Our goal is to examine whether mutations in the glucocerebrosidase (GBA) gene are a risk factor and biomarker for Dementia with Lewy Bodies (DLB). GBA has recently been demonstrated to be a risk factor for Parkinson disease (PD). In a recent autopsy study of patients with DLB, PD, Alzheimer disease (AD), and without dementia, we sequenced the GBA gene in each of 187 brains. Carriers of GBA mutations were more likely to have DLB (with findings of cortical Lewy bodies), even in the presence of AD pathology (plaques and tangles), although they were less likely to have such AD pathology. Conversely, those with AP0E-?4 were more likely to have AD pathological findings, and less likely to have DLB pathology. Thus, just as AP0E-?4 is a risk factor for AD, it is possible that GBA is a risk factor and marker for DLB. Here we propose to further study the relation of GBA to DLB in living ADRC subjects by sequencing the GBA gene in 800 consecutive well-characterized ADRC subjects with full UDS data, and available DNA, and APOE genotype. We will: (1) compare carriers and non-carriers for disease diagnosis and severity, for clinical symptoms common in DLB including hallucinations, parkinsonism, and fluctuations, and for neuropsychological test characteristics of DLB, such as relative preservation of memory, but impaired subcortical and visuospatial function;(2) compare disease, symptoms, and neuropsychological test characteristics, in carriers who have GBA mutations thought to be of "mild" phenotype even when homozygous, to those carrying mutations known to be of "severe" phenotype when homozygous;(3) determine in the collected cerebrospinal fluid (CSF) of 100 ADRC subjects whether there is decreased GBA enzymatic activity in CSF of patients who are GBA mutation carriers of mild type or severe type, versus noncarriers, and in unaffected individuals. We hypothesize that GBA mutations may be a marker for DLB, and that decreased GBA activity may predispose to DLB. Our results may allow improved accuracy of diagnosis of DLB during life, and may have related implications on making prognostic statements and treatment plans for patients with dementia.
Dementia with Lewy Bodies (DLB) is the second most common (after Alzheimer disease, AD) neurodegenerative pathology. However, it is difficult to diagnose DLB accurately during life, and distinguish it from AD. The results of these studies may improve diagnosis, suggest a mechanism in which GBA may relate to development of DLB, and improve the ability to prognosticate and treat persons with DLB.
|Vardarajan, Badri N; Zhang, Yalun; Lee, Joseph H et al. (2015) Coding mutations in SORL1 and Alzheimer disease. Ann Neurol 77:215-27|
|Mecozzi, Vincent J; Berman, Diego E; Simoes, Sabrina et al. (2014) Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol 10:443-9|
|Pan, Jie J; Lee, Michelle; Honig, Lawrence S et al. (2014) Alzheimer's-related changes in non-demented essential tremor patients vs. controls: links between tau and tremor? Parkinsonism Relat Disord 20:655-8|
|Baleriola, Jimena; Walker, Chandler A; Jean, Ying Y et al. (2014) Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell 158:1159-72|
|Pelton, Gregory H; Andrews, Howard; Roose, Steven P et al. (2014) Donepezil treatment of older adults with cognitive impairment and depression (DOTCODE study): clinical rationale and design. Contemp Clin Trials 37:200-8|
|Sproul, Andrew A; Jacob, Samson; Pre, Deborah et al. (2014) Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors. PLoS One 9:e84547|
|Khan, Usman A; Liu, Li; Provenzano, Frank A et al. (2014) Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat Neurosci 17:304-11|
|Salloway, Stephen; Sperling, Reisa; Fox, Nick C et al. (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 370:322-33|
|Choi, Ben Jiwon; Imlach, Wendy L; Jiao, Wei et al. (2014) Miniature neurotransmission regulates Drosophila synaptic structural maturation. Neuron 82:618-34|
|Salm, Melissa; Abbate, Kristopher; Appelbaum, Paul et al. (2014) Use of genetic tests among neurologists and psychiatrists: knowledge, attitudes, behaviors, and needs for training. J Genet Couns 23:156-63|
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