The Modifying Effect of Age on Survival in Parkinson's Disease: A Population-Based Cohort Study.

BACKGROUND: To estimate the survival of a population-based cohort of Parkinson's disease (PD) patients stratified by age and sex over a 13-year period. METHODS: The dynamic PD cohort included 6,622 incident PD patients who initiated anti-parkinsonian medications at age >40 years. The reference population (n = 401,498) consisted of members of a large health maintenance organization. We estimated the PD patients' death risk and sex- and age-specific standardized mortality ratio (SMR). RESULTS: During a follow-up of 5.2 ± 3.3 years, 36% of the cohort died. Older age at first PD treatment was associated with a 55% increase in mortality (for 5-year increase, p < 0.01). More PD patients died when compared to the same age and sex reference population in all age groups, with significant results at age groups >60 years at first treatment. The age-pooled SMR was twofold (SMR for the males = 2.05, 95% CI 1.73-2.42; SMR females = 2.13, 95% CI 1.74-2.62). The highest excess death for males was 2.5-fold for those aged 60-69 years, decreasing to twofold for those in the age range 70-79 years and to 1.5-fold for those aged 80+ years. A similar trend was found among females. CONCLUSION: Our large-scale cohort enabled us to find an age-differential standardized death risk among PD patients, with the largest increased risk at ages 60-69 years. Comorbidities and other contributory factors warrant further investigation.

Higher serum cholesterol and decreased Parkinson's disease risk: A statin-free cohort study.

BACKGROUND: Higher levels of serum cholesterol are well-established risk factors for coronary artery disease and stroke. The role of serum cholesterol in neurodegeneration is not clear. OBJECTIVE: We evaluated the association between serum cholesterol levels over time and the risk of Parkinson's disease (PD) among statin-free individuals. METHODS: A population-based cohort study of 261,638 statin-free individuals (aged 40-79 years at their first serum cholesterol test, 42.7% men), with repeated measures of total, low, and high-density lipoprotein cholesterol was performed from 1999 to 2012. Individuals were followed from their first cholesterol test until PD incidence, death, or end of study. The PD incidence was assessed using a validated antiparkinsonian-drug tracing approach. Cox models stratified by sex and age with time-dependent cholesterol variables were applied to estimate PD hazard ratios. RESULTS: A total of 764 (3.3% patients aged 65 + years) incident PD cases were detected during a mean follow-up of 7.9 (±3.6) years. Among men, the middle and upper tertiles of total and low-density lipoprotein cholesterol compared to the lowest were significantly associated with a lower PD risk. Age-pooled hazard ratios (95% confidence interval) for middle and upper tertiles were 0.82 (0.66-1.01) and 0.71 (0.55-0.93), respectively, for total cholesterol, and 0.80 (0.65-0.98) and 0.72 (0.54-0.95) respectively, for low-density lipoprotein cholesterol. Among women, the association between total and low-density lipoprotein cholesterol levels with PD risk was not significant. Null results were found for both sexes for high-density lipoprotein cholesterol. CONCLUSIONS: Higher levels of total and low-density lipoprotein cholesterol among men over time indicated a decreased PD risk. The potential role of cholesterol in disease protection warrants further investigation. © 2018 International Parkinson and Movement Disorder Society.

Mutational analysis of glycyl-tRNA synthetase (GARS) gene in Hirayama disease.

Sporadic juvenile muscular atrophy of the distal upper extremity or Hirayama's disease (HD) and autosomal dominant motor distal neuronopathy/axonopathy (CMT2D/dSMA-V), produced by glycyl-tRNA synthetase (GARS) gene mutations, share some clinical features including: young age of onset, predilection for the distal upper extremity, asymmetry, sparing of proximal muscles and unusual cold sensitivity. However, incomplete penetrance of GARS gene mutations may account for apparently non-familial cases. In order to inquire whether GARS gene mutations are associated with HD we studied seven patients fulfilling the clinical and electrodiagnostic criteria for HD. All patients underwent MRI of cervical spine that excluded compressive myelopathy in neutral position and intramedullary pathology. Each patient was tested for the presence of mutations in GARS by sequencing all coding exons amplified from genomic DNA. No pathogenic mutations were found, excluding the role of GARS gene as a possible factor in the aetiology of HD in this cohort.

Anemia in men and increased Parkinson's disease risk: A population-based large scale cohort study.

