Association of disability with mortality in the Spanish adult non-institutionalised population.

BACKGROUND: There are scant studies focused on measuring the association between disability and all-cause mortality based on large representative national samples of the community-dwelling adult population; moreover, the number of such studies which also include cause-specific mortality is yet lower. METHODS: Longitudinal cohort study that used baseline data from 162 381 adults who participated in a countrywide disability survey (2008). A nationally representative sample was selected and interviewed in their homes. We present data on people ≥18 years. Disability was considered as any substantial limitation found on a list of 44 life activities that have lasted or are expected to last more than 1 year and originate from an impairment. Cause-specific mortality data were obtained from the Spanish Statistical Office. Subjects contributed follow-up time from baseline interview until death or the censoring date (31 December 2017). We computed standardised rate ratios (SRRs), with age, sex, living with a partner and education level distribution of the total group as standard population. RESULTS: Adults with disability (11%) had an adjusted mortality rate more than twice as high as adults without disability (SRR 2.37, 95% CI 2.24 to 2.50). The increased mortality risk remained over the 10-year follow-up period. Mortality due to diseases of the nervous system (SRR 4.86, 95% CI 3.93 to 6.01), diseases of the musculoskeletal system (SRR 3.45, 95% CI 2.18 to 5.47), infectious diseases (SRR 3.38, 95% CI 2.27 to 5.01) and diabetes mellitus (SRR 3.56, 95% CI 2.71 to 4.68) was particularly high in those with disability. CONCLUSIONS: All-cause mortality rates are markedly higher among adults with disability. Preventive measures and health promotion initiatives are needed to reduce mortality risk in this population. Special attention should be paid to disabled people with certain specific diseases.

Human prion disease surveillance in Spain, 1993-2018: an overview.

In Spain, human transmissible spongiform encephalopathies (TSEs) have been undergoing continuous surveillance for over 25 years. In 1995, the system was launched as an EU Concerted Action, with EU surveillance network procedures being incorporated from 2002 onwards. The aim of this report was to describe performance and outcomes of this surveillance system across the period 1993-2018. Neurology and public health specialists from every region reported cases to a central hub at the Carlos III Health Institute, Madrid. In all, eight accidentally transmitted cases and five definite variant Creutzfeldt-Jakob disease (vCJD) patients were reported. All vCJD cases were diagnosed between 2005 and 2008. Two of these were family/dietary-related and spatially linked to a third. Yearly incidence of sporadic CJD per million was 1.25 across the period 1998-2018, and displayed a north-south gradient with the highest incidence in La Rioja, Navarre and the Basque Country. Genetic TSEs were observed to be clustered in the Basque Country, with a 4-fold incidence over the national rate. A total of 120 (5.6%) non-TSE sporadic, conformational, rapidly progressing neurodegenerative and vascular brain disorders were reported as suspect CJD. We conclude that TSEs in Spain displayed geographically uneven, stable medium incidences for the sporadic and genetic forms, a temporal and spatial family cluster for vCJD, and decreasing numbers for dura-mater-associated forms. The vCJD surveillance, framed within the EU network, might require continuing to cover all prion disorders. There is need for further strategic surveillance research focusing on case definition of rapid-course, conformational encephalopathies and surgical risk.

Survival Patterns of Human Prion Diseases in Spain, 1998-2018: Clinical Phenotypes and Etiological Clues.

BACKGROUND: Human transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative disorders of short duration. There are few studies on TSE survival. This study sought to analyze the survival and related factors of a TSE patient cohort, based on a nationwide surveillance system in Spain. METHODS: Survival analyses were performed on 1,530 cases diagnosed across the period 1998-2018 in Spain. We calculated median survival times and plotted survival curves using the Kaplan-Meier method for all cases and for sporadic TSE (sTSE) and genetic TSE (gTSE). Crude and adjusted Cox proportional hazard models were used to identify variables associated with shorter survival. FINDINGS: Median age at onset decreased from the sporadic forms to gTSE and, lastly, to acquired TSE. Overall median and interquartile range (IQR) survival time was 5.2 (IQR, 3.0-11.7) months and 4.9 (IQR, 2.8-10.8) months in sporadic cases and 9 (IQR, 4.9 to over 12) months in genetic cases, p < 0.001. Male sex, older age at onset, presence of 14-3-3 protein, typical MRI, and MM and VV polymorphisms at codon 129 were associated with shorter survival. gTSE showed higher survival in crude comparisons but not after adjustment. INTERPRETATION: TSE survival in Spain replicates both the magnitude of that shown and the TSE entity-specific population patterns observed in Western countries but differs from features described in Asian populations, such as the Japanese. The reduction in differences in survival between gTSE and sTSE on adjusting for covariates and international patterns might support the view that gTSE and sTSE share causal and pathophysiological features.

