Cerebrospinal Fluid α-Synuclein Predicts Cognitive Decline in Parkinson Disease Progression in the DATATOP Cohort

Most patients with Parkinson disease (PD) develop both cognitive and motor impairment, and biomarkers for progression are urgently needed. Although α-synuclein is altered in cerebrospinal fluid of patients with PD, it is not known whether it predicts motor or cognitive deterioration. We examined clinical data and α-synuclein in >300 unmedicated patients with PD who participated in the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study, with up to 8 years of follow-up. Longitudinal measures of motor and cognitive function were studied before (phase 1) and during (phase 2) levodopa therapy; cerebrospinal fluid was collected at the beginning of each phase. Correlations and linear mixed models were used to assess α-synuclein association with disease severity and prediction of progression in the subsequent follow-up period. Despite decreasing α-synuclein (phase 1 to phase 2 change of −0.05 ± 0.21 log-transformed values, P < 0.001), no correlations were observed between α-synuclein and motor symptoms. Longitudinally, lower α-synuclein predicted better preservation of cognitive function by several measures [Selective Reminding Test total recall α-synuclein × time interaction effect coefficient, −0.12 (P = 0.037); delayed recall, −0.05 (P = 0.002); New Dot Test, −0.03 (P = 0.002)]. Thus, α-synuclein, although not clinically useful for motor progression, might predict cognitive decline, and future longitudinal studies should include this outcome for further validation

The RAB39B p.G192R mutation causes X-linked dominant Parkinson’s disease

Objective: To identify the causal gene in a multi-incident U.S. kindred with Parkinson’s disease (PD). Methods: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. Results: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Conclusions: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0045-4) contains supplementary material, which is available to authorized users

The relationship between neuropsychological functioning and driving ability in dementia: A meta-analysis

A meta-analysis of 27 primary studies was conducted to examine the relationship between neuropsychological functioning and driving ability for adults with dementia. When studies using a control group were included, the relationship between cognitive measures and on-road or non-road driving measures was significant for all reported domains; mean correlations ranged from .35 to .65. Caregiver reports of driving ability and cognitive variables were correlated significantly only on measures of mental status and visuospatial skills. When studies using a control group were excluded, moderate mean correlations were observed for visuospatial skills and on-road or non-road measures, and for mental status with non-road tests. Other effects were small or nonsignificant. Implications for basing driving recommendations on neuropsychological testing are discussed

Association of Cognition and Dementia With Neuropathologic Changes of Alzheimer Disease and Other Conditions in the Oldest-Old.

Background and objectivesAge is the largest risk factor for dementia. However, dementia is not universal, even among the oldest-old age groups. Following contemporary neuropathologic guidelines, our objectives were to describe the key neuropathologic lesions and their associations with antemortem cognition in oldest-old individuals.MethodsParticipants were those enrolled in The 90+ Study, a longitudinal, population-based study of aging/dementia in the oldest-old, who agreed to postmortem brain examination. All autopsied brains as of December 2020 were evaluated for prevalence of Alzheimer's disease neuropathologic change (ADNC) and non-ADNC neuropathologic comorbidities. Associations between neuropathologic lesions or total neuropathologic burden score (sum of the individual scores) and cognition were assessed using multinomial logistic regression and multiple linear regression. Separate regression analyses evaluated relationships between limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and hippocampal sclerosis (HS) or ADNC/primary age-related tauopathy (PART). Resistance, or failure to develop ADNC/PART, and resilience, inferred from higher than expected cognitive functioning, were evaluated in the presence or absence of non-ADNC neuropathologic features.ResultsThe most common neuropathologic features in the sample (n=367) were ADNC/PART-related. Increased dementia odds were associated with elevated total neuropathologic burden (OR=1.5 [95% CI 1.3-1.7] p&lt;0.0001), beta amyloid (OR=1.6 [95% CI 1.2-2.0] p&lt;0.0001), neurofibrillary tangles (OR=2.6 [95% CI 1.7-4.1] p&lt;0.0001), and LATE-NC (OR=2.3 [95% CI 1.7-3.1] p&lt;0.0001), correcting for multiple comparisons. LATE-NC was associated with dementia with (OR=6.1 [95% CI 2.0-18.7] p=0.002) and without (OR=5.0 [95% CI 2.6-9.7] p&lt;0.0001) co-occurring HS, and increased the odds of dementia among participants with ADNC (OR=5.0 [95% CI 2.7-9.2] p&lt;0.0001). Resistance to moderate/severe ADNC/PART was rare (3%), but resilience to ADNC/PART was not (55%). Resilience was rarer in the presence of non-ADNC comorbid lesions, particularly LATE-NC. Among those with moderate/severe ADNC/PART, dementia odds increased with each non-ADNC comorbid lesion (e.g., 1 lesion: OR=2.4 [95% CI 1.3-4.5] p&lt;0.005; 2 lesions: OR=5.9 [95% CI 2.8-12.3] p&lt;0.0001).ConclusionThese results highlight the importance of non-ADNC neuropathologic comorbidity, predominantly LATE-NC, to cognition in the oldest-old. Given the cumulative effects of non-ADNC comorbid neuropathologic abnormalities, reducing their prevalence, especially LATE-NC, will be vital to the ultimate goal of reducing dementia burden in the oldest-old individuals

Cerebrospinal Fluid alpha-Synuclein Predicts Cognitive Decline in Parkinson Disease Progression in the DATATOP Cohort

Michael J. Fox Foundation; Parkinson Study Group; NTH grants [NIEHS T32ES015459, AG033398, ES004696-5897, ES007033-6364, ES016873, ES019277, NS057567, NS060252, NS062684-6221, NS082137]Most patients with Parkinson disease (PD) develop both cognitive and motor impairment, and biomarkers for progression are urgently needed. Although alpha-synuclein is altered in cerebrospinal fluid of patients with PD, it is not known whether it predicts motor or cognitive deterioration. We examined clinical data and alpha-synuclein in >300 unmedicated patients with PD who participated in the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study, with up to 8 years of follow-up. Longitudinal measures of motor and cognitive function were studied before (phase 1) and during (phase 2) levodopa therapy; cerebrospinal fluid was collected at the beginning of each phase. Correlations and linear mixed models were used to assess alpha-synuclein association with disease severity and prediction of progression in the subsequent follow-up period. Despite decreasing cc-synuclein (phase 1 to phase 2 change of -0.05 +/- 0.21 log-transformed values, P < 0.001), no correlations were observed between alpha-synuclein and motor symptoms. Longitudinally, lower alpha-synuclein predicted better preservation of cognitive function by several measures [Selective Reminding Test total recall alpha-synuclein x time interaction effect coefficient, -0.12 (P = 0.037); delayed recall, -0.05 (P = 0.002); New Dot Test, -0.03 (P = 0.002)]. Thus, alpha-synuclein, although not clinically useful for motor progression, might predict cognitive decline, and future longitudinal studies should include this outcome for further validation