OBJECTIVE: To evaluate the association between anemia and Parkinson's disease risk (PD) in men and women. METHODS: A population-based cohort of 474,129 individuals (aged 40-79 years at date of first Hb test, 47.4% men) with repeated Hb levels was derived from a large Healthcare Maintenance Organization that serves 2 million citizens in Israel (study-period 1.1.1999-31.12.2012). An annual anemia indicator [Hb levels (g/dL) for men <13; for women <12.0] was assessed for each individual and they were followed from first Hb test until the date of PD incidence, death or end of the study. Cox-proportional hazards models, stratified by sex and age, with time-dependent anemia covariate were used to estimate adjusted Hazard Ratio with 95% of confidence intervals (HR, 95%CI) for PD. RESULTS: During a mean follow up of 8.8 ±â€¯3.9 years (7.0 ±â€¯3.6 for men and 7.9 ±â€¯4.1 for women), 2427 incident PD cases were detected. Cumulative PD incidence at ages over 65 years was 3.3%. The mean levels of Hb at baseline was 14.8 ±â€¯1.1 g/dL among men; 12.8 ±â€¯1.1 g/dL among women. Anemia was associated with significant PD risk among men, age-pooled HR = 1.19 (95%CI: 1.04-1.37), with the highest risk between ages 60-64 years [HR = 1.41 (95%CI: 1.03-1.93)]. Anemia was not associated with PD risk among women across all age-groups. The age-pooled HR for women was 1.02 (95%CI 0.95-1.09). CONCLUSIONS: The finding that anemia was associated with PD risk in men, especially in middle age, warrants further investigations on common pathophysiologic processes between Hb abnormalities and brain dysfunction.

Insomnia in circadian dysrhythmias.

Insomnia is one of the most common symptoms of disordered sleep. The etiology of insomnia is multifaceted, and the correct diagnosis will lead to effective treatment. One cause of insomnia that is often overlooked results from a conflict in schedules and desynchronization between the intrinsic sleep-wake propensity of a person and his or her 24-hour physical and social environment. Sleep propensity is governed by the complex interactions of an oscillating circadian rhythm and a monotonous homeostatic process. This review describes the basic physiology of the circadian system and, based on these understandings, discusses the various clinical manifestations of and treatments for circadian rhythm sleep disorders.

Statin adherence and the risk of Parkinson's disease: A population-based cohort study.

BACKGROUND: While experimental data provided some compelling evidence on the benefits of statins on dopaminergic neurons, observational studies reported conflicting results regarding the potential of statins to effect the risk of Parkinson's disease (PD). OBJECTIVES: To evaluate the association between changes in statin adherence over time and PD risk. METHODS: A population-based cohort of new statin users (ages 40-79, years 1999-2012) was derived from a large Israeli healthcare services organization. Data included history of statin purchases and low density lipoprotein cholesterol (LDL-C) levels. Personal statin adherence was measured annually by the proportion of days covered (PDC). PD was detected employing a drug-tracer approach. Stratified (by sex, LDL-C levels at baseline and age) Cox proportional hazards models with time-dependent covariates were used to compute adjusted Hazard Ratio (HR) with 95%CI. RESULTS: The cohort included 232,877 individuals, 49.3% men. Mean age at first statin purchase was 56.5 (±9.8) years for men and 58.7 (±9.2) years for women. PDC distribution for the whole follow up period differed between men and women: medians 58.3% and 54.1% respectively. During a mean follow up of 7.6 (±3.4) years, 2,550 (1.1%) PD cases were identified. In a 1-year lagged analysis, we found no association between annual statin adherence and PD risk in all age-groups regardless of statin type and potency. Age-pooled HR (95%CI) for men and women with LDL-C levels at baseline ≤160mg/dL were: 0.99 (0.99-1.01), 1.01 (1.00-1.02); and for men and women with LDL-C >160mg/dL levels: 0.99 (0.98-1.01), 0.97 (0.98-1.01). CONCLUSIONS: Our findings suggest that statin adherence over time does not affect PD risk. Future studies should use large-scale cohorts and refining assessments of long-term profiles in statin adherence.

[The biological clock in health and illness].

The biological clock in mammals is located in the suprachiasmatic nuclei of the hypothalamus. The combined output of multiple neuronal cellular oscillators determines the master circadian rhythm, which paces the myriad periodic functions of the organism, including, to a certain degree, the sleep-wake rhythm. The intrinsic master circadian rhythm, which is slightly longer than 24 hours, is synchronized daily to the extrinsic 24-hour day by the entrainment process, governed mainly by exposure to the environmental light at specific times. The pineal hormone melatonin is a specific and sensitive marker of the circadian clock activity, and its secretion is tightly coupled to the output of the biological clock and the circadian phase. Chronobiology is a young scientific discipline which deals with research of the biological clocks and its implication to the clinical medicine. Circadian rhythm disorders are manifest mainly as inappropriate sleep-wake timing, and patients complain about various combinations of insomnia or excessive sleepiness at inappropriate times. Treatment of circadian rhythm disorders by sleeping pills or wake-promoting agents, without taking chronobiological considerations into account, may be futile, or even detrimental to a patient's well-being. The current issue of "Harefuah" includes a review by Doljansky and Dagan, which exemplifies the chronobiological approach to sleep-wake rhythm disturbances in patients with Alzheimer's disease. Adoption of this approach to other disorders of the circadian clock may benefit care of patients.