Validity of the Global Activity Limitation Indicator (GALI) to evaluate severity of disability.

Our aim was to estimate the validity of the Global Activity Limitation Indicator (GALI) when measuring the severity level of disability. Data came from 153 residents of Spain, who requested an evaluation of their degree of disability. We compared disability classifications (severe vs. non-severe) from GALI against those from the 36-item questionnaire WHODAS 2.0, the current gold standard measure of disability. The sensitivity of GALI to detect severe disability was 58.3% [95% confidence interval (CI):43.2-72.4], and the specificity was 84.8% (95% CI: 76.4-91.0). Thus, the validity of GALI to accurately categorize the degree of severity of an individual's disability is not high, this in great part due to its limited sensitivity.

Age at onset in genetic prion disease and the design of preventive clinical trials.

OBJECTIVE: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease. METHODS: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials. RESULTS: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. CONCLUSION: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.

Facility ownership and mortality among older adults residing in care homes.

BACKGROUND AND OBJECTIVES: Nursing or care home characteristics may have a long-term impact on the residents' mortality risks that has not been studied previously. The study's main objective was to assess the association between facility ownership and long-term, all-cause mortality. RESEARCH DESIGN AND METHODS: We conducted a mortality follow-up study on a cohort of 611 nursing-home residents in the city Madrid, Spain, from their 1998-1999 baseline interviews up to September 2013. Residents lived in three types of facilities: public, subsidized and private, which were also sub-classified according to size (number of beds). Residents' information was collected by interviewing the residents themselves, their caregivers and facility physicians. We used time-to-event multivariable models and inverse probability weighting to estimate standardized mortality risk differences. RESULTS: After a 3728 person-year follow-up (median/maximum of 4.8/15.2 years), 519 participants had died. In fully-adjusted models, the standardized mortality risk difference at 5 years of follow-up between medium-sized private facilities and large-sized public facilities was -18.9% (95% confidence interval [CI]: -33.4 to -4.5%), with a median survival (95% CI) of 3.6 (0.5 to 6.8) additional years. The fully-standardized 5-year mortality difference (95% CIs) between for-profit private facilities and not-for-profit public institutions was -15.1% (-31.1% to 0.9%), and the fully-standardized median survival difference (95% CIs) was 3.0 (-1.7 to 7.7) years. DISCUSSION AND IMPLICATIONS: These results are compatible with an association between factors related with the ownership of facilities and the long-term mortality risk of their residents. One of these factors, the facility size, could partly explain this association.

Risk of transmission of sporadic Creutzfeldt-Jakob disease by surgical procedures: systematic reviews and quality of evidence.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (sCJD) is potentially transmissible to humans. OBJECTIVE: This study aimed to summarise and rate the quality of the evidence of the association between surgery and sCJD. DESIGN AND METHODS: Firstly, we conducted systematic reviews and meta-analyses of case-control studies with major surgical procedures as exposures under study. To assess quality of evidence, we used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Secondly, we conducted a systematic review of sCJD case reports after sharing neurosurgical instruments. RESULTS: Thirteen case-control studies met the inclusion criteria for the systematic review of case-control studies. sCJD was positively associated with heart surgery, heart and vascular surgery and eye surgery, negatively associated with tonsillectomy and appendectomy, and not associated with neurosurgery or unspecified major surgery. The overall quality of evidence was rated as very low. A single case-control study with a low risk of bias found a strong association between surgery conducted more than 20 years before disease onset and sCJD. Seven cases were described as potentially transmitted by reused neurosurgical instruments. CONCLUSION: The association between surgery and sCJD remains uncertain. Measures currently recommended for preventing sCJD transmission should be strongly maintained. Future studies should focus on the potential association between sCJD and surgery undergone a long time previously.

