Citations

ABSTRACTBackgroundThe Movement Disorder Society clinical criteria for progressive supranuclear palsy (PSP) provide a framework for assessing the presence/severity of clinical symptoms and define a speech/language variant of PSP.ObjectivesTo evaluate the clinical criteria in a cohort of speech/language patients with longitudinal follow‐up.MethodsA total of 52 patients presenting with progressive apraxia of speech and/or agrammatic aphasia were followed longitudinally for up to 6 visits with clinical assessments and magnetic resonance imaging. We assessed oculomotor, postural instability, and akinesia diagnostic levels and determined whether patients met criteria for possible PSP‐speech/language or probable PSP at each visit. Kaplan‐Meier curves assessed time‐to‐event probabilities according to age. Statistical parametric mapping and midbrain volume were assessed according to disease progression.ResultsFew PSP symptoms were observed early in the disease, with oculomotor abnormalities and falls first observed 2 years after onset. Falls were more common than vertical supranuclear gaze palsy. Bradykinesia and rigidity commonly developed but axial was rarely greater than appendicular rigidity. During follow‐up, 54% met criteria for possible PSP‐speech/language, 38% for probable PSP‐Richardson's syndrome, and 38% for probable PSP‐parkinsonism, most commonly 6 to 6.9 years after onset. The probability of developing PSP was greater when onset was at an age older than 70 years. Patients who progressed to probable PSP had more parkinsonism and oculomotor impairment at baseline and greater midbrain atrophy when compared with those who did not develop probable PSP.ConclusionsSymptoms typical of PSP commonly develop in patients presenting with a progressive speech/language disorder. Older age appears to be an important prognostic factor in these patients.

Abstract Agrammatic aphasia affects grammatical language production and can result from a neurodegenerative disease. Although it typically presents with concomitant apraxia of speech, this is not always the case. Little is known about the clinical course and imaging features of patients that present with agrammatism in the absence of apraxia of speech, which we will refer to as progressive agrammatic aphasia. We aimed to make a detailed description of the longitudinal clinical, linguistic, and neuroimaging features of a cohort of 11 patients with progressive agrammatic aphasia to provide a complete picture of this syndrome. All patients underwent detailed speech and language, neurological and neuropsychological assessments, 3 T structural and diffusion tensor imaging MRI, 18F-fluorodeoxyglucose and Pittsburgh compound B PET. The 11 patients were matched by age and gender to 22 patients who had mixed apraxia of speech and agrammatism. The progressive agrammatic aphasia patients performed abnormally on tests of language, general cognition, executive function, and functional ability at baseline and declined in these measures over time. Only two patients eventually developed apraxia of speech, while parkinsonism was absent-to-mild throughout all visits for all patients. When compared to the patients with mixed apraxia of speech and agrammatism, the patients with progressive agrammatic aphasia performed better on tests of motor speech and parkinsonism but more poorly, and declined faster over time, on tests of general aphasia severity, agrammatism, and naming. The patients with progressive agrammatic aphasia also showed different neuroimaging abnormalities, with greater atrophy, hypometabolism and white matter tract degeneration in the prefrontal and anterior temporal lobes compared to patients with mixed apraxia of speech and agrammatism. These differences were more pronounced as the disease progressed. These results demonstrate that progressive agrammatic aphasia has a different clinical disease course and different underlying neuroanatomical abnormalities than patients with the more common syndrome of mixed agrammatism and apraxia of speech. This supports the distinction of progressive agrammatic aphasia and has implications for the classification of patients with agrammatic aphasia.

AbstractIntroductionPrimary age‐related tauopathy (PART) is characterized by the presence of neurofibrillary tangles and absent‐minimal β‐amyloid deposition. Transactive response DNA‐binding protein of 43 kDa (TDP‐43), a third protein, has recently garnished a lot of attention in Alzheimer's disease where it is associated with memory loss and amygdala and hippocampal atrophy. We aimed to determine whether TDP‐43 is associated with brain atrophy in PART.MethodsWe assessed the frequency of TDP‐43 in PART and performed voxel‐level analysis in SPM12, as well as region‐of‐interest analysis using linear regression modeling, controlling for variables of interest, to assess for associations between TDP‐43 and brain atrophy.ResultsOf 116 PART cases, 31 (26.7%) had TDP‐43. The presence of TDP‐43 was associated with significantly greater amygdala, hippocampal, and anterior temporal atrophy in both the region‐of‐interest and the voxel level analyses.DiscussionTDP‐43 is associated with greater brain atrophy in PART.

