Premium
IC‐P‐139: NEURODEGENERATION ASSOCIATED WITH LONGITUDINAL CHANGES OF AB1‐42 AND FIBRILLARY AMYLOID
Author(s) -
Cheewakriengkrai Laksanun,
Manitsirikul Sarinporn,
Mohades Sara,
Wang Seqian,
Shin Monica,
Benedet Andrea Lessa,
Leuzy Antoine,
Parent Maxime,
Zimmer Eduardo Rigon,
Kang Min Su,
Schilling Lucas Porcello,
Farajat Daliah,
Fonov Vladmir,
Beaudry Thomas,
Mathotaarachchi Sulantha,
Gauthier Serge,
RosaNeto Pedro
Publication year - 2014
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.2014.05.145
Subject(s) - medicine , neurodegeneration , biomarker , dementia , cerebrospinal fluid , cohort , endocrinology , amyloid (mycology) , positron emission tomography , nuclear medicine , pathology , psychology , chemistry , disease , biochemistry
Background: Mutations in the Presenilin 1 (PSEN1) gene are associated with autosomal dominant early onset Alzheimer disease (EOAD). Posterior cerebral atrophy (PCA), a progressive neurodegenerative syndrome affecting visual processing accompanied by atrophy and hypometabolism in the parieto-occipital brain, has been associated with AD and certain PSEN1 gene mutations.Methods:Clinical, neuropsychological, and neuroimaging studies were performed. Postmortem neuropathologic studies of the brain were carried out. Histological methods included hematoxylinand eosin-Luxol fast blue and Thioflavin S. For immunohistochemistry, antibodies against b-amyloid, tau, and a-synuclein were used. DNA was extracted from brain or blood for gene sequencing. Results: At 47, the proband developed memory loss, unsteady gait, pyramidal signs, and visual disturbance (loss of depth perception, intermittent visual loss suggestive of a visual apraxia, eventual blindness.) MRI revealed greater atrophy in parietal than frontal lobes. DNA sequencing revealed an ATT to TTT nucleotide mutation, resulting in a phenylalanine for isoleucine substitution (I229F) in the PSEN1 gene. The proband’s daughters enrolled in the Dominantly Inherited Alzheimer Network. At 39, one daughter developed memory loss, unsteady gait, and visual disturbance. DNA sequencing confirmed a PSEN1 I229F mutation. Neuropsychological evaluation revealed inability to copy a simple geometric design, recall visual information, and a WAIS-R Block Design raw score of 0/51, indicating markedly impaired visuospatial abilities. Structural MRI revealed greater bilateral parieto-occipital lobe gray matter volume loss relative to frontal gray matter. FDG-PET confirmed notable hypometabolism in bilateral parietal lobes. PIB-PET showed high signal consistent with amyloid deposition throughout cortex, including parieto-occipital lobes. She died at 44. Histological and immunohistochemical studies confirmed AD in both brains. The proband’s brain showed severe cerebral atrophy of parieto-occipital lobes relative to the frontal and temporal lobes. The daughter’s brain showed disproportionate thinning of occipital cortex relative to other lobes and reduction of occipital white matter. In both brains, b-amyloid and tau burdens were severe in occipital cortex. The proband also had corticospinal tract degeneration. Conclusions: Prominent visual disturbances in EOADmay suggest the PCA syndrome. Our findings suggest that PCA may be associated with the PSEN1 I229F mutation. (Grants: P30AG35982, P30AG 010133, U19AG032438)