Ross, Owen A.

AbstractBackgroundGenetic variation at the microtubule‐associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule‐associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease.ObjectivesTo evaluate associations of microtubule‐associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases.MethodsFive hundred eighty‐five autopsy‐confirmed Lewy body disease cases were included. Six microtubule‐associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule‐associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen.ResultsThe common microtubule‐associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule‐associated protein tau haplotypes (P = 0.0016). Microtubule‐associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule‐associated protein tau H1 subhaplotypes and neuropathological outcomes were observed.ConclusionsA rare microtubule‐associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule‐associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk. © 2019 International Parkinson and Movement Disorder Society

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.

AbstractIntroductionOur primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy‐confirmed cohort of Alzheimer's disease cases.MethodsA retrospective study was conducted in the Florida Autopsied Multi‐Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self‐reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539).ResultsHispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups.DiscussionDespite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.

Introduction: Across 269 international sites, the POINT trial randomly assigned 4881 patients with minor ischemic stroke or high-risk transient ischemic attack to receive either clopidogrel at a loading dose of 600 mg on day 1 followed by 75 mg per day, plus aspirin at a dose of 50-325 mg per day or the same range of doses of aspirin alone. Dual antiplatelet therapy significantly reduced the incidence of major ischemic events, but also significantly increased the incidence of major hemorrhage. Clopidogrel is a prodrug that requires metabolism by the cytochrome P450 complex to act on the P2Y12 platelet receptor. CYP2C19 (cytochrome P450 family 2 subfamily C polypeptide 19) variants are associated with variable rates of metabolism of clopidogrel and thus pharmacogenomic effects may be clinically relevant. Methods: Genomic DNA was extracted from peripheral blood monocytes using the standard protocols. Genotyping for CYP2C19 *2, *3 and *17 alleles (rs4244285, rs4986893 and rs12248560) defines metabolizer/activator status and was performed using custom TaqMan Allelic Discrimination Assays on a QuantStudio™ 7 Flex Real-Time PCR System. Results: As of June 28, 2018, a total of 445 trial participants had DNA available for analysis. CYP2C19 allele genotyping demonstrated approximately one quarter of subjects (n=127; 28.6%) would be defined as poor or Intermediate metabolizers of clopidogrel. Conclusions: Based on targeted cytochrome P 450 genotyping, about one quarter of POINT patients have reduced clopidogrel activation. Additional genotyping is ongoing. We plan to present results assessing whether the treatment effect of clopidogrel is limited to those with CYP2C19 genotypes associated with normal drug metabolism.