High burden of neurological disease in the older general population: results from the Canadian Longitudinal Study on Aging.

BACKGROUND AND PURPOSE: Our objective was to study the association between the presence of a neurological disease and the comorbidity burden as well as healthcare utilization (HCU). METHODS: Using baseline data from the Canadian Longitudinal Study on Aging (CLSA), we examined the burden of five neurological conditions. The CLSA is a population-based study of approximately 50 000 individuals, aged 45-85 years at baseline. We used multivariable Poisson regression to identify correlates of comorbidity burden and HCU. RESULTS: The lifetime prevalence of five neurological diseases is presented: epilepsy, Parkinson's disease/parkinsonism, stroke/transient ischaemic attack, multiple sclerosis and migraine. We found the somatic and psychiatric comorbidity burden to be higher in those individuals with a neurological disease (an 18-45% mean increase in the number of chronic conditions) as compared with the comparison group without a neurological disease, except for Parkinson's disease/parkinsonism. The presence of a neurological disease was associated with only a modest increase in the probability of visiting a general practitioner but was associated with a greatly increased probability of visiting a medical specialist (up to 68% more likely) or an emergency department (up to 79% more likely) and an overnight hospitalization (up to 108% more likely). CONCLUSIONS: We found striking associations between our neurological diseases and increased comorbidity burdens and HCU. These findings are important for informing public policy planning as well as driving avenues for future research. The present study established the CLSA as an important research platform for the study of neurological conditions in an aging general population.

The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies.

Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French-Canadians are known. GBA was fully sequenced using targeted next generation and Sanger sequencing in French-Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)-sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity-by-descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism-chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French-Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

EEG rhythmic and arrhythmic spectral components and functional connectivity at resting state may predict the development of synucleinopathies in idiopathic REM sleep behavior disorder.

STUDY OBJECTIVES: Idiopathic/isolated REM-sleep behavior disorder (iRBD) often precedes the onset of synucleinopathies. Here, we investigated whether baseline resting-state EEG advanced spectral power and functional connectivity differ between iRBD patients who converted towards a synucleinopathy at follow-up and those who did not. METHODS: Eighty-one participants with iRBD (66.89±6.91 years) underwent a baseline resting-state EEG recording, a neuropsychological assessment and a neurological examination. We estimated EEG power spectral density using standard analyses and derived spectral estimates of rhythmic and arrhythmic components. Global and pairwise EEG functional connectivity analyses were computed using the weighted phase-lag index (wPLI). Pixel-based permutation tests were used to compare groups. RESULTS: After a mean follow-up of 5.01±2.76 years, 34 patients were diagnosed with a synucleinopathy (67.81±7.34 years) and 47 remained disease-free (65.53±7.09 years). Among patients who converted, 22 were diagnosed with Parkinson's disease and 12 with dementia with Lewy bodies. As compared to patients who did not convert, patients who converted exhibited at baseline higher relative theta standard power, steeper slopes of the arrhythmic component and higher theta rhythmic power mostly in occipital regions. Furthermore, patients who converted showed higher beta global wPLI but lower alpha wPLI between left temporal and occipital regions. CONCLUSION: Analyses of resting-state EEG rhythmic and arrhythmic components and functional connectivity suggest an imbalanced excitatory-to-inhibitory activity within large-scale networks, which is associated with later development of a synucleinopathy in iRBD patients.

How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder.

