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P4‐010: Genome‐wide association study of the robust aging in adult changes of thought (ACT)
Author(s) -
Mukherjee Shubhabrata,
Gibbons Laura E.,
Donald Christine Mac,
Keene C. Dirk,
Montine Thomas J.,
Larson Eric B.,
Crane Paul K.
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.1714
Subject(s) - genome wide association study , single nucleotide polymorphism , snp , genetic association , population , phenotype , biology , genetics , gerontology , medicine , gene , genotype , environmental health
tissue. Antibodies against tau, amyloid b, a-synuclein and TDP-43 were used. Results:At age 59, the proband, a female, presented motor dysfunction while dancing. Neurological and neuropsychological evaluation revealed a mild cognitive impairment, at age 63. She was diagnosed with Parkinsonism at age 65; she declined rapidly and at 66 became aphasic. At this time, a neurologic exam revealed progressive dysfluency and poor left arm dexterity. Later, resting right hand tremor and short-stepped gait were noted. Neurological examination, at age 68, showed minimal verbal output; comprehension, reading and writing were impaired. Rigidity, bradykinesia and impaired postural reflexes were recorded. MRI showed atrophy of frontal and temporal lobes. She became dependent on activities of daily living and died at age 68. Blood serum revealed decreased levels of progranulin. At autopsy, the fresh brain weighed 900 grams, showing severe atrophy of frontal and temporal lobes. Histologically, there was severe neuronal loss and gliosis in neocortex, caudate nucleus, putamen, globus pallidus, hippocampus, dentate nucleus, inferior olivary nucleus. Atrophy of the centrum semiovale was observed. TDP-43-immunoreactive neuronal cytoplasmic and, occasionally, intranuclear inclusions as well as dystrophic neurites were detected in frontal, parietal and temporal cortices, cingulate gyrus, precuneus, thalamus, subthalamic nucleus, hippocampus, and entorhinal cortex. Rare neurofibrillary tangles and tau-immunoreactive neurons were found in putamen, substantia innominata, hippocampus, and entorhinal cortex. Analysis of DNA extracted from blood revealed a g.1642delTGAG deletion in a putative splicing consensus sequence in GRN. The study of this family (8 siblings) demonstrated segregation of the variant with disease. Conclusions:The study of this patient and future studies of other family members will give insight about the natural history of disease, including biomarker and brain imaging alterations in asymptomatic and symptomatic subjects.