Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study.

OBJECTIVES: The objective of this study was to determine phenotypic features that differentiate nonparkinsonian first-degree relatives of PD leucine-rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. METHODS: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unrelated healthy controls participating in established multiplex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for daytime sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward variable selection, validated with bootstrap resampling, to establish the best combination of motor and nonmotor features that differentiates nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases from unrelated healthy controls. RESULTS: We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The combination of past or current symptoms of anxiety (adjusted odds ratio, 4.16; 95% confidence interval, 2.01-8.63), less daytime sleepiness (adjusted odds ratio [1 unit], 0.90; 95% confidence interval, 0.83-0.97], and worse motor UPDRS score (adjusted odds ratio [1 unit], 1.4; 95% confidence interval, 1.20-1.67) distinguished nonparkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve = 79.3%). CONCLUSIONS: A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S probands, regardless of mutation status, from unrelated healthy controls. Environmental or non-LRRK2 genetic factors in LRRK2-associated PD may influence penetrance of the LRRK2 G2019S mutation. The relationship of these features to actual PD risk requires longitudinal observation of LRRK2 familial PD cohorts. © 2018 International Parkinson and Movement Disorder Society.

Heart rate variability in leucine-rich repeat kinase 2-associated Parkinson's disease.

BACKGROUND: Heart rate variability is reduced in idiopathic PD, indicating cardiac autonomic dysfunction likely resulting from peripheral autonomic synucleinopathy. Little is known about heart rate variability in leucine-rich repeat kinase 2-associated PD. OBJECTIVES: This study investigated heart rate variability in LRRK2-associated PD. METHODS: Resting electrocardiograms were obtained from 20 individuals with LRRK2-associated PD, 37 nonmanifesting carriers, 48 related noncarriers, 26 idiopathic PD patients, and 32 controls. Linear regression modelling compared time and frequency domain values, adjusting for age, sex, heart rate, and disease duration. RESULTS: Low-frequency power and the ratio of low-high frequency power were reduced in idiopathic PD versus controls (P < .008, P < .029 respectively). In contrast, individuals with LRRK2-associated PD were not statistically different from controls in any parameter measured. Furthermore, all parameters trended toward being higher in LRRK2-associated PD when compared with idiopathic PD. CONCLUSIONS: Heart rate variability may remain intact in LRRK2-associated PD, adding to a growing literature supporting clinical-pathologic differences between LRRK2-associated and idiopathic PD. © 2017 International Parkinson and Movement Disorder Society.

Pharmacological treatment of Parkinson disease: a review.

IMPORTANCE: Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. OBJECTIVE: To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. EVIDENCE REVIEW: References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. RESULTS: Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, ß-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies. CONCLUSIONS AND RELEVANCE: Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.

High-intensity interval versus moderate-intensity continuous cycling training in Parkinson's disease: a randomized trial.

Exercise training is recommended to improve the quality of life in those living with Parkinson's disease (PD); however, the optimal prescription to improve cardiorespiratory fitness and disease-related motor symptoms remains unknown. Twenty-nine participants with PD were randomly allocated to either 10 wk of high-intensity interval training (HIIT) (n = 15; 6 female) or moderate-intensity continuous training (MICT) (n = 14; 5 female). The primary outcome was the change in maximal oxygen consumption (V̇o2peak). Secondary outcomes included changes in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III motor score, Parkinson's Fatigue Scale (PFS)-16, resting and exercise cardiovascular measures, gait, balance, and knee extensor strength and fatigability. Exercise training increased V̇o2peak (main effect of time, P < 0.01), with a clinically meaningful difference in the change following HIIT versus MICT (Δ3.7 ± 3.7 vs. 1.7 ± 3.2 mL·kg-1·min-1, P = 0.099). The UPDRS motor score improved over time (P < 0.001) but without any differences between HIIT versus MICT (Δ-9.7 ± 1.3 vs. -8.4 ± 1.4, P = 0.51). Self-reported subjective fatigue (PFS-16) decreased over time (P < 0.01) but was similar between HIIT and MICT groups (P = 0.6). Gait, balance, blood pressure (BP), and heart rate (HR) were unchanged with training (all P > 0.09). Knee extensor strength increased over time (P = 0.03) but did not differ between HIIT versus MICT (Δ8.2 ± 5.9 vs. 11.7 ± 6.2 Nm, P = 0.69). HIIT alone increased the muscular endurance of the knee extensors during an isotonic fatigue task to failure (P = 0.04). In participants with PD, HIIT and MICT both increased V̇o2peak and led to improvements in motor symptoms and perceived fatigue; HIIT may offer the potential for larger changes in V̇o2peak and reduced knee extensor fatigability.NEW & NOTEWORTHY The optimal exercise prescription to improve cardiorespiratory fitness and disease-related motor symptoms in adults with Parkinson's disease remains unknown. In a single-center randomized trial consisting of either 10 wk of high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), we found that both training modes increased V̇o2peak, with a larger clinically meaningful difference following HIIT. Both exercise modes improved motor symptoms and subjective fatigue, whereas HIIT increased the muscular endurance of the knee extensors.

MELAS syndrome, cardiomyopathy, rhabdomyolysis, and autism associated with the A3260G mitochondrial DNA mutation.

The A to G transition mutation at position 3260 of the mitochondrial genome is usually associated with cardiomyopathy and myopathy. One Japanese kindred reported the phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS syndrome) in association with the A3260G mtDNA mutation. We describe the first Caucasian cases of MELAS syndrome associated with the A3260G mutation. Furthermore, this mutation was associated with exercise-induced rhabdomyolysis, hearing loss, seizures, cardiomyopathy, and autism in the large kindred. We conclude that the A3260G mtDNA mutation is associated with wide phenotypic heterogeneity with MELAS and other "classical" mitochondrial phenotypes being manifestations.

