anterior frontal cortex, striatum and subthalamic nucleus suggests the striatal afferent connection to the dorsolateral prefrontal cortex and basal ganglia circuitry are the earliest neural network connections affected by corticobasal degeneration-related tau pathology. Differential distribution of the tau pathology to selective cortical regions in these preclinical cases implies phenotypic presentation may be predetermined at a very early stage of the disease process. Neuronal loss of the substantia nigra was either absent or very mild in the preclinical cases and was moderate to severe in end-stage corticobasal degeneration cases (P < 0.05). Our findings suggest that a threshold of pathological burden in the 'right' anatomical regions needs to be reached before the onset of clinical symptoms. The early prominence of the astrocytic plaques in relation to sparse neuronal lesions leads one to speculate that corticobasal degeneration may begin as an astrogliopathy at a very early disease stage but neuronal lesions gradually take over as the predominant lesion type in advanced disease.

Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration.

We provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy. To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA-in whom either PSP or CBD was eventually confirmed at autopsy-at initial presentation and at 1-year follow-up. A prospective longitudinal clinical-pathological study was conducted in a tertiary research clinic that specialized in cognitive disorders. Fourteen patients were evaluated between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging within 6 months of initial evaluation; and a postmortem pathological diagnosis of PSP or CBD. Ten matched healthy control participants were also included. Clinical, cognitive, and neuroimaging longitudinal data were analyzed to characterize the whole nfvPPA-4-repeat-tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD both at presentation and longitudinally. Patient groups did not differ significantly in age, sex, or handedness (nfvPPA-PSP group: median [interquartile range (IQR)] age, 74 [67-76] years; 1 of 5 male [20%]; 1 of 5 left-handed [20%]; and nfvPPA-CBD group: mean [IQR] age, 65 [54-81] years; 3 of 9 male [33%]; 0 left-handed). Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria (Motor Speech Examination median [IQR] score: nfvPPA-PSP, 4 [2-7]; nfvPPA-CBD, 0 [0-4]; P = .02), depression (Geriatric Depression Scale median [IQR] score: nfvPPA-PSP, 19 [3-28]; nfvPPA-CBD, 4 [0-16]; P = .04), and relatively selective white matter atrophy were typical of the nfvPPA-PSP group, while greater gray matter atrophy and a trend toward greater sentence comprehension deficits (median [IQR] sentence comprehension correct: nfvPPA-PSP, 98% [80-100]; nfvPPA-CBD, 81% [65-98]; P = .08) were found in the nfvPPA-CBD group. At follow-up after 1 year, we observed no significant differences in any speech or language measures. Furthermore, atrophy in patients with PSP progressed within the subcortical/brainstem motor system generating greater oculomotors deficits and swallowing difficulty; atrophy in patients with CBD spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral symptoms. In patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and a greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.

Argyrophilic Grains Are Reliable Disease-Specific Features of Corticobasal Degeneration

Argyrophilic grains are discrete punctate structures that bind to silver stains; they can be observed within the neuropil of the limbic system, particularly in the elderly. It has been reported that argyrophilic grains are more frequent in patients with corticobasal degeneration (CBD) compared with the elderly population in general. To determine the frequency and significance of argyrophilic grains in CBD, we examined the temporal lobes from 35 patients with autopsy-proven CBD (mean age, 69.1 years) and 28 patients with argyrophilic grain disease (mean age, 95.7 years). Grain distributions and densities were evaluated semiquantitatively using Gallyas-Braak stains and immunohistochemistry with AT8 and RD4 antibodies. Argyrophilic grains were observed in all CBD cases (100%) despite a lower average age at death in this population. We also observed the following features that were specific to argyrophilic grains in CBD: 1) grains were likely to be widespread throughout the temporal lobe, 2) grains were consistently found with abundant argyrophilic threads, and 3) the ultrastructure of grains contained paired helical filaments with a periodicity of 120 to 130 nm. In conclusion, we confirm that argyrophilic grains in CBD are specifically related to the 4-repeat tau pathology of CBD and are not simply a result of aging.

