Frailty among Older Adults and Its Distribution in England.

BACKGROUND: Information on the spatial distribution of the frail population is crucial to inform service planning in health and social care. OBJECTIVES: To estimate small-area frailty prevalence among older adults using survey data. To assess whether prevalence differs between urban, rural, coastal and inland areas of England. DESIGN: Using data from the English Longitudinal Study of Ageing (ELSA), ordinal logistic regression was used to predict the probability of frailty, according to age, sex and area deprivation. Probabilities were applied to demographic and economic information in 2020 population projections to estimate the district-level prevalence of frailty. RESULTS: The prevalence of frailty in adults aged 50+ (2020) in England was estimated to be 8.1 [95% CI 7.3-8.8]%. We found substantial geographic variation, with the prevalence of frailty varying by a factor of 4.0 [3.5-4.4] between the most and least frail areas. A higher prevalence of frailty was found for urban than rural areas, and coastal than inland areas. There are widespread geographic inequalities in healthy ageing in England, with older people in urban and coastal areas disproportionately frail relative to those in rural and inland areas. CONCLUSIONS: Interventions aimed at reducing inequalities in healthy ageing should be targeted at urban and coastal areas, where the greatest benefit may be achieved.

Epidemiological pathology of Aß deposition in the ageing brain in CFAS: addition of multiple Aß-derived measures does not improve dementia assessment using logistic regression and machine learning approaches.

Aß-amyloid deposition is a key feature of Alzheimer's disease, but Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessment, based on neuritic plaque density, shows a limited relationships to dementia. Thal phase is based on a neuroanatomical hierarchy of Aß-deposition, and in combination with Braak neurofibrillary tangle staging also allows derivation of primary age-related tauopathy (PART). We sought to determine whether Thal Aß phase predicts dementia better than CERAD in a population-representative cohort (n = 186) derived from the Cognitive Function and Ageing Study (CFAS). Cerebral amyloid angiopathy (CAA) was quantitied as the number of neuroanatomical areas involved and cases meeting criteria for PART were defined to determine if they are a distinct pathological group within the ageing population. Agreement with the Thal scheme was excellent. In univariate analysis Thal phase performed less well as a predictor of dementia than CERAD, Braak or CAA. Logistic regression, decision tree and linear discriminant analysis were performed for multivariable analysis, with similar results. Thal phase did not provide a better explanation of dementia than CERAD, and there was no additional benefit to including more than one assessment of Aß in the model. Number of areas involved by CAA was highly correlated with assessment based on a severity score (p < 0.001). The presence of capillary involvement (CAA type I) was associated with higher Thal phase and Braak stage (p < 0.001). CAA was not associated with microinfarcts (p = 0.1). Cases satisfying pathological criteria for PART were present at a frequency of 10.2% but were not older and did not have a higher likelihood of dementia than a comparison group of individuals with similar Braak stage but with more Aß. They also did not have higher hippocampal-tau stage, although PART was weakly associated with increased presence of thorn-shaped astrocytes (p = 0.048), suggesting common age-related mechanisms. Thal phase is highly applicable in a population-representative setting and allows definition of pathological subgroups, such as PART. Thal phase, plaque density, and extent and type of CAA measure different aspects of Aß pathology, but addition of more than one Aß measure does not improve dementia prediction, probably because these variables are highly correlated. Machine learning predictions reveal the importance of combining neuropathological measurements for the assessment of dementia.

Impact of social care supply on healthcare utilisation by older adults: a systematic review and meta-analysis.

Objective: to investigate the impact of the availability and supply of social care on healthcare utilisation (HCU) by older adults in high income countries. Design: systematic review and meta-analysis. Data sources: medline, EMBASE, Scopus, Health Management Information Consortium, Cochrane Database of Systematic Reviews, NIHR Health Technology Assessment, NHS Economic Evaluation Database, Database of Abstracts of Reviews of Effectiveness, SCIE Online and ASSIA. Searches were carried out October 2016 (updated April 2017 and May 2018). (PROSPERO CRD42016050772). Study selection: observational studies from high income countries, published after 2000 examining the relationship between the availability of social care (support at home or in care homes with or without nursing) and healthcare utilisation by adults >60 years. Studies were quality assessed. Results: twelve studies were included from 11,757 citations; ten were eligible for meta-analysis. Most studies (7/12) were from the UK. All reported analysis of administrative data. Seven studies were rated good in quality, one fair and four poor. Higher social care expenditure and greater availability of nursing and residential care were associated with fewer hospital readmissions, fewer delayed discharges, reduced length of stay and expenditure on secondary healthcare services. The overall direction of evidence was consistent, but effect sizes could not be confidently quantified. Little evidence examined the influence of home-based social care, and no data was found on primary care use. Conclusions: adequate availability of social care has the potential to reduce demand on secondary health services. At a time of financial stringencies, this is an important message for policy-makers.

