Log in / Register
Home arrow Health arrow Cognitive impairment and dementia in Parkinson disease


Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA) cause Gaucher’s disease, an autosomal recessive lysosomal storage disorder. The observation that patients with Gaucher’s disease develop parkinsonism [61] in association with deposition of Lewy bodies in the brainstem and cortex [62] led to the hypothesis that GBA mutations may also contribute to the development of idiopathic PD. Over the past decade, this association has been firmly established: GBA mutations are significantly overrepresented even in seemingly sporadic PD, and are the most common single genetic cause of PD identified to date [63]. The mechanism underlying this association remains unclear; however, neuropathological studies have demonstrated that glucocerebrosidase co-localizes with Lewy bodies in mutation carriers, supporting the theory that mutant glucocerebrosidase may contribute to increased aggregation of a-synuclein [64]. On this basis, GBA mutations would also be expected to predispose to dementia in PD, and clinical comparisons have shown that this is indeed the case.

A recent cross-sectional study of 225 PD cases reported that dementia affected 50% of GBA mutation carriers (n = 22) versus 24% of non-carriers (n = 203), corresponding to an odds ratio for dementia of 5.8 (95% CI 1.98-17.2) after adjustment for age, disease duration, and gender [65]. This is in line with a prevalence of cognitive decline or dementia of 48% among GBA mutation carriers (n = 33) in a larger study of 790 pathologically confirmed PD cases. Neuropathological examination revealed more pronounced Lewy body pathology in the GBA mutation carriers than in the non-carriers, spreading into limbic and diffuse neocortical regions [66]. Another study which employed detailed cross-sectional neuropsychological assessment in early onset PD cases reported a higher frequency of memory and visuospatial impairments in those carrying a GBA mutation (n = 26) compared with non-carriers (n = 39) [67].

Our own work [68] has evaluated the influence of GBA mutations on cognitive phenotype in an unselected incident cohort (n = 121). Interestingly, at diagnosis GBA mutation carriers were clinically indistinguishable from non-carriers, with only a minor trend towards lower MMSE scores. However, over a 10-year follow-up period, GBA mutation carriers (n = 4) had an increased risk of developing dementia compared with non-carriers, after adjustment for MAPT genotype (HR 4.6; 95% CI 1.3-15.9). Furthermore, patients carrying more common GBA polymorphisms (n = 11), which have not consistently been associated with risk for PD, had a greater propensity than non-carriers to develop dementia (HR 3.3; 95% CI 1.1-10.0), suggesting that these variants may contribute to the heterogeneity of cognitive impairment in PD. Although GBA mutations are relatively rare and might only make a modest contribution to the overall burden of dementia in PD, they may provide important insights into the converging pathological mechanisms that contribute to this aspect of the disease.

Found a mistake? Please highlight the word and press Shift + Enter  
< Prev   CONTENTS   Next >
Business & Finance
Computer Science
Language & Literature
Political science