Comparison of Selegiline and Rasagiline Therapies in Parkinson Disease: A Real-life Study.

BACKGROUND: We aimed to compare indicators of Parkinson disease (PD) progression between patients first prescribed either selegiline or rasagiline as their antiparkinsonian drugs (APDs) on the basis of real-life data. METHODS: Pharmacy data on members of a large Israeli health maintenance organization, treated as patients with PD during 2001-2012 and prescribed selegiline or rasagiline as their first APD, were analyzed. The first APD was selegiline for 349 patients (2001-2006) and rasagiline for 485 patients (2007-2012). Time from monoamine oxidase type B inhibitor prescription until initiating treatment with dopamine agonists (DAs) or levodopa was compared between the groups using Cox regression adjusted to sex and age at initiation of APD. RESULTS: The selegiline group was significantly older at first monoamine oxidase type B inhibitor purchase. In a similar follow-up time (3.0 [1.7] year for selegiline group, 3.1 y [1.4] for rasagiline group), the time to initiation of levodopa treatment did not differ between the 2 groups (adjusted hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.86-1.31). The time to initiation of DA treatment was longer in the selegiline group (adjusted HR, 1.93; 95% CI, 1.49-2.53). For those who were treated with DA before levodopa (n = 276), the time to initiation of levodopa treatment was longer in the rasagiline group (adjusted HR, 0.77; 95% CI, 0.56-1.07). CONCLUSIONS: The similarity in time to levodopa in both groups suggests no differences between selegiline and rasagiline in their effect on the natural history of PD. A possible interaction effect between rasagiline and DA might exist. A better symptomatic profile of selegiline more than that of rasagiline in the earlier stages of PD may explain the difference between the 2 groups in time to DA initiation.

Cancer incidence among Parkinson's disease patients in a 10-yrs time-window around disease onset: A large-scale cohort study.

OBJECTIVE: To compare the incidences of any cancer and specific types among patients with Parkinson's disease (PD) in a 10-yrs time window around diagnosis, to that of the general population. METHODS: We conducted a population-based, retrospective large-scale cohort study on 7125 newly diagnosed PD patients who had just initiated anti-parkinsonian medications between 1.1.2000 and 12.31.2012; all members of Maccabi Health Services (MHS), a large Israeli HMO. Cancer incidence during the same period was collected from MHS cancer-registry. Standardized-Incidence-Ratio (SIR) accounting for age, chronological-year and sex were calculated to compare cancer risks of PD patients to that of MHS population. RESULTS: The PD cohort (54% males) had a mean age at initiation of anti-parkinsonian medications of 71.2 ± 10.3years. In a time-window of 6.6 ± 3.4years before and 4.0 ± 3.9years after PD was first treated, 21% of the men and 15% of the women were diagnosed with incident-cancer. We found no-difference in any cancer risk for the PD cohort compared to the reference population: SIR = 0.99 (95%CI: 0.92-1.06) for males and 0.98 (95%CI: 0.89-1.07) for females. Risks for lung and colon cancers in the PD cohort were significantly lower for both sexes compared to the reference population. Risks for breast, central nervous system, kidney, leukemia, lymphoma, melanoma, ovarian, pancreatic, prostatic, rectal and thyroid were similar for the two populations. The SIRs did not differ between the sexes. CONCLUSIONS: We found no difference in the risk of any-type of cancer among PD patients compared to the general population, focusing on 10yrs time-window around the initiation of anti-parkinsonian medications.

Parkinson's disease patients first treated at age 75 years or older: a comparative study.

BACKGROUND: Parkinson's disease (PD) first diagnosed at older age reportedly has different clinical characteristics and survival rates than when it is first diagnosed at younger age. We compared these features among PD patients who initiated anti-parkinsonian drugs at age 75-85 years (elderly) with those who started treatment at age 50-74 years (younger). METHODS: We used a population-based cohort of 4449 incident cases of PD patients aged 50-85 at treatment initiation, based on a pharmacy registry of Maccabi Health Maintenance Organization, with definite/probable/possible certainty of having PD. Mean follow-up was 3.9 ± 2.6 years. The two age groups were compared for time/risk to levodopa and to death, using Kaplan-Meier curves and Cox regression. Gender-specific standardized mortality rates (SMRs) accounting for Israeli death rates were also compared. RESULTS: One-half of the entire cohort (n = 2148) were elderly (>75 years) and more likely to be given levodopa (Hazard Rate (HR) = 1.48, P < 0.05), had a significantly higher frequency of comorbidities (e.g., heart disease, hypertension and cancer), and had a 3-fold increased risk to die (HR = 2.97, P < 0.05) within the same follow-up time as the youngers. Accounting for the general Israeli population death rates, female PD patients had a significantly lower risk to die compared to males especially females who were elderly at treatment initiation (SMR = 1.53 for females vs. 1.73 for males, P < 0.05). CONCLUSIONS: PD patients first diagnosed and treated at >74 years of age comprise a unique cluster for inclusion into drugs studies, mortality risk analyses and for projection of disease burden.