Cognitive reserve as a moderator of the negative association between mood and cognition: evidence from a population-representative cohort.

BACKGROUND: Cognitive reserve (CR) has been associated with better cognitive function and lower risk of depression in older people, yet it remains unclear whether CR moderates the association between mood and cognition. This study aimed to investigate whether a comprehensive indicator of CR, including education, occupation and engagement in cognitive and social activities, acts as a moderator of this association. METHODS: This was a cross-sectional study utilising baseline data from the Cognitive Function and Ageing Study II (CFAS II), a large population-based cohort of people aged 65+ in England. Complete data on the measures of CR, mood and cognition were available for 6565 dementia-free individuals. Linear regression models were used to investigate the potential modifying effect of CR on the association between cognition and mood with adjustment for age, sex and missing data. RESULTS: Levels of CR did moderate the negative association between mood and cognition; the difference in cognition between those with and without a clinical level mood disorder was significantly smaller in the middle (-2.28; 95% confidence interval (CI) -3.65 to -0.90) and higher (-1.30; 95% CI -2.46 to -0.15) CR groups compared with the lower CR group (-4.01; 95% CI -5.53 to -2.49). The individual components of CR did not significantly moderate the negative association between mood and cognition. CONCLUSION: These results demonstrate that CR, indexed by a composite score based on multiple indicators, can moderate the negative association between lowered mood and cognition, emphasising the importance of continuing to build CR across the lifespan in order to maintain cognitive health.

A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II.

Dramatic global increases in future numbers of people with dementia have been predicted. No multicentre population-based study powered to detect changes over time has reported dementia incidence. MRC Cognitive Function and Ageing Study (CFAS) undertook baseline interviews in populations aged 65+ years in England and Wales (1989-1994). Three areas (CFAS I) were selected for new sampling two decades later (2008-2011) with same geographical boundaries, sampling and approach methods (CFAS II). At 2 years CFAS I interviewed 5,156 (76% response) with 5,288 interviewed in CFAS II (74% response). Here we report a 20% drop in incidence (95% CI: 0-40%), driven by a reduction in men across all ages above 65. In the UK we estimate 209,600 new dementia cases per year. This study was uniquely designed to test for differences across geography and time. A reduction of age-specific incidence means that the numbers of people estimated to develop dementia in any year has remained relatively stable.

Brain haemosiderin in older people: pathological evidence for an ischaemic origin of magnetic resonance imaging (MRI) microbleeds.

INTRODUCTION: Magnetic resonance imaging (MRI) cerebral microbleeds (CMB) arise from ferromagnetic haemosiderin iron assumed to derive from extravasation of erythrocytes. Light microscopy of ageing brain frequently reveals foci of haemosiderin from single crystalloids to larger, predominantly perivascular, aggregates. The pathological and radiological relationship between these findings is not resolved. METHODS: Haemosiderin deposition and vascular pathology in the putamen were quantified in 200 brains donated to the population-representative Medical Research Council Cognitive Function and Ageing Study. Molecular markers of gliosis and tissue integrity were assessed by immunohistochemistry in brains with highest (n = 20) and lowest (n = 20) levels of putamen haemosiderin. The association between haemosiderin counts and degenerative and vascular brain pathology, clinical data, and the haemochromatosis (HFE) gene H63D genotype were analysed. The frequency of MRI CMB in 10 cases with highest and lowest burden of putamen haemosiderin, was compared using post mortem 3T MRI. RESULTS: Greater putamen haemosiderin was significantly associated with putaminal indices of small vessel ischaemia (microinfarcts, P < 0.05; arteriolosclerosis, P < 0.05; perivascular attenuation, P < 0.001) and with lacunes in any brain region (P < 0.023) but not large vessel disease, or whole brain measures of neurodegenerative pathology. Higher levels of putamen haemosiderin correlated with more CMB (P < 0.003). CONCLUSIONS: The MRI-CMB concept should take account of brain iron homeostasis, and small vessel ischaemic change in later life, rather than only as a marker for minor episodes of cerebrovascular extravasation. These data are of clinical relevance, suggesting that basal ganglia MRI microbleeds may be a surrogate for ischaemic small vessel disease rather than exclusively a haemorrhagic diathesis.

Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain.

AIMS: Calcium dyshomeostasis is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease. However, much of the previous research has focused on changes in neuronal calcium signalling. In a recent microarray study we identified dysregulation of several key signalling pathways including the Ca(2+) signalling pathway in astrocytes as Alzheimer-type pathology developed. In this study we sought to determine the expression of calpain-10 and calcium/calmodulin-dependent kinase alpha (CamKIIα) in relation to Alzheimer-type pathology in a population-based study. METHODS: Using post mortem temporal cortex samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) ageing brain cohort we examined calpain-10 and CamKIIα gene and protein expression using quantitative polymerase chain reaction and immunohistochemistry. RESULTS: We demonstrate that astrocytic expression of calpain-10 is up-regulated, and CamKIIα down-regulated with increasing Braak stage. Using immunohistochemistry we confirm protein expression of calpain-10 in astrocytes throughout the temporal cortex and demonstrate that calpain-10 immunoreactivity is correlated with both local and global measures of Alzheimer-type pathology. In addition, we identify a subpopulation of calpain-10 immunoreactive interlaminar astrocytes that extend processes deep into the cortex. CamKIIα is predominantly neuronal in localization and is associated with the presence of diffuse plaques in the ageing brain. DISCUSSION: Dysregulated expression of key calcium signalling molecules occurs with progression of Alzheimer-type pathology in the ageing brain, highlighting the need for further functional studies of astrocytic calcium signalling with respect to disease progression.

The association between social stress and global cognitive function in a population-based study: the European Prospective Investigation into Cancer (EPIC)-Norfolk study.

BACKGROUND: Stress is thought to exert both positive and negative effects on cognition, but the precise cognitive effects of social stress and individuals' response to stress remain unclear. We aimed to investigate the association between different measures of social stress and cognitive function in a middle- to older-aged population using data from the European Prospective Investigation into Cancer (EPIC)-Norfolk study. METHOD: Participants completed a comprehensive assessment of lifetime social adversity between 1993 and 1997 and the short form of the Mini Mental State Examination (SF-MMSE), an assessment of global cognitive function, during the third health check between 2004 and 2011 (a median of 10.5 years later). A low MMSE score was defined as a score in the bottom quartile (20-26). RESULTS: Completed MMSE scores and stress measures were available for 5129 participants aged 48-90 years. Participants who reported that their lives had been more stressful over the previous 10 years were significantly more likely to have low MMSE scores [odds ratio (OR) 1.14, 95% confidence interval (CI) 1.04-1.24 per unit increase in perceived stress], independently of sociodemographic factors, physical and emotional health. The effects were restricted to the highest level of stress and the association was stronger among participants with a lower educational level. Adaptation following life event experiences also seemed to be associated with MMSE scores after adjusting for sociodemographic factors, but the association was attenuated with further adjustment. CONCLUSIONS: In this generally high-functioning population, individuals' interpretations and responses to stressful events, rather than the events themselves, were associated with cognitive function.

Mesial temporal astrocyte tau pathology in the MRC-CFAS ageing brain cohort.

BACKGROUND: Glial tau pathology is seen in certain tauopathies and in ageing. We determined its frequency in ageing mesial temporal lobe and its relationship to other tau pathologies in the MRC-CFAS population-representative neuropathology cohort. METHODS: Mesial temporal lobe, including hippocampus, amygdala, entorhinal cortex and white matter, was examined using immunohistochemistry with the AT8 antibody to phospho-tau and RD3 and RD4 antibodies to 3R and 4R tau isoforms. Gallyas silver stain was used to detect fibrillar aggregates. RESULTS: Thorn-shaped astrocytes (TSA), positive with AT8, RD4 and Gallyas, were present in 49% of cases. They were particularly prevalent in subpial, periventricular and white matter perivascular locations and were less frequent in grey matter. Coiled bodies were seen in 18.8%. TSA were not related to Braak neurofibrillary tangle or hippocampal tangle pathology stages. TSA in grey matter were associated with coiled bodies (p = 0.011) and argyrophilic grains (p = 0.048), which were identified in 11.5% of cases. They did not correlate with dementia. CONCLUSIONS: Astrocyte tau pathology is common in the ageing mesial temporal lobe. Its formation is independent of Alzheimer-type pathology. It is a 4R tauopathy, which may form part of a mesial temporal age-related 4R tauopathy that includes oligodendroglial tau and argyrophilic grains.