Parkinsonism, as a gradually progressive disorder, has a prodromal interval during which neurodegeneration has begun but cardinal manifestations have not fully developed. A systematic direct assessment of this interval has never been performed. Since patients with idiopathic REM sleep behaviour disorder are at very high risk of parkinsonism, they provide a unique opportunity to observe directly the development of parkinsonism. Patients with idiopathic REM sleep behaviour disorder in an ongoing cohort study were evaluated annually with several quantitative motor measures, including the Unified Parkinson's Disease Rating Scale, Purdue Pegboard, alternate-tap test and timed up-and-go. Patients who developed parkinsonism were identified from this cohort and matched according to age to normal controls. Their results on motor testing from the preceding years were plotted, and then assessed with regression analysis, to determine when markers first deviated from normal values. Sensitivity and specificity of quantitative motor markers for diagnosing prodromal parkinsonism were assessed. Of 78 patients, 20 developed parkinsonism. On regression analysis, the Unified Parkinson's Disease Rating Scale first intersected normal values at an estimated 4.5 years before diagnosis. Voice and face akinesia intersected earliest (estimated prodromal interval = 9.8 years), followed by rigidity (4.4 years), gait abnormalities (4.4 years) and limb bradykinesia (4.2 years). Quantitative motor tests intersected normal values at longer prodromal intervals than subjective examination (Purdue Pegboard = 8.6 years, alternate-tap = 8.2, timed up-and-go = 6.3). Using Purdue Pegboard and the alternate-tap test, parkinsonism could be detected with 71-82% sensitivity and specificity 3 years before diagnosis, whereas a Unified Parkinson's Disease Rating Scale score >4 identified prodromal parkinsonism with 88% sensitivity and 94% specificity 2 years before diagnosis. Removal of action tremor scores improved sensitivity to 94% and specificity to 97% at 2 years before diagnosis (cut-off >3). Although distinction between conditions was often difficult, prodromal dementia with Lewy bodies appeared to have a slower progression than Parkinson's disease (prodromal interval = 6.0 versus 3.8 years). Using a cut-off of Unified Parkinson's Disease Rating Scale >3 (excluding action tremor), 25% of patients with 'still-idiopathic' REM sleep behaviour disorder demonstrated evidence of possible prodromal parkinsonism. Therefore, using direct assessment of motor examination before parkinsonism in a REM sleep behaviour disorder, we have estimated a prodromal interval of ∼4.5 years on the Unified Parkinson's Disease Rating Scale; other quantitative markers may detect parkinsonism earlier. Simple quantitative motor measures may be capable of reliably detecting parkinsonism, even before a clinical diagnosis can be made by experienced movement disorders neurologists.

Clinical prediction of Parkinson's disease: planning for the age of neuroprotection.

As a chronic progressive disease, Parkinson's disease (PD) has a presymptomatic interval; that is, a period during which the pathological process has begun, but motor signs required for the clinical diagnosis are absent. The ability to identify this preclinical stage may be critical in the development and eventual use of neuroprotective therapy. Recently proposed staging systems of PD have suggested that degeneration may occur initially in areas outside the substantia nigra, suggesting that non-motor manifestations may be markers of presymptomatic PD. Decreased olfaction has recently been demonstrated to predict PD in prospective pathological studies, although the lead time may be relatively short, and the positive predictive value is low. Idiopathic RBD has a very high predictive value, with approximately 50% of affected individuals developing PD or dementia within 10 years. This implies that idiopathic RBD patients are ideal candidates to test potential preclinical markers. However, the specificity of symptom screens for RBD is not established, not all persons with PD develop RBD, and there are only limited ways to predict which RBD patients will develop PD. Other simple screens based upon autonomic symptoms, depression and personality changes, quantitative motor testing and other sleep disorders may also be useful markers, but have not been extensively tested. Other more expensive measures such as detailed autonomic testing, cardiac MIBG-scintigraphy, dopaminergic imaging and transcranial ultrasound may be especially useful in defining disease risk in those identified through primary screening.

Markers of neurodegeneration in idiopathic rapid eye movement sleep behaviour disorder and Parkinson's disease.