Investigating Voice as a Biomarker for Leucine-Rich Repeat Kinase 2-Associated Parkinson's Disease.

We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2-associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts.

Actigraphy Detects Greater Intra-Individual Variability During Gait in Non-Manifesting LRRK2 Mutation Carriers.

BACKGROUND: With recent advances in the search for disease-modifying therapies for Parkinson's disease (PD) the importance of identifying prodromal markers becomes greater. Non-manifesting LRRK2 mutation carriers (NMC) are at risk for developing PD, and provide a population in which to identify possible markers. OBJECTIVE: The aim of this study was to test the hypothesis that NMC have differences in daily activity, fragmentation of sleep, arm swing asymmetry, and movement variability during walking, detectable by actigraphy, as compared to matched control subjects. METHODS: Eleven NMC, fourteen PD patients (4 LRRK2-PD, 10 idiopathic PD (iPD)), and twenty-nine controls wore wristbands containing an accelerometer for seven days, and performed a daily walking task. Outcome measures included daily activity, fragmentation of activity, fragmentation of sleep, arm swing asymmetry during walking, and intra-individual variability. RESULTS: Compared to healthy controls, both NMC and LRRK2/iPD showed higher intra-individual variability in activity during walking compared to healthy controls. Individuals with LRRK2-PD/iPD, but not NMC, tend to have lower activity levels, more arm swing asymmetry and less increase of arm swing with transition from slow to faster walking speed compared to healthy controls. CONCLUSION: Higher intra-individual variability of gait-associated movements might be a useful biomarker of prodromal PD. These results encourage replication in a larger sample and longitudinal analysis is warranted.

Famotidine, a Histamine H2 Receptor Antagonist, Does Not Reduce Levodopa-Induced Dyskinesia in Parkinson's Disease: A Proof-of-Concept Study.

The neural mechanisms underlying levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) may involve histamine (H2) receptors on striatopallidal pathways. We recently demonstrated that the clinically available oral histamine H2 receptor antagonist (H2 RA), famotidine, can reduce l-dopa-induced chorea in MPTP-lesioned macaques. We hypothesized that famotidine may be useful in the treatment of LID in PD patients. We performed a proof-of-concept, double-blind, randomized, multiple cross-over (4×) trial. Seven PD subjects with bothersome dyskinesia were randomized to oral famotidine 80, 120, and 160 mg/day and placebo. Each subject was randomized to receive each of the four treatment phases for 14 days followed by a 7-day wash-out period between each treatment phase. The primary outcome measure was change in the Unified Dyskinesia Rating Scale (UDysRS; part III) between placebo and famotidine. Secondary outcomes were UDysRS (parts I and II), Global Impression of Change, Lang-Fahn Activities of Daily Living Dyskinesia Scale, Unified Parkinson's Disease Rating part III, and adverse events (AEs). Outcomes were evaluated pre- and post-treatment per dose and analyzed using a mixed-effects linear model. There was no significant effect of famotidine treatment on any of the primary or secondary outcome measures compared to placebo (each dose and all doses combined). There were no significant AEs. Even though the sample size of the current study is limited, famotidine seems to be safe in patients with PD and LID, but showed no potential as an antidyskinetic agent.

Drug treatments for the neuropsychiatric complications of Parkinson's disease.

Psychiatric symptoms are now well described in Parkinson's disease (PD). Most are due to the disease pathology with exacerbation caused by dopaminergic treatment. Anxiety and depression may predate the onset of motor symptoms and can continue to occur with advancing disease. In patients with parkinsonism, well-formed hallucinations are highly specific for PD and some patients may progress to other psychotic symptoms. Cognitive impairment, ranging from mild impairment to dementia is common. Management of these symptoms involves initial recognition and secondly, appropriate medications. Pharmacological treatments are not specific for PD and are the same as those currently used in nonPD populations. The choice of agent is determined by a balance between potential benefit versus side effects, mostly in terms of worsening motor PD symptoms. This article will review current treatment approaches to mood disorders, psychosis and cognitive problems in PD, as well as management of dopamine-induced impulse control disorders.

A meta-analysis of published literature on waist-to-hip ratio and risk of breast cancer.

Epidemiological studies have identified body weight as a risk factor for breast cancer. Beyond the amount of adipose tissue a woman has, its distribution, particularly abdominally, may be a risk factor in breast cancer etiology. Body fat distribution is commonly measured by a waist-to-hip circumference ratio lpar;WHR). We performed a meta-analysis to summarize the published literature on WHR and breast cancer risk. After assembling all published studies, we extracted mean WHRs for study participants and adjusted risk estimates comparing highest with lowest partition of WHR and calculated weighted mean differences in WHR between cases and noncases and summary risk estimates based on study design and menopausal status. The weighted mean difference was 0.016 [95% confidence interval (CI) = 0.005-0.028] for all studies combined. The summary risk estimates were 1.80 (95% CI = 1.29-2.50) for case-control studies and 1.27 (95% CI = 1.07-1.51) for cohort studies. By menopausal status, the summary risks were 1.79 (95% CI = 1.22-2.62) for premenopausal women and 1.50 (95% CI = 1.10-2.04) for postmenopausal women. For all studies combined, the summary risk was 1.62 (95% CI = 1.28-2.04). This meta-analysis indicates that a greater WHR is associated with increased risk of breast cancer and suggests that the avoidance of abdominal obesity may reduce risk of the disease.