Parkinson's Disease Subtypes Identified from Cluster Analysis of Motor and Non-motor Symptoms.

Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity. Non-motor symptoms play a key role in the trajectory of Parkinson's disease, from prodromal premotor to end stages. To understand the clinical heterogeneity of Parkinson's disease, this study used cluster analysis to search for subtypes from a large, multi-center, international, and well-characterized cohort of Parkinson's disease patients across all motor stages, using a combination of cardinal motor features (bradykinesia, rigidity, tremor, axial signs) and, for the first time, specific validated rater-based non-motor symptom scales. Two independent international cohort studies were used: (a) the validation study of the Non-Motor Symptoms Scale (n = 411) and (b) baseline data from the global Non-Motor International Longitudinal Study (n = 540). k-means cluster analyses were performed on the non-motor and motor domains (domains clustering) and the 30 individual non-motor symptoms alone (symptoms clustering), and hierarchical agglomerative clustering was performed to group symptoms together. Four clusters are identified from the domains clustering supporting previous studies: mild, non-motor dominant, motor-dominant, and severe. In addition, six new smaller clusters are identified from the symptoms clustering, each characterized by clinically-relevant non-motor symptoms. The clusters identified in this study present statistical confirmation of the increasingly important role of non-motor symptoms (NMS) in Parkinson's disease heterogeneity and take steps toward subtype-specific treatment packages.

Similarities of Variant Creutzfeldt-Jakob Disease Strain in Mother and Son in Spain to UK Reference Case.

We investigated transmission characteristics of variant Creutzfeldt-Jakob disease in a mother and son from Spain. Despite differences in patient age and disease manifestations, we found the same strain properties in these patients as in UK vCJD cases. A single strain of agent appears to be responsible for all vCJD cases to date.

Spinal Cord Injury due to Tumour or Metastasis in Aragón, Northeastern Spain (1991-2008): Incidence, Time Trends, and Neurological Function.

PURPOSE: Understanding the presentation of spinal cord injury (SCI) due to tumours considering population distribution and temporal trends is key to managing SCI health services. This study quantified incidence rates, function scores, and trends of SCI due to tumour or metastasis over an 18-year time period in a defined region in Spain. METHODS: A retrospective cohort study included in-and outpatients with nontraumatic SCI due to tumour or metastasis admitted to a metropolitan hospital in Spain between 1991 and 2008. Main outcome measures were crude and age- and sex-adjusted incidence rates, tumour location and type, distribution by spinal level, neurological level of injury, and impairment ASIA scores. RESULTS: Primary tumour or metastasis accounted for 32.5% of nontraumatic SCI with an incidence rate of 4.1 per million population. Increasing rates with age and over time were observed. Major pathology groups were intradural-extramedullary masses from which meningiomas and neurinomas accounted for 40%. Lesions were mostly incomplete with predominant ASIA Grade D. CONCLUSIONS: Increasing incidence rates of tumour-related SCI over time in the middle-aged and the elderly suggest a growing need for neurooncology health resources in the future.

A protective personal factor against disability and dependence in the elderly: an ordinal regression analysis with nine geographically-defined samples from Spain.