Use of a refined drug tracer algorithm to estimate prevalence and incidence of Parkinson's disease in a large israeli population.

Estimating rates of Parkinson's disease (PD) is essential for health services planning and studies of disease determinants. However, few PD registries exist. We aimed to estimate annual prevalence and incidence of PD in a large Israeli population over the past decade using computerized drug purchase data. Based on profiles of anti-parkinsonian drugs, age at first purchase, purchase density, and follow-up time, we developed a refined algorithm for PD assessment (definite, probable or possible) and validated it against clinical diagnoses. We used the prescription database of the second largest Health Maintenance Organization in Israel (covers ~25% of population), for the years 1998-2008. PD rates by age, gender and year were calculated and compared using Poisson models. The algorithm was found to be highly sensitive (96%) for detecting PD cases. We identified 7,134 prevalent cases (67% definite/probable), and 5,288 incident cases (65% definite/probable), with mean age at first purchase 69 ± 13 years. Over the years 2000-2007, PD incidence rate of 33/100,000 was stable, and the prevalence rate increased from 170/100,000 to 256/100,000. For ages 50+, 60+, 70+, median prevalence rates were 1%, 2%, 3%, respectively. Incidence rates also increased with age (RR = 1.76, 95%CI 1.75-1.77, ages 50+, 5-year interval). For ages 50+, rates were higher among men for both prevalence (RR = 1.38, 95%CI 1.37-1.39) and incidence (RR = 1.45, 95%CI 1.42-1.48). In conclusion, our refined algorithm for PD assessment, based on computerized drug purchases data, may be a reliable tool for population-based studies. The findings indicate a burden of PD in Israel higher than previously assumed.

Forty- versus 20-minute trials of the maintenance of wakefulness test regimen for licensing of drivers.

STUDY OBJECTIVES: Objective assessment of the ability to maintain wakefulness, although very important, is still equivocal. A recent study from our lab has shown that the Maintenance of Wakefulness Test (MWT), when performed with the 20-minute protocol (MWT20), is unreliable in assessing patients who are highly motivated to maintain wakefulness. In this study, we sought to examine whether the 40-minute protocol (MWT40) is a better tool in assessing such individuals. METHODS: One hundred sixty-four consecutive subjects referred to our sleep lab by the Medical Institute for Driving Safety were studied. All subjects underwent a full-night polysomnogram followed by an MWT, 4 trials of 40 minutes each. All subjects knew that if they failed the wakefulness test their driving license would be revoked. RESULTS: Forty-one subjects out of 164 (25%) fell asleep at least once. Of 39 subjects with severe obstructive sleep apnea, (respiratory disturbance index > 40/h), 19 fell asleep (48.7%). Of 13 subjects with a minimum oxygen saturation level below 65%, 7 fell asleep (53%). In the MWT20, only 7% of patients with severe obstructive sleep apnea fell asleep at least once. CONCLUSIONS: We conclude that the MWT40 is superior to the MWT20 in detecting difficulties maintaining wakefulness in a highly motivated population. However, our results yield a significantly lower detection of difficulties maintaining wakefulness than those reported in healthy subjects, suggesting that the MWT40 is also highly affected by motivation. We believe that, for a highly motivated population (such as for a driver's license validation), different average sleep-latency threshold should be used than in general population.

Effect of sleep apnea on cognition and mood.

Obstructive sleep apnea syndrome (OSAS) is a common disorder in adults and children, which is characterized by repetitive transient reversible upper airway obstructions during sleep. Due to disrupted sleep architecture and intermittent hypoxemia, OSAS leads to impaired daytime functioning in various neuropsychological and affective domains. The most common abnormalities are executive dysfunction, impaired vigilance, depression, and possibly anxiety and, in children, hyperactivity. Optimal treatment of OSAS with continuous positive airway pressure may reverse the cognitive and affective dysfunction, however, in some patients a residual impairment persists. This persistent deficit, despite effective treatment, raises the possibility of a remaining subtle structural brain damage; such damage has been demonstrated through the use of sensitive functional and other neuroimaging techniques. Prefrontal cortical damage may underlie the cognitive dysfunction in OSAS. Early recognition and treatment may prevent this untoward effect of OSAS.