The neuropathological profile of mild cognitive impairment (MCI): a systematic review.

Whether mild cognitive impairment (MCI) has a distinct neuropathological profile that reflects an intermediate state between no cognitive impairment and dementia is not clear. Identifying which biological events occur at the earliest stage of progressive disease and which are secondary to the neuropathological process is important for understating pathological pathways and for targeted disease prevention. Many studies have now reported on the neurobiology of this intermediate stage. In this systematic review, we synthesize current evidence on the neuropathological profile of MCI. A total of 162 studies were identified with varied definition of MCI, settings ranging from population to specialist clinics and a wide range of objectives. From these studies, it is clear that MCI is neuropathologically complex and cannot be understood within a single framework. Pathological changes identified include plaque and tangle formation, vascular pathologies, neurochemical deficits, cellular injury, inflammation, oxidative stress, mitochondrial changes, changes in genomic activity, synaptic dysfunction, disturbed protein metabolism and disrupted metabolic homeostasis. Determining which factors primarily drive neurodegeneration and dementia and which are secondary features of disease progression still requires further research. Standardization of the definition of MCI and reporting of pathology would greatly assist in building an integrated picture of the clinical and neuropathological profile of MCI.

Association between APOE genotype, neuropathology and dementia in the older population of England and Wales.

AIMS: Apolipoprotein E (APOE) genotype is the major genetic risk factor for sporadic Alzheimer's disease (AD) but it is unclear how this is mediated. Most studies of APOE genotype have used case-control design to compare groups differing by two variables: i.e. dementia and AD pathology, so it is unclear to which of these variables APOE genotype is more strongly related. The prospective Medical Research Council Cognitive Function and Ageing Study neuropathology cohort is population-based sample in which donations are unbiased by dementia status. METHODS: We investigated the association between APOE genotypes and neuropathological and cognitive data in this cohort (n = 310). RESULTS: APOEε4 was associated with an increased risk of diffuse plaques, neuritic plaques, tangles and cerebral amyloid angiopathy. APOEε4 was not associated with infarcts, lacunes, haemorrhages or small vessel disease. APOEε2 appeared to have a protective effect on AD pathology and also on the risk of cortical atrophy. APOE genotype had a non-significant effect on the presence of dementia after adjusting for AD pathology. CONCLUSIONS: APOE genotype is associated with each of the key features of AD pathology but not with cerebrovascular disease other than cerebral amyloid angiopathy. The excess risk of dementia in those with an APOEε4 allele is explained by the pathological features of AD. However, it remains unclear to what extent cognitive dysfunction is caused by these specific pathological features or more directly by closely related APOE-associated mechanisms.

APOE and ACE polymorphisms and dementia risk in the older population over prolonged follow-up: 10 years of incidence in the MRC CFA Study.

BACKGROUND: dementia risk conferred by apolipoprotein-E (APOE) and angiotensin-1-converting enzyme (ACE) polymorphisms have been reported for the MRC Cognitive Function and Ageing Study (CFAS) at 6-year follow-up. We concentrate on incident dementia risk over 10 years. METHODS: participants come from MRC CFAS, a multi-centre longitudinal population-based study of ageing in England and Wales. Three follow-up waves of data collection were used: 2, 6 and 10 years. Logistic regressions were undertaken to investigate associations between APOE (n = 955) and ACE (n = 856) alleles/genotypes and incident dementia. Two types of control groups were used: non-demented and highly functioning non-demented. Results were back-weighted. RESULTS: compared to APOE epsilon3, epsilon2 conferred protection of odds ratio (OR) = 0.3 (95% confidence interval, CI = 0.1-0.6) and epsilon4 risk of OR = 2.9 (95% CI = 1.7-4.9) for incident dementia. Compared to epsilon3/epsilon3, the epsilon3/epsilon4 and epsilon4/epsilon4 genotypes conferred risks of OR = 3.6 (95% CI = 1.8-7.3) and OR = 7.9 (95% CI = 1.6-39.2), respectively. The epsilon3/epsilon2 genotype protected against dementia (OR = 0.2, 95% CI = 0.1-0.7), and epsilon2/epsilon2 had a similar protective effect but with wide CIs (OR = 0.3, 95% CI = 0.1-1.7). Restricting the control group accentuated these differentials. The effects of ACE alleles/genotypes on incident dementia risk were small. CONCLUSIONS: APOE but not ACE is associated with late-onset incident dementia in the population. Using longer term follow-up with proper adjustment for attrition and incident cases increases estimates of risk.

Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain.

AIMS: Increasing evidence suggests a role for oxidative damage to DNA in brain ageing and in neurodegenerative disorders, including Alzheimer's disease. Most studies have focussed on the reduced capacity for DNA repair by neurones, and have not taken into account the effect of oxidative stress on astrocytes, and their contribution to pathology. METHODS: We examined levels of oxidative stress, DNA damage and DNA repair mechanisms in astrocytes in a population-based sample derived from the Medical Research Council Cognitive Function and Ageing Neuropathology Study. RESULTS: We demonstrate wide variation in parameters for oxidative stress and DNA damage in astrocytes in the ageing population. We show that there is a significant reduction (P = 0.002) in the lipid peroxidation marker malondialdehyde with increasing Braak stage in Alzheimer's disease. Furthermore, we demonstrate that expression of the DNA damage-associated molecules H2AX and DNA-dependent protein kinase do not increase with increasing Braak stage, rather there is evidence of a nonsignificant reduction in DNA-dependent protein kinase expression by neurones and astrocytes, and in H2AX by neurones with increasing levels of Alzheimer's type pathology. CONCLUSIONS: These findings suggest that the changes in oxidative stress and the astrocyte DNA damage response are not accounted for as an accumulating effect due to established Alzheimer-type pathology. We hypothesize that astrocyte damage, leading to impaired function, may contribute to the development of ageing brain pathology in some individuals.

Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain.

Astrocyte pathology occurs in association with Alzheimer's disease (AD) and in brain ageing, but is poorly characterised. We sought to define the detailed cellular pathology of astrocytes, the extent of population variation and the relationship to Alzheimer-type changes in a population-based cohort. Three staining patterns were associated with GFAP and excitatory amino acid transporter 2 (EAAT2): minimal, moderate or extensive immunoreactivity. GFAP and EAAT2 expression were inversely related (p=0.015), with trends to increased expression of GFAP (p=0.019) and decreased expression of EAAT2 (p=ns) with increasing Braak stage. GFAP and EAAT2 correlated incompletely with beta-amyloid and tau immunoreactivity. However, gliosis increased with increasing burden of neuritic (p=0.011), but not diffuse (p=ns), plaques. Double-staining revealed distinct subsets of astrocytes; GFAP(+)EAAT(-), GFAP(-)EAAT(+), or GFAP(+)EAAT(+). In contrast to the variation in GFAP and EAAT2, levels of EAAT1 and S100B showed consistent staining patterns. Alzheimer-type pathology only partially explains the variation in gliosis and astrocyte functional markers, suggesting that other factors contribute to the population variance in astrocyte pathology.

Biomarkers, dementia, and public health.

Public health is defined as the organized efforts of society to improve health. This is often framed in terms of prevention, with primary, secondary, and tertiary prevention representing, respectively, fundamental prevention through understanding of causation, to alteration of natural history, through understanding of pathophysiological mechanisms and palliation. Biomarkers play a role in all of these levels of prevention of dementias. The clearest application of biomarkers from a public health perspective is in the setting of screening. Screening has particular meaning for public health and includes early detection as a core element, coupled with treatments or preventative actions to reduce the burden of disease. Here, we will cover the range of evidence required if biomarkers are to play a part in population prevention of dementia, including scientific and technical aspects together with ethical, legal, and social considerations. Ensuring research activity that addresses these wider perspectives is essential.

Population variation in glial fibrillary acidic protein levels in brain ageing: relationship to Alzheimer-type pathology and dementia.