BACKGROUND: Sense of Coherence (SOC) is defined as a tendency to perceive life experiences as comprehensible, manageable and meaningful. The construct is split in three major domains: Comprehensibility, Manageability, and Meaningfulness. SOC has been associated with successful coping strategies in the face of illness and traumatic events and is a predictor of self-reported and objective health in a variety of contexts. In the present study we aim to evaluate the association of SOC with disability and dependence in Spanish elders. METHODS: A total of 377 participants aged 75 years or over from nine locations across Spain participated in the study (Mean age: 80.9 years; 65.3% women). SOC levels were considered independent variables in two ordinal logistic models on disability and dependence, respectively. Disability was established with the World health Organization-Disability Assessment Schedule 2.0 (36-item version), while dependence was measured with the Extended Katz Index on personal and instrumental activities of daily living. The models included personal (sex, age, social contacts, availability of an intimate confidant), environmental (municipality size, access to social resources) and health-related covariates (morbidity). RESULTS: High Meaningfulness was a strong protective factor against both disability (Odds Ratio [OR] = 0.50; 95% Confidence Interval [CI] = 0.29-0.87) and dependence (OR = 0.33; 95% CI = 0.19-0.58) while moderate and high Comprehensibility was protective for disability (OR = 0.40; 95% CI = 0.22-0.70 and OR = 0.39; 95%CI = 0.21-0.74), but not for dependence. Easy access to social and health resources was also highly protective against both disability and dependence. CONCLUSIONS: Our results are consistent with the view that high levels of SOC are protective against disability and dependence in the elderly. Elderly individuals with limited access to social and health resources and with low SOC may be a group at risk for dependence and disability in Spain.

Urinary incontinence and mortality among older adults residing in care homes.

AIM: To assess the association between baseline urinary incontinence and long-term, all-cause mortality. BACKGROUND: Urinary incontinence is a common disorder among older institutionalised adults, with important consequences for morbidity and quality of life. Moreover, while it is a consistent mortality marker, the extent to which this association might be causal remains controversial. DESIGN: A cohort study. METHODS: We conducted a mortality follow-up study on a cohort of 675 nursing-home residents in the city of Madrid (Spain), from their 1998-1999 baseline interviews to September 2013. Study subjects or their caregivers were asked whether the resident had experienced any involuntary leakage of urine in the preceding 14 days, with subjects being subsequently defined as continent, mildly incontinent, or severely incontinent. Hazard ratios for all-cause mortality were estimated using Cox proportional hazards models. RESULTS: After a 4061 person-year follow-up (median/maximum of 4·6/15·2 years), 576 participants had died. In fully-adjusted models, urinary incontinence was associated with a 24 per cent increased risk of all-cause mortality. There was a graded relationship across severity levels, with hazard ratios 7% higher for mild and 44% higher for severe incontinence as compared with the continent group. The adjusted mortality fraction attributable to urinary incontinence was 11 per cent. CONCLUSION: It would appear that urinary incontinence is not only a marker but also a real determinant of survival in the institutionalized population. This finding, which seems plausible in a population of frail older adults, warrants further research into mechanisms that could help to elucidate this hypothesis.

Etiologic Framework for the Study of Neurodegenerative Disorders as Well as Vascular and Metabolic Comorbidities on the Grounds of Shared Epidemiologic and Biologic Features.

BACKGROUND: During the last two decades, protein aggregation at all organismal levels, from viruses to humans, has emerged from a neglected area of protein science to become a central issue in biology and biomedicine. This article constitutes a risk-based review aimed at supporting an etiologic scenario of selected, sporadic, protein-associated, i.e., conformational, neurodegenerative disorders (NDDs), and their vascular- and metabolic-associated ailments. METHODS: A rationale is adopted, to incorporate selected clinical data and results from animal-model research, complementing epidemiologic evidences reported in two prior articles. FINDINGS: Theory is formulated assuming an underlying conformational transmission mechanism, mediated either by horizontal transfer of mammalian genes coding for specific aggregation-prone proteins, or by xeno-templating between bacterial and host proteins. We build a few population-based and experimentally-testable hypotheses focusing on: (1) non-disposable surgical instruments for sporadic Creutzfeldt-Jakob disease (sCJD) and other rapid progressive neurodegenerative dementia (sRPNDd), multiple system atrophy (MSA), and motor neuron disease (MND); and (2) specific bacterial infections such as B. pertussis and E. coli for all forms, but particularly for late-life sporadic conformational, NDDs, type 2 diabetes mellitus (T2DM), and atherosclerosis where natural protein fibrils present in such organisms as a result of adaptation to the human host induce prion-like mechanisms. CONCLUSION: Implications for cohort alignment and experimental animal research are discussed and research lines proposed.

