Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods:We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results:An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a wellbehaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions:Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology ® 2012;78:690-695

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To determine the roles of intensity and duration of nocturnal physical activity in causing rapid phase shifts of human circadian rhythms, eight healthy men were studied three times under constant conditions with no exercise, a 3-h bout of moderate-intensity exercise, or a 1-h bout of high-intensity exercise. Exercise stimulus was centered at 0100. Circadian phase was estimated from the onsets of the nocturnal elevation of plasma thyrotropin (TSH) and melatonin. Mean phase shifts of TSH onsets were -18 +/- 8 (baseline), -78 +/- 10 (low-intensity exercise, P < 0.01), and -95 +/- 19 min (high-intensity exercise, P < 0.01). Mean phase delays of melatonin onsets were -23 +/- 10 (baseline), -63 +/- 8 (low-intensity exercise, P < 0.04), and -55 +/- 15 min (high-intensity exercise, P < 0.12). Taken together with our previous findings, this study indicates that nocturnal physical activity may phase delay human circadian rhythms and demonstrates that phase-shifting effects may be determined with exercise durations and intensities compatible with the demands of a real-life setting.

Objective: Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms. Background: CSF alpha‐synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha‐synuclein differentiate these groups is controversial. Correlations of alpha‐synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta‐amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear. Methods: BioFIND, a cross‐sectional, observational study, examines clinical and biomarker characteristics in moderate‐advanced PD and matched healthy controls. We compared alpha‐synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS‐UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined. Results: CSF alpha‐synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha‐synuclein did not differ between PD and controls, and alpha‐synuclein did not significantly correlate among biofluids. CSF beta‐amyloid1‐42 was lower in PD versus controls (P < .01), and correlated weakly with MoCA recall scores (r = 0.23, P = .02). CSF alpha‐synuclein was lower in the postural instability/gait difficulty phenotype than other motor phenotypes (P < .01). No CSF biomarkers predicted or correlated with total motor or rapid eye movement sleep behavior disorder scores. CSF alpha‐synuclein correlated with beta‐amyloid1‐42, total‐tau, and phosphorylated‐tau (r = 0.41, 0.81, 0.43, respectively; Ps < .001). Conclusion: Lower CSF alpha‐synuclein is associated with diagnosis and motor phenotype in moderate‐advanced PD. Plasma and saliva alpha‐synuclein neither correlate with CSF alpha‐synuclein, nor distinguish PD from controls. CSF beta‐amyloid1‐42 remains a potential biomarker for cognitive impairment in PD. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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