Tauopathies are rare neurodegenerative disorders related to microtubule-associated protein tau, which functions to stabilize microtubules. Pathological changes caused by overexpression or hyperphosphorylation of tau lead to the disengagement of tau from microtubules and accumulation of toxic intracellular inclusions. Tau pathology is the underlying mechanism for several sporadic and genetic disorders. These are collectively known as tauopathies. Each tauopathy is differentiated from others by its neuropathological features such as the presence of specific isoforms of tau, type of cellular inclusions, and the regions of the brain affected. Neuropathological features, with a few exceptions however, do not correspond to distinct clinical phenotypes. There is considerable phenotypic overlap between the different tauopathies. Interaction between tau and other protein inclusions further alters the clinical phenotype.Recent advances in the development of tau biomarkers, especially the development of tau radioligands used in positron emission tomography neuroimaging, and a better understanding of biology and pathology of tau are important first steps toward the ultimate goal of accurate diagnosis and disease modification in tauopathies.

Abstract Background The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. Methods We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy‐confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. Results Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. Conclusions The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society

AbstractIntroductionLittle is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD).MethodsRegional tau and β‐amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model.ResultsAge was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β‐amyloid differed little by age. Age showed a stronger association with tau than volume and β‐amyloid in all cortical regions. Age was not associated with cognitive performance.DiscussionAge is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake.

Abstract Background In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Methods Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3‐year cutoff. Results A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. Conclusion The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society

AbstractBackgroundPosterior cortical atrophy and dementia with Lewy bodies are 2 distinct clinical syndromes, yet they can overlap in symptoms and occipital hypometabolism. Patients with dementia with Lewy bodies often have overlapping Alzheimer's disease pathology. Similarly, Lewy bodies can be found in patients with posterior cortical atrophy. We investigated differences in the distribution and magnitude of F18‐AV‐1451 uptake in patients with these 2 syndromes.MethodsConsecutive patients with probable dementia with Lewy bodies (n = 33), posterior cortical atrophy (n = 18), and cognitively unimpaired controls (n = 100) underwent 18F‐AV‐1451 positron emission tomography. Regional differences in AV‐1451 uptake were assessed using voxel‐wise and an atlas‐based approach. The greatest differences in AV‐1451 uptake between patient groups were identified using area under receiver operating curve statistics, and a composite region was derived.ResultsAV‐1451 uptake in both patient groups was predominantly localized to the lateral occipital regions, but the magnitude of uptake was markedly greater in posterior cortical atrophy compared with dementia with Lewy bodies. The posterior cortical atrophy group showed the greatest AV‐1451 uptake throughout all the gray matter compared with that in other groups. The occipital composite region, consisting of superior, middle, and inferior occipital cortices, distinguished posterior cortical atrophy from dementia with Lewy bodies (area under the curve >0.97; P < 0.001, Bonferroni‐corrected) with excellent sensitivity (88%) and specificity (100%).ConclusionsPosterior cortical atrophy and dementia with Lewy bodies can share clinical features, and although the pattern of AV‐1451 uptake in occipital cortices overlaps between these 2 syndromes, its magnitude is significantly higher in posterior cortical atrophy. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

This study examined the rate of producing alternating motion rates, sequential motion rates (SMRs), and repeated words in 27 individuals with the semantic variant of Primary Progressive Aphasia (svPPA). Only the rate of producing SMRs was significantly elevated in svPPA compared to controls. This may be associated with concomitant neuropsychiatric symptoms in svPPA, as correlation analysis showed a relationship between increased SMR rate and the Neuropsychiatric Inventory Questionnaire, which documented anxiety and disinhibition. Future studies will assess these findings in a larger cohort and work to better understand if this phenomenon is a manifestation of behavioral and/or motor changes.