Prevalence of and factors associated with homebound status among adults in urban and rural Spanish populations.

BACKGROUND: There is a marked growth in the number of homebound older adults, due mainly to increased life expectancy. Although this group has special characteristics and needs, it has not been properly studied. This study thus aimed to measure the prevalence of homebound status in a community-dwelling population, and its association with both socio-demographic, medical and functional characteristics and the use of health care and social services. METHODS: We used instruments coming under the WHO International Classification of Functioning (ICF) framework to carry out a cross-sectional study on populations aged 50 years and over in the province of Zaragoza (Spain), covering a total of 1622 participants. Persons who reported severe or extreme difficulty in getting out of the house in the last 30 days were deemed to be homebound. We studied associations between homebound status and several relevant variables in a group of 790 subjects who tested positive to the WHODAS-12 disability screening tool. RESULTS: Prevalence of homebound status was 9.8 % (95 % CI: 8.4 to 11.3 %). Homebound participants tended to be older, female and display a lower educational level, a higher number of diseases, poorer cognition and a higher degree of disability. In fully adjusted models including disability as measured with the ICF-Checklist, the associated variables (odds ratios and [95 % confidence intervals]) were: female gender (3.75 [2.10-6.68]); urban population (2.36 [1.30-4.29]); WHODAS-12 disability (6.27 [2.56-15.40]); depressive symptoms (2.95 [1.86-4.68]); moderate pain (2.37 [1.30-4.31] and severe pain (3.03 [1.31-7.01]), as compared to the group with no/mild pain; hospital admissions in the previous 3 months (2.98 [1.25-7.11]); and diabetes (1.87 [1.03-3.41]). Adjustment for ICF-Checklist disability had a notable impact on most associations. CONCLUSIONS: The study shows that homebound status is a common problem in our setting, and that being disabled is its main determinant. Socio-demographic characteristics, barriers and chronic diseases can also be assumed to be playing a role in the onset of this condition, indicating the need for further research, including longitudinal studies on its incidence and associated factors.

Associations between chronic conditions, body functions, activity limitations and participation restrictions: a cross-sectional approach in Spanish non-clinical populations.

OBJECTIVES: To analyse the relationships between chronic conditions, body functions, activity limitations and participation restrictions in the International Classification of Functioning, Disability and Health (ICF) framework. DESIGN: A cross-sectional study. SETTING: 2 geographical areas in the Autonomous Region of Aragon, Spain, namely, a rural area, Cinco Villas, and an urban area in the city of Zaragoza. PARTICIPANTS: 864 individuals selected by simple random sampling from the register of Social Security card holders, aged 50 years and over, positive to disability screening. MAIN OUTCOME MEASURES: ICF Checklist-body function domains, WHO Disability Assessment Schedule 2.0 (WHODAS 2.0, 36-item (WHODAS-36)) global scores and medical diagnoses (chronic conditions) from primary care records. RESULTS: Mild disability (WHODAS-36 level 5-24%) was present in 51.5% of the sample. In the adjusted ordinal regression model with WHODAS-36 as the dependent variable, disability was substantially associated with moderate-to-complete impairment in the following functions: mental, OR 212.8 (95% CI 72 to 628.9); neuromusculoskeletal, OR 44.8 (24.2 to 82.8); and sensory and pain, OR 6.3 (3.5 to 11.2). In the relationship between health conditions and body function impairments, the strongest links were seen for: dementia with mental functions, OR 50.6 (25.1 to 102.1); cerebrovascular disease with neuromusculoskeletal function, OR 5.8 (3.5 to 9.7); and chronic renal failure with sensory function and pain, OR 3.0 (1.49 to 6.4). Dementia, OR 8.1 (4.4 to 14.7) and cerebrovascular disease, OR 4.1 (2.7 to 6.4) were associated with WHODAS-36 scores. CONCLUSIONS: Body functions are heterogeneously linked to limitations in activities and restrictions on participation, with the highest impact being due to mental and musculoskeletal functions. This may be relevant for disability assessment and intervention design, particularly if defined on a body function basis. Control of specific health conditions, such as dementia and cerebrovascular disease, appears to be paramount in reducing disability among persons aged 50 years and over.