Idiopathic rapid eye movement sleep behaviour disorder is an important risk factor in the development of Parkinson's disease. Numerous potential predictive markers of Parkinson's disease may present before motor symptoms emerge, but testing of these markers in rapid eye movement sleep behaviour disorder has been performed only in small studies. There has been no comparison of markers between patients with idiopathic rapid eye movement sleep behaviour disorder and Parkinson's disease, and between men and women. We evaluated an array of potential Parkinson's disease predictive markers in 159 patients; including 68 with idiopathic rapid eye movement sleep behaviour disorder, 36 controls, 34 Parkinson's patients with rapid eye movement sleep behaviour disorder and 21 Parkinson's patients without rapid eye movement sleep behaviour disorder. Compared with controls, patients with idiopathic rapid eye movement sleep behaviour disorder demonstrated substantial olfactory loss (P < 0.001). Olfaction was more impaired in Parkinson's disease than idiopathic rapid eye movement sleep behaviour disorder and did not differ between Parkinson's patients with, or without, rapid eye movement sleep behaviour disorder. Numerous measures of motor function including the Unified Parkinson Disease Rating Scale alternate tap, Purdue Peg Board and Timed 'Up and Go' were impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.01). All of these motor measures were worse with Parkinson's disease than with idiopathic rapid eye movement sleep behaviour disorder, regardless of rapid eye movement sleep behaviour disorder status. Autonomic symptoms and systolic blood pressure drop were impaired in patients with idiopathic rapid eye movement sleep behaviour disorder compared with controls (P = 0.003). Orthostatic abnormalities in Parkinson's disease were found in the group with rapid eye movement sleep behaviour disorder (P < 0.001). However, Parkinson's patients without rapid eye movement sleep behaviour disorder were not different than controls and had less impairment than those with idiopathic rapid eye movement sleep behaviour disorder (P = 0.004) and Parkinson's patients with rapid eye movement sleep behaviour disorder (P < 0.001). Colour vision was impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.001). However, only Parkinson's patients with rapid eye movement sleep behaviour disorder had abnormalities significantly different than controls (P < 0.001), and there were significant differences between Parkinson's patients with or without rapid eye movement sleep behaviour disorder (P < 0.04). Idiopathic rapid eye movement sleep behaviour disorder patients had slightly increased harm avoidance scores on personality testing (P = 0.04). Other than slightly better performances among women in the Purdue Peg Board, there was no difference in any measure between men and women, suggesting similar pathogenic processes underlying rapid eye movement sleep behaviour disorder. Patients with idiopathic rapid eye movement sleep behaviour disorder demonstrate abnormalities in numerous potential markers of neurodegenerative disease--these markers are heterogeneous, generally correlate with each other and occur equally in men and women. Although these abnormalities are usually intermediate between control values and Parkinson's patients, autonomic dysfunction and colour vision appear to be more linked to rapid eye movement sleep behaviour disorder status than Parkinson's disease, suggesting a unique pathophysiology of these abnormalities.

Basic clinical features do not predict dopamine transporter binding in idiopathic REM behavior disorder.

REM sleep behavior disorder (RBD) is strongly associated with development of Parkinson's Disease and other α-synuclein-related disorders. Dopamine transporter (DAT) binding deficit predicts conversion to α-synuclein-related disorders in individuals with RBD. In turn, identifying which individuals with RBD have the highest likelihood of having abnormal DAT binding would be useful. The objective of this analysis was to examine if there are basic clinical predictors of DAT deficit in RBD. Participants referred for inclusion in the RBD cohort of the Parkinson Progression Markers Initiative were included. Assessments at the screening visit including DAT SPECT imaging, physical examination, cognitive function screen, and questionnaire-based non-motor assessment. The group with DAT binding deficit (n = 49) was compared to those without (n = 26). There were no significant differences in demographic or clinical features between the two groups. When recruiting RBD cohorts enriched for high risk of neurodegenerative disorders, our data support the need for objective biomarker assessments.

REM sleep behaviour disorder in Parkinson's disease is associated with specific motor features.

BACKGROUND: Rapid eye movement (REM) sleep behaviour disorder (RBD) is commonly associated with Parkinson's disease (PD), and recent studies have suggested that RBD in PD is associated with increased cognitive impairment, waking EEG slowing, autonomic impairment and lower quality of life on mental health components. However, it is unclear whether the association of RBD in PD has implications for motor manifestations of the disease. METHODS: The study evaluated 36 patients with PD for the presence of RBD by polysomnography. Patients underwent an extensive evaluation on and off medication by a movement disorders specialist blinded to the polysomnography results. Measures of disease severity, quantitative motor indices, motor subtypes, complications of therapy and response to therapy were assessed and compared using regression analysis that adjusted for disease duration and age. RESULTS: Patients with PD and RBD were less likely to be tremor predominant (14% vs 53%; p<0.02) and had a lower proportion of their Unified Parkinson Disease Rating Scale (UPDRS) score accounted for by tremor (8.2% vs 19.0%; p<0.01). An increased frequency of falls was noted among patients with RBD (38% vs 7%; p = 0.04). Patients with RBD demonstrated a lower amplitude response to their medication (UPDRS improvement 16.2% vs 34.8%; p = 0.049). Markers of overall disease severity, quantitative motor testing and motor complications did not differ between groups. CONCLUSIONS: The presence of altered motor subtypes in PD with RBD suggests that patients with PD and RBD may have a different underlying pattern of neurodegeneration than PD patients without RBD.

Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder.

