The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic–molecular cohorts.

Objective Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies. Methods We searched PubMed (January 2007–February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability. Conclusions OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a ‘malignant’ phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.

Comparative outcomes among different monogenic forms of Parkinson disease after subthalamic nucleus deep brain stimulation (STN DBS) remain unclear. To compare clinical outcomes in patients with the most common monogenic forms of Parkinson disease treated with STN DBS. Systematic review and meta-analysis in which a PubMed search of interventional and noninterventional studies of Parkinson disease with LRRK2, GBA, or PRKN gene mutations published between January 1, 1990, and May 1, 2018, was conducted. Among the inclusion criteria were articles that reported the Motor subscale of the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) before and after STN DBS treatment, that involved human participants, and that were published in the English language. Studies that used aggregated data from patients with different genetic mutations were excluded, and so were studies with assumed but not confirmed genetic data or incomplete follow-up data. Changes in UPDRS-III scores and levodopa equivalent daily dose (LEDD) were analyzed for each monogenic form of Parkinson disease. Additional end points included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), and cognitive function. Of the 611 eligible studies, 17 (2.8%) met the full inclusion criteria; these 17 studies consisted of 8 cohort studies (47.1%), 3 case series (17.6%), and 6 case reports (35.3%), and they involved a total of 518 patients. The UPDRS-III score improved by 46% in LRRK2 (mean change, 23.0 points; 95% CI, 15.2-30.8; P < .001), 49% in GBA (20.0 points; 95% CI, 4.5-35.5; P = .01), 43% in PRKN (24.1 points; 95% CI, 12.4-35.9; P < .001), and 53% in idiopathic Parkinson disease (25.2 points; 95% CI, 21.3-29.2; P < .001). The LEDD was reduced by 61% in LRRK2 (mean change, 711.9 mg/d; 95% CI, 491.8-932.0; P < .001), 22% in GBA (269.2 mg/d; 95% CI, 226.8-311.5; P < .001), 61% in PRKN (494.8 mg/d; 95% CI, -18.1 to -1007.8; P = .06), and 55% in idiopathic Parkinson disease (681.8 mg/d; 95% CI, 544.4-819.1; P < .001). Carriers of the PRKN mutations showed sustained improvements in UPDRS-II and UPDRS-IV, whereas LRRK2 mutation carriers sustained improvements only in UPDRS-IV. Carriers of the GBA mutation showed worse postsurgical cognitive and functional performance. Treatment with STN DBS for patients with Parkinson disease with LRRK2, GBA, or PRKN mutations appears to be associated with similar motor outcomes but different changes in dopaminergic dose, activities of daily living, motor complications, and cognitive functions.