Guillain-Barré syndrome following the 2009 pandemic monovalent and seasonal trivalent influenza vaccination campaigns in Spain from 2009 to 2011: outcomes from active surveillance by a neurologist network, and records from a country-wide hospital discharge database.

BACKGROUND: Studies have shown a slight excess risk in Guillain-Barré syndrome (GBS) incidence associated with A(H1N1)pdm09 vaccination campaign and seasonal trivalent influenza vaccine immunisations in 2009-2010. We aimed to assess the incidence of GBS as a potential adverse effect of A(H1N1)pdm09 vaccination. METHODS: A neurologist-led network, active at the neurology departments of ten general hospitals serving an adult population of 4.68 million, conducted GBS surveillance in Spain in 2009-2011. The network, established in 1996, carried out a retrospective and a prospective study to estimate monthly alarm thresholds in GBS incidence and tested them in 1998-1999 in a pilot study. Such incidence thresholds additionally to observation of GBS cases with immunisation antecedent in the 42 days prior to clinical onset were taken as alarm signals for 2009-2011, since November 2009 onwards. For purpose of surveillance, in 2009 we updated both the available centres and the populations served by the network. We also did a retrospective countrywide review of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis from January 2009 to December 2011. RESULTS: Among 141 confirmed of 148 notified cases of GBS or Miller-Fisher syndrome, Brighton 1-2 criteria in 96 %, not a single patient was identified with clinical onset during the 42-day time interval following A(H1N1)pdm09 vaccination. In contrast, seven cases were seen during a similar period after seasonal campaigns. Monthly incidence figures did not, however, exceed the upper 95 % CI limit of expected incidence. A retrospective countrywide review of the registry of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis did not suggest higher admission rates in critical months across the period December 2009-February 2010. CONCLUSIONS: Despite limited power and underlying reporting bias in 2010-2011, an increase in GBS incidence over background GBS, associated with A(H1N1)pdm09 monovalent or trivalent influenza immunisations, appears unlikely.

Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders.

BACKGROUND: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific "drivers", i.e., risk factors with impact on specific deposits, such as amyloid-ß, tau, or α-synuclein, acting across entities. OBJECTIVES AND METHODS: Redefining drivers as "neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms", we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns. RESULTS: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson's disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer's disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus. CONCLUSION: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-ß, tau, Langerhans islet peptide, and transthyretin) or established combinations of these.

Quantifying prion disease penetrance using large population control cohorts.

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Accuracy of screening instruments for detection of neuropsychiatric syndromes in Parkinson's disease.

Parkinson's disease includes neuropsychiatric manifestations, such as depression, anxiety, apathy, psychosis, and impulse control disorders, which often are unreported by patients and caregivers or undetected by doctors. Given their substantial impact on patients and caregivers as well as the existence of effective therapies for some of these disorders, screening for neuropsychiatric symptoms is important. Instruments for screening have a particular methodology for validation, and their performance is expressed in terms of accuracy compared with formal diagnostic criteria. The present study reviews the attributes of the screening instruments applied for detection of the aforementioned major neuropsychiatric symptoms in Parkinson's disease. A quasi-systematic review (including predefined selection criteria, but not evaluating the quality of the reviewed studies) was carried out on the basis of previous systematic reviews (commissioned by the American Academy of Neurology and the Movement Disorder Society) and made current by conducting a literature search (2005-2014). For depression, 11 scales and questionnaires were shown to be valid for Parkinson's disease screening. The recently developed Parkinson Anxiety Scale and the Geriatric Anxiety Inventory demonstrate satisfactory properties as screening instruments for anxiety, and the Lille Apathy Rating Scale for detection of apathy. No scale adequately screens for psychosis, so a specific psychosis instrument should be developed. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (Questionnaire and Rating Scale) are valid for comprehensive screening of impulse control disorders, and the Parkinson's Disease-Sexual Addiction Screening Test for hypersexuality specifically.