INTRODUCTION: Cognitive decline is common in Parkinson's disease (PD), and identifying patients at highest risk for it is essential. We aimed to examine the effect of possible REM sleep behavior disorder (pRBD) on rate of cognitive decline in early PD, for both global cognition and in specific cognitive domains. METHODS: Parkinson's Progression Markers Initiative (PPMI) is a multi-site, international study of PD patients untreated at enrollment. pRBD was assessed with the REM sleep behavior disorder questionnaire (RBDSQ). Global cognition was assessed at baseline and annually using the Montreal Cognitive Assessment (MoCA) and a cognitive battery. Linear mixed effects models were used to examine the relationship between pRBD (RBDSQ≥6) and rate of change in cognitive variables. Age, sex, years of education, and baseline motor and cognitive scores were included as covariates. RESULTS: The baseline sample consisted of 423 individuals with PD, mean age 61.7 years and 65.5% male. Data was available on 389, 366, and 196 participants at 1-year, 2-year, and 3-year follow-up respectively. Possible RBD occurred in 108 (25.5%) at baseline. In multivariate analyses, baseline RBD was associated with greater annual rate of decline in MoCA score (ß = -0.34, 95%CI -0.54, -0.13, p < 0.001), Symbol Digit Modalities Test (ß = -0.69, 95%CI -1.3, -0.09, p = 0.024), and Hopkins Verbal Learning Test-Revised, delayed free recall (ß = -0.21, 95%CI -0.41, -0.013, p = 0.037). CONCLUSIONS: Possible RBD is common in early PD and predicts future cognitive decline, particularly in attention and memory domains.

Is childhood schizophrenia a cholinergic disease? I. Muscle morphology.

Four hypotonic boys (aged 4 years and 11 months, 6 years and 9 months, 7 years and 4 months, and 8 years and 10 months, respectively), all of whom demonstrated a formal thought disorder, had been psychotic for more than six months, and met the DSM-III criteria for chronic undifferentiated schizophrenia, were studied with respect to skeletal muscle morphology. A significant difference between the mean fiber diameters of type I and type II muscle fibers was observed in the three boys with the most severe thought disorder, type II muscle fibers being consistently smaller. No significant difference in the mean fiber diameter between the two fiber types were seen in the fourth boy, who was also the only one who demonstrated any secondary thought process. The boys differed in their activity levels, but there was no correlation between type II muscle fiber atrophy and hypoactivity. It is hypothesized that a depressed cholinergic system is implicated in the pathogenesis of both the muscle fiber atrophy and the formal thought disorder.

Parkinson's Disease Genetic Loci in Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.

Effects of the amyloid protein precursor of Alzheimer's disease and other ligands of the LDL receptor-related protein on neurite outgrowth from sympathetic neurons in culture.

The amyloid protein precursor (APP) of Alzheimer's disease can stimulate neurite outgrowth in vitro. The receptor responsible for this effect has not been identified. Kunitz protease inhibitor (KPI)-containing forms of APP bind to the low-density lipoprotein receptor-related protein (LRP). As LRP may regulate neurite outgrowth, we examined whether the effects of APP are mediated by LRP. Inhibitors of LRP decreased neurite outgrowth from chick sympathetic neurons. Most LRP ligands (alpha2-macroglobulin, lactoferrin, and lipoprotein lipase) stimulated outgrowth. However, in soluble form, the KPI-containing APP751 was a weak inhibitor of outgrowth. In substrate-bound form, both APP751 and APP695 (which does not bind to LRP) stimulated outgrowth. Thus the effect of substrate-bound APP on neurite outgrowth is not mediated by LRP.

Liver disease in infants receiving total parenteral nutrition.

Progressive cholestasis and abnormal elevations of liver enzymes occurred in one third of 92, mostly preterm, newborn infants who received total parenteral nutrition (TPN) with protein hydrolysates, synthetic L-amino acids, and intravenous fat emulsion. The synthetic amino acid plus intravenous fat emulsion was not superior to the protein hydrolysate in preventing liver disease. The liver function returned to normal after discontinuation of TPN, which suggests a causal relationship. Hepatic microscopy was abnormal in 12 of 14 infants examined. The main features were progressive cholestasis and portal tract fibrosis and infiltration, which led to liver failure and death in two infants. In our experience, liver disease is the major metabolic complication of TPN in infants.

Muscle biopsy in hypotonic schizophrenic children: a preliminary report.

Two hypotonic boys, aged 7 years, 3 months and 7 yers, 7 months, who possessed sufficient speech to demonstrate a severe thought disorder and who differed markedly in their activity levels, were subjected to a biopsy of the quadriceps muscle. The biopsies revealed atrophy of type 2 muscle fibers, as well as variability in the size of these fibers. The findings could be compatible with a denervation phenomenon.

Inhibition of neurite outgrowth from chick sympathetic neurons by cholinesterase inhibitors is not mediated by binding to cholinesterases.

Several studies have suggested a role for cholinesterases in regulating neurite outgrowth. Some acetylcholinesterase (AChE) inhibitors can inhibit neurite outgrowth, but it is unclear if this is due to inhibition of AChE. In this study, the effect of cholinesterase inhibitors on neurite outgrowth from chick sympathetic neurons was examined. Very high (micromolar) concentrations of tacrine and BW284c51 were needed to inhibit neurite outgrowth. In contrast, nanomolar concentrations were required to block cholinesterase activity. No correlation was found between the type of inhibitor or potency of cholinesterase inhibition and inhibition of neurite outgrowth. Both tacrine and BW284c51 were neurotoxic at concentrations that inhibited outgrowth. Therefore, the action of cholinesterase inhibitors on neurite outgrowth may be due to non-specific toxicity rather than to cholinesterase binding.

Whole bowel irrigation in pediatric patients.

Whole bowel irrigation was used in 24 patients ages 8 to 17 yr, mean 13 yr, in preparation for colonoscopy (18), colon surgery (2), therapeutic irrigation for treatment of drug overdose (2), and constipation (2). An average of 9 liters warm, normal saline with added KCL (5 mEq/liter) was infused through a nasogastric tube over a period of 7 +/- 2 hr (mean +/- SD). This resulted in a weight gain of 2% and a mild hyperchloremia. The vital signs remained stable and there were no complications. The colonic preparation was complete in 10, adequate in 8 and unsatisfactory in 2. The irrigation was effective in the treatment of overdose ingestion and constipation. It is concluded that whole bowel irrigation is a satisfactory method of colonic preparation of pediatric patients.

The pediatric general surgery undergraduate medical curriculum: what should medical students learn?

Pediatric general surgery should be included in the undergraduate medical curriculum for reasons of improving the total surgical care of infants and children, to enable teachers to serve as role models to students considering a career in pediatric surgery and to ensure survival of pediatric surgery in the medical school curriculum. A survey of recent medical literature and surgical textbooks revealed little or no discussion concerning the aims, objectives, content, and design of the pediatric surgical curriculum. A survey of 15 Canadian medical schools showed that students are assigned very little didactic time for pediatric surgery (average total seven hours) and only 25% of graduates proceed to a clerkship in pediatric surgery, usually as an elective. The Association hereby proposes an undergraduate medical education curriculum in pediatric surgery for Canadian medical schools in order to stimulate discussion and achieve uniform input of pediatric surgery in the undergraduate medical program.

Whole bowel irrigation in pediatric patients: a comparison of irrigating solutions.

The effect of whole bowel irrigation (WBI) with a polyethylene glycol electrolyte lavage solution (PEG-ELS; 27 children) was compared to the WBI with two electrolytic solutions: normal saline with added potassium chloride (NS; 25 children) and Ringer's injection (RI; 29 children). The PEG-ELS required less volume and time, and did not cause the weight gain, hemodilution, and hyperchloremia associated with use of the electrolytic solutions. A balanced PEG-ELS is preferred in WBI of children.

Extreme short-bowel syndrome in an infant.

This full term male infant required a 90% enterectomy for congenital intestinal volvulus shortly after birth. The remaining small bowel consisted of 8 cm of proximal jejunum anastomosed to 5 cm of terminal ileum. The ileocecal valve was intact. Parenteral nutrition was administered for the first 21 months, including 17 months of home parenteral nutrition. The child's oral diet was mother's milk until 28 months of age when he was switched to an elemental diet. Solids were introduced at 6 months of age. Presently, at 36 months of age, the infant is off parenteral nutrition and is maintaining good nutritional status on a diet of 150 calories per kilo per day. His major problem has been an extreme allergy to cow's-milk protein. This infant is remarkable, since, despite record short bowel length, he maintained a completely normal growth and development, had remarkably few serious complications, spent relatively little time in hospital, and has documented improvement of G.I. absorption and radiographic contrast studies.