BACKGROUND: The cellular pathology of astrocytes in brain ageing and their role in modulating the brain's response to neurodegenerative pathology remain incompletely understood. METHODS: Using quantitative ELISA, we have investigated glial fibrillary acidic protein (GFAP) expression in the population-based neuropathology cohort of the Medical Research Council Cognitive Function and Ageing Study to determine: (1) the population variation in the astroglial hypertrophic response, (2) its relationship to the presence of Alzheimer-type pathology, and (3) its association with cognition. RESULTS: Increasing GFAP was found with increasing Braak stage, levels increasing even at early stages. Within Braak stages, GFAP did not differ between demented and non-demented individuals, but there was greater variance in GFAP in the demented. Possession of ApoE epsilon4 was associated with slightly increased GFAP levels (not significant) for given amyloid beta protein loads. CONCLUSION: In a population-based sample, increasing gliosis precedes development of Alzheimer lesions. Population variation in GFAP with varying Alzheimer lesion burdens suggests that they are not the only driver for astrogliosis. GFAP was not independently predictive of dementia, but the variation in astrocytic responses may be a factor modulating brain responses to neurodegenerative pathology.

Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study.

Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the 'tauopathies', which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Abeta pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Abeta, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Abeta was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.

Dementia and survival in Parkinson disease: a 12-year population study.

BACKGROUND: The risk for dementia in Parkinson disease (PD) is high, with important clinical consequences for patients with PD. However, the absolute risk of dementia and how it affects survival in PD are not known. Such questions are important for patients, their families, and service providers but require long-term studies. METHODS: This study is a prospective longitudinal cohort study with patients from a prevalence study of PD in Norway. Patients were reassessed 4, 8, 9, 10, 11, and 12 years after prevalence day. A dementia diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, criteria was based on a semistructured caregiver interview, cognitive rating scales, and neuropsychological tests. Progression from PD to PD with dementia and death was modeled using a continuous-time three-state irreversible Markov model. RESULTS: A total of 233 PD patients were included, and 140 patients (60%, 95% CI 54% to 66%) had developed dementia by the end of the study period. The cumulative incidence of dementia steadily increases with age and duration of PD and, conditional on survival, increases to 80% to 90% by age 90 years. Women live with PD longer than men and spend more years with dementia. At age 70 years, a man with PD but no dementia has a life expectancy of 8 years, of which 5 years would be expected to be dementia free and 3 years would be expected to be with dementia. CONCLUSION: Dementia is a key part of survival in Parkinson disease and must be planned for in services for this condition.

Patterns and stages of alpha-synucleinopathy: Relevance in a population-based cohort.

BACKGROUND: It is proposed that alpha-synucleinopathy (AS) initially affects the medulla oblongata and progresses to more rostral brain areas in a hierarchical sequence ("Braak hypothesis"). Predominant involvement of the amygdala is also described. This study examines the applicability of these patterns, and their relationship to Alzheimer disease (AD) pathology, in brains of a population-based donor cohort. METHODS: Brains donated in two of six Cognitive Function and Ageing Study cohorts (Cambridgeshire and Nottingham) were examined. More than 80% were older than 80 years at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein was carried out in 208 brains to establish Braak stage and the pattern and severity of AS. RESULTS: Seventy-six brains showed Lewy bodies. Half (51%) conformed to the Braak hypothesis while 17% had pathology in a higher region which was absent in a lower region. A further 29% showed amygdala-predominant pathology. Six brains showed predominant neocortical pathology with minimal pathology in amygdala or substantia nigra. The stage of AD pathology was not associated with particular patterns of AS. CONCLUSION: alpha-Synucleinopathy (AS) is common in older people, and frequently associated with Alzheimer disease-type pathology. Although half of brains corresponded to the Braak hypothesis, and 29% to amygdala-predominant AS, there were a high proportion of cases which did not fit a staging system. An unexpectedly high proportion with a cortical form of Lewy body disease was identified.

A 12-channel, real-time near-infrared spectroscopy instrument for brain-computer interface applications.

A continuous wave near-infrared spectroscopy (NIRS) instrument for brain-computer interface (BCI) applications is presented. In the literature, experiments have been carried out on subjects with such motor degenerative diseases as amyotrophic lateral sclerosis, which have demonstrated the suitability of NIRS to access intentional functional activity, which could be used in a BCI as a communication aid. Specifically, a real-time, multiple channel NIRS tool is needed to realise access to even a few different mental states, for reasonable baud rates. The 12-channel instrument described here has a spatial resolution of 30 mm, employing a flexible software demodulation scheme. Temporal resolution of approximately 100 ms is maintained since typical topographic imaging is not needed, since we are only interested in exploiting the vascular response for BCI control. A simple experiment demonstrates the ability of the system to report on haemodynamics during single trial mental arithmetic tasks. Multiple trial averaging is not required.