Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study.

Parkinson's disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the 'Dual Syndrome' hypothesis for cognitive impairment in Parkinson's disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson's disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson's disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson's disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson's disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson's disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson's disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson's disease.

Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort.

Carriers of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson's disease. The frequency of GBA mutations in unselected Parkinson's disease populations has not been established. Furthermore, no previous studies have investigated the influence of GBA mutations on the natural history of Parkinson's disease using prospective follow-up. We studied DNA from 262 cases who had been recruited at diagnosis into one of two independent community-based incidence studies of Parkinson's disease. In 121 cases, longitudinal data regarding progression of motor disability and cognitive function were derived from follow-up assessments conducted every 18 months for a median of 71 months. Sequencing of the GBA was performed after two-stage polymerase chain reaction amplification. The carrier frequency of genetic variants in GBA was determined. Baseline demographic and clinical variables were compared between cases who were either GBA mutation carriers, polymorphism carriers or wild-type homozygotes. Cox regression analysis was used to model progression to major motor (Hoehn and Yahr stage 3), and cognitive (dementia) end-points in cases followed longitudinally. We show that in a representative, unselected UK Parkinson's disease population, GBA mutations are present at a frequency of 3.5%. This is higher than the prevalence of other genetic mutations currently associated with Parkinson's disease and indicates that GBA mutations make an important contribution to Parkinson's disease encountered in the community setting. Baseline clinical characteristics did not differ significantly between cases with and without GBA sequence variants. However, the hazard ratio for progression both to dementia (5.7, P = 0.003) and Hoehn and Yahr stage 3 (4.2, P = 0.003) were significantly greater in GBA mutation carriers. We also show that carriers of polymorphisms in GBA which are not generally considered to increase Parkinson's disease risk are at significantly increased risk of progression to Hoehn and Yahr stage 3 (3.2, P = 0.004). Our results indicate that genetic variation in GBA has an important impact on the natural history of Parkinson's disease. To our knowledge, this is the first time a genetic locus has been shown to influence motor progression in Parkinson's disease. If confirmed in further studies, this may indicate that GBA mutation status could be used as a prognostic marker in Parkinson's disease. Elucidation of the molecular mechanisms that underlie this effect will further our understanding of the pathogenesis of the disease and may in turn suggest novel therapeutic strategies.

Genetic and pathological links between Parkinson's disease and the lysosomal disorder Sanfilippo syndrome.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. The characteristic α-synuclein aggregation of PD is also a feature of Sanfilippo syndrome, a storage disorder caused by α-N-acetylglucosaminidase (NAGLU) gene mutations. We explored genetic links between these disorders and studied the pathology of Sanfilippo syndrome to investigate a common pathway toward α-synuclein aggregation. METHODS: We typed the 2 single-nucleotide polymorphisms that tag the common haplotypes of NAGLU in 926 PD patients and 2308 controls and also stained cortical tissue from 2 cases of Sanfilippo A syndrome using the anti-α-synuclein antibody, Per7. RESULTS: Allelic analysis showed an association between rs2071046 and risk for PD (P 1.3 × 10(-3) ). Intracellular α-synuclein accumulation was observed in the cortical tissue of both Sanfilippo A syndrome cases. CONCLUSIONS: This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for α-synuclein aggregation in the brain in lysosomal storage disorders. Our findings support a mechanism involving lysosomal dysfunction more generally in the pathogenesis of PD.

Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals.

Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging.