Olfactory dysfunction is common in Parkinson’s disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory ...bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of “pre-motor” PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.
Photoelectrochemical (PEC) water splitting to produce hydrogen fuel was first reported 50 years ago
, yet artificial photosynthesis has not become a widespread technology. Although planar Si solar ...cells have become a ubiquitous electrical energy source economically competitive with fossil fuels, analogous PEC devices have not been realized, and standard Si p-type/n-type (p-n) junctions cannot be used for water splitting because the bandgap precludes the generation of the needed photovoltage. An alternative paradigm, the particle suspension reactor (PSR), forgoes the rigid design in favour of individual PEC particles suspended in solution, a potentially low-cost option compared with planar systems
. Here we report Si-based PSRs by synthesizing high-photovoltage multijunction Si nanowires (SiNWs) that are co-functionalized to catalytically split water. By encoding a p-type-intrinsic-n-type (p-i-n) superlattice within single SiNWs, tunable photovoltages exceeding 10 V were observed under 1 sun illumination. Spatioselective photoelectrodeposition of oxygen and hydrogen evolution co-catalysts enabled water splitting at infrared wavelengths up to approximately 1,050 nm, with the efficiency and spectral dependence of hydrogen generation dictated by the photonic characteristics of the sub-wavelength-diameter SiNWs. Although initial energy conversion efficiencies are low, multijunction SiNWs bring the photonic advantages of a tunable, mesoscale geometry and the material advantages of Si-including the small bandgap and economies of scale-to the PSR design, providing a new approach for water-splitting reactors.
OBJECTIVE:To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods.
METHODS:A ...prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors.
RESULTS:We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinsonʼs Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001).
CONCLUSIONS:Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.
Abstract Objective To evaluate the association between baseline olfaction and both cross-sectional and longitudinal cognitive assessments, motor symptoms, non-motor symptoms (NMS), and CSF biomarkers ...in early Parkinson's disease (PD). Methods Parkinson's Progression Marker's Initiative (PPMI) participants underwent baseline olfactory testing with the University of Pennsylvania Smell Identification Test (UPSIT). Serial assessments included measures of motor symptoms, NMS, neuropsychological assessment, and CSF biomarkers. Up to three years follow-up data were included. Results At baseline, worse olfaction (lowest tertile) was associated with more severe NMS, including anxiety and autonomic symptoms. Those in the lowest olfactory tertile were more likely to report cognitive impairment (37.4%) compared to those in the middle (24.4%) and highest olfactory tertiles (14.2%, p < 0.001). Aβ1-42 was significantly lower, and tau/Aβ1-42 ratio was higher in those with worse olfaction. In longitudinal analyses, lower UPSIT score was associated with greater decline in MoCA score (β = 0.02 0.01, 0.03, p = 0.001) over time, as were composite measures of UPSIT score and either Aβ1-42 or tau/Aβ1-42 ratio. In a Cox proportional hazards model, a composite measure of olfaction and Aβ1-42 was a significant predictor of conversion from normal cognition to mild cognitive impairment (MCI; i.e., MoCA < 26), with subjects most impaired on both measures being 87% more likely to develop incident MCI (HR = 1.87 1.16, 3.01, p = 0.01). Conclusions Worse baseline olfaction is associated with long-term cognitive decline. The addition of AD CSF biomarkers to olfactory testing may increase the likelihood of identifying those at highest risk for cognitive decline and progression to MCI.
Given the increasing recognition that neurodegeneration begins decades before the appearance of motor symptoms of Parkinson disease (PD), recent attention has turned to methods of preclinical or ...prodromal diagnosis. Accurate preclinical diagnosis of individuals at high risk of developing manifest motor PD can improve clinical counseling as well as provide an enriched cohort for studies of possible disease-modifying therapies. In this review article, the authors synthesize the myriad clinical, radiographic, and biochemical signatures of preclinical PD, with an emphasis on biomarkers that may provide accurate population screening for the disease. As individual biomarkers have relatively lowsensitivity and specificity, any population-based approach to preclinical diagnosis will likely combine multiple biomarkers to improve both negative and positive predictive value.
•The long latent period of Parkinson disease (PD) provides an opportunity for early diagnosis and possible intervention.•Clinical, radiographic, and biochemical signatures of latent PD can be used to identify those at high risk of PD.•Early diagnosis will improve prognostic counseling and provide an enriched cohort for trials of disease-modifying therapies.
Monitoring physical activity is important in Parkinson disease (PD), but patient recall may be unreliable. We examined relationships between self-reported activity, objective monitoring, and clinical ...characteristics.
Participants completed the self-reported Physical Activity Scale in the Elderly (PASE) to determine subjective minutes of moderate-vigorous physical activity (MVPA); a subset wore an Actigraph monitor capturing step count and objective MVPA using a PD-specific algorithm. Relationships between subjective and objective measurements were determined using partial correlations controlling for age and disease stage.
Sixty-six subjects completed subjective reporting; median age (interquartile range IQR) was 70 (69–74) years and median disease duration (IQR) was 4 (1.5–7.5) years. Age-adjusted median PASE was 135.3. Median daily step count was 3615 (IQR 1772–4870), which was moderately well-correlated with PASE (ρ = 0.56, p = 0.003). Median MVPA was 8.1 min/day (IQR 2.2–23.2), which was not correlated with PASE (ρ = -0.003, p = 0.98).
Physical activity in this cohort of Veterans with PD is low and consists mostly of low-intensity steps rather than MVPA. The symptomatic and disease-modifying potential of lower intensity activity is uncertain. These data emphasize the need for interventions to increase MVPA in PD and the importance of objective monitoring using wearable technology.
•Self-reported activity in PD is associated with total daily steps.•Self-reported activity in PD is not well-correlated with moderate-vigorous physical activity.•Objective assessment with wearables may improve assessment of activity levels in PD.
Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to ...quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.
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•Meta-analysis of rare copy-number variants (rCNVs) in nearly one million humans•Discovered hundreds of rCNV-disease associations across 54 disorders•Convergence of rCNVs & damaging coding variants at dosage sensitive loci•Ensemble machine learning identified 3,635 highly dosage sensitive genes
Harmonizing genomic data from nearly one million individuals yields insights into the properties of rare copy-number variants across disorders and dosage sensitivity predictions for all autosomal protein-coding genes.
The correlation between longevity and stress resistance observed in long-lived mutant animals suggests that the ability to sense and respond to environmental challenges could be important for the ...regulation of life span. We therefore examined the role of heat shock factor (HSF-1), a master transcriptional regulator of stress-inducible gene expression and protein folding homeostasis, in the regulation of longevity. Down-regulation of hsf-1 by RNA interference suppressed longevity of mutants in an insulin-like signaling (ILS) pathway that functions in the nervous system of Caenorhabditis elegans to influence aging. hsf-1 was also required for temperature-induced dauer larvae formation in an ILS mutant. Using tissue-specific expression of wild-type or dominant negative HSF-1, we demonstrated that HSF-1 acts in multiple tissues to regulate longevity. Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals. However, suppression by individual chaperones was to a lesser extent, suggesting an important role for networks of chaperones. The interaction of ILS with HSF-1 could represent an important molecular strategy to couple the regulation of longevity with an ancient genetic switch that governs the ability of cells to sense and respond to stress.
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