Pathology and sensitivity of current clinical criteria in corticobasal syndrome

The aim of this study was to investigate corticobasal syndrome with respect to underlying pathologies, the ability of current clinical criteria to detect early stages of disease, and symptoms and signs predicting background pathologies. We retrospectively analyzed the clinicopathological findings from patients with corticobasal syndrome. We also analyzed whether those findings fulfilled the diagnostic criteria for corticobasal degeneration (CBD). Finally, we investigated characteristic clinical features that are specific to each background pathology. Of 10 consecutive autopsied patients who had corticobasal syndrome (mean age ± standard deviation, 67.9 ± 9.3 years; male:female ratio, 6:4), three had corticobasal degeneration pathology, three had progressive supranuclear palsy, three had Alzheimer's disease, and one had atypical four-repeat tauopathy. Nine patients fulfilled Mayo criteria, and all 10 patients fulfilled modified Cambridge criteria at the later stage, but only two patients fulfilled either clinical criteria within 2 years of disease onset. Five patients fulfilled the clinical criteria for possible CBD (p-CBD), and one patient fulfilled the clinical research criteria for probable sporadic CBD (cr-CBD) at the later stage. Only two patients fulfilled the criteria for either p-CBD or cr-CBD within 2 years of disease onset. Although we could not find any predictive characteristic clinical features that were specific to CBD pathology, only patients with progressive supranuclear palsy developed apraxia of eyelid opening and cerebellar ataxia. Myoclonus and memory impairment, especially if they appear at an early stage of the disease, may predict Alzheimer's disease pathology. Sensitivity of the available clinical criteria for corticobasal syndrome was poor within 2 years of disease onset.

Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72

BackgroundCases of Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND) associated with expansions in C9ORF72 gene are characterised pathologically by the presence of TDP-43 negative, but p62 positive, inclusions in granule cells of the cerebellum and in cells of dentate gyrus and area CA4 of the hippocampus.ResultsWe screened 84 cases of pathologically confirmed FTLD and 23 cases of MND for the presence of p62 positive inclusions in these three brain regions, and identified 13 positive cases of FTLD and 3 of MND. All cases demonstrated expansions in C9ORF72 by Southern blotting where frozen tissues were available. The p62 positive inclusions in both cerebellum and hippocampus were immunostained by antibodies to dipeptide repeat proteins (DPR), poly Gly-Ala (poly-GA), poly Gly-Pro (poly-GP) and poly Gly-Arg (poly-GR), these arising from a putative non-ATG initiated (RAN) sense translation of the GGGGCC expansion. There was also some slight, but variable, immunostaining with poly-AP antibody implying some antisense translation might also occur, though the relative paucity of immunostaining could reflect poor antigen avidity on the part of the antisense antibodies. Of the FTLD cases with DPR, 6 showed TDP-43 type A and 6 had TDP-43 type B histology; one had FTLD-tau with the pathology of corticobasal degeneration. There were no qualitative or quantitative differences in the pattern of immunostaining with antibodies to DPR, or p62, proteins between TDP-43 type A and type B cases. Ratings for frequency of inclusions immunostained by these poly-GA, poly-GP and poly-GR antibodies broadly correlated with those for immunolabelled by p62 antibody in all three regions.ConclusionWe conclude that DPR are a major component of p62 positive inclusions in FTLD and MND.

Midbrain atrophy is not a biomarker of progressive supranuclear palsy pathology

Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), although it is unclear whether it is associated with the PSP syndrome (PSPS) or PSP pathology. The aim of the present study was to determine whether midbrain atrophy is a useful biomarker of PSP pathology, or whether it is only associated with typical PSPS. All autopsy-confirmed subjects were identified with the PSP clinical phenotype (i.e. PSPS) or PSP pathology and a volumetric MRI. Of 24 subjects with PSP pathology, 11 had a clinical diagnosis of PSPS (PSP-PSPS), and 13 had a non-PSPS clinical diagnosis (PSP-other). Three subjects had PSPS and corticobasal degeneration pathology (CBD-PSPS). Healthy control and disease control groups (i.e. a group without PSPS or PSP pathology) and a group with CBD pathology and corticobasal syndrome (CBD-CBS) were selected. The midbrain area was measured in all subjects. [Correction added on 21 June 2013, after first online publication: the abbreviation of corticobasal degeneration pathology was changed from CBD-PSP to CBD-PSPS.] The midbrain area was reduced in each group with clinical PSPS (with and without PSP pathology). The group with PSP pathology and non-PSPS clinical syndromes did not show reduced midbrain area. Midbrain area was smaller in the subjects with PSPS than in those without PSPS (P<0.0001), with an area under the receiver operator curve of 0.99 (0.88, 0.99). A midbrain area cut-point of 92mm(2) provided optimum sensitivity (93%) and specificity (89%) for differentiation. Midbrain atrophy is associated with the clinical presentation of PSPS, but not with the pathological diagnosis of PSP in the absence of clinical PSPS. This finding has important implications for the utility of midbrain measurements as diagnostic biomarkers for PSP pathology.