Dickson, Dennis W.

AbstractProgressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) has been reported as a rare clinical subtype, but the underlying pathology of its cerebellar ataxia remains unclear. Here, we report a patient with the coexistence of PSP with pontocerebellar atrophy and myotonic dystrophy type 1 (DM1). A 73-year-old man who was an asymptomatic carrier of DM1 (66 CTG repeats) started developing ataxic gait with multiple falls, visual blurring, double vision, and word finding difficulty at age 62 and was initially diagnosed with multiple system atrophy (MSA). Subsequently, the diagnosis was changed to PSP due to hypometric downward gaze, reduced blink frequency, symmetric bradykinesia, rigidity, and the absence of autonomic dysfunction. He eventually developed delayed grip opening with percussion myotonia at age 72. At autopsy, severe neuronal degeneration and astrogliosis in the pontocerebellar structures suggested MSA, but immunohistochemistry for α-synuclein did not reveal neuronal or glial cytoplasmic inclusions. Immunohistochemistry for phospho-tau and 4-repeat tau confirmed a neuropathological diagnosis of PSP with exceptionally numerous coiled bodies and threads in the pontine base and cerebellar white matter. This unusual distribution of 4-repeat tau pathology and neuronal degeneration with astrogliosis is a plausible clinicopathological substrate of PSP-C.

AbstractChronic traumatic encephalopathy is a debilitating neurodegenerative disorder associated with repetitive traumatic brain injuries often sustained through prior contact sport participation. The frequency of this disorder in a diverse population, including amateur athletes, is unknown. Primary historical obituary and yearbook records were queried for 2566 autopsy cases in the Mayo Clinic Tissue Registry resulting in identification of 300 former athletes and 450 non‐athletes. In these cases, neocortical tissue was screened for tau pathology with immunohistochemistry, including pathology consistent with chronic traumatic encephalopathy, blinded to exposure or demographic information. Using research infrastructure of the Rochester Epidemiology Project, a comprehensive and established medical records‐linkage system of care providers in southern Minnesota and western Wisconsin, medical diagnostic billing codes pertaining to head trauma, dementia, movement disorders, substance abuse disorders and psychiatric disorders were recorded for cases and controls in a blinded manner. A total of 42 individuals had pathology consistent with, or features of, chronic traumatic encephalopathy. It was more frequent in athletes compared to non‐athletes (27 cases versus 15 cases) and was largely observed in men (except for one woman). For contact sports, American football had the highest frequency of chronic traumatic encephalopathy pathology (15% of cases) and an odds ratio of 2.62 (P‐value = 0.005). Cases with chronic traumatic encephalopathy pathology had higher frequencies of antemortem clinical features of dementia, psychosis, movement disorders and alcohol abuse compared to cases without chronic traumatic encephalopathy pathology. Understanding the frequency of chronic traumatic encephalopathy pathology in a large autopsy cohort with diverse exposure backgrounds provides a baseline for future prospective studies assessing the epidemiology and public health impact of chronic traumatic encephalopathy and sports‐related repetitive head trauma.

Abstract Introduction Neuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential. Methods We compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB‐PET), 18 F‐fluorodeoxyglucose PET (FDG‐PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed. Results PiB‐PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG‐PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with “none” or “sparse” neuritic plaque scores had elevated PiB‐PET signal due to diffuse amyloid plaque. Participants with findings characterized as “suspected non‐Alzheimer's pathophysiology” represented 15% of the group. Discussion PiB‐PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG‐PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non‐Alzheimer's pathophysiology most commonly had primary age‐related tauopathy.

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.

AbstractBackground[11C]pyridinyl‐butadienyl‐benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP.ObjectivesTo explore the usefulness of [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients.MethodsWe assessed 13 PSP patients and 13 age‐matched healthy control subjects. Individuals negative for amyloid β PET with [11C]Pittsburgh compound B underwent clinical scoring, MR scans, and [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET.ResultsThere were significant differences in binding potential for [11C]pyridinyl‐butadienyl‐benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [11C]pyridinyl‐butadienyl‐benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [11C]pyridinyl‐butadienyl‐benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl‐butadienyl‐benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues.ConclusionsOur findings support the in vivo detectability of tau fibrils characteristic of PSP by [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET potentially provides a neuroimaging‐based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.