Predictors and prognosis of population-based subjective cognitive decline: longitudinal evidence from the Caerphilly Prospective Study (CaPS).

OBJECTIVES: To understand associations between the subjective experience of cognitive decline and objective cognition. This subjective experience is often conceptualised as an early step towards neurodegeneration, but this has not been scrutinised at the population level. An alternative explanation is poor meta-cognition, the extreme of which is seen in functional cognitive disorder (FCD). DESIGN: Prospective cohort (Caerphilly Prospective Study). SETTING: Population-based, South Wales, UK. PARTICIPANTS: This men-only study began in 1979; 1225 men participated at an average age of 73 in 2002-2004, including assessments of simple subjective cognitive decline (sSCD, defined as a subjective report of worsening memory or concentration). Dementia outcomes were followed up to 2012-2014. Data on non-completers was additionally obtained from death certificates and local health records. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was incident dementia over 10 years. Secondary outcome measures included prospective change in objective cognition and cross-sectional cognitive internal inconsistency (the existence of a cognitive ability at some times, and its absence at other times, with no intervening explanatory factors except for focus of attention). RESULTS: sSCD was common (30%) and only weakly associated with prior objective cognitive decline (sensitivity 36% (95% CI 30 to 42) and specificity 72% (95% CI 68 to 75)). Independent predictors of sSCD were older age, poor sleep quality and higher trait anxiety. Those with sSCD did not have excess cognitive internal inconsistency, but results suggested a mild attentional deficit. sSCD did not predict objective cognitive change (linear regression coefficient -0.01 (95% CI -0.13 to 0.15)) nor dementia (odds ratio 1.35 (0.61 to 2.99)) 10 years later. CONCLUSIONS: sSCD is weakly associated with prior objective cognitive decline and does not predict future cognition. Prior sleep difficulties and anxiety were the most robust predictors of sSCD. sSCD in the absence of objective decline appears to be a highly prevalent example of poor meta-cognition (ie, poor self-awareness of cognitive performance), which could be a driver for later FCD.

A Diagnostic Test Accuracy Study Investigating General Practitioner Clinical Impression and Brief Cognitive Assessments for Dementia in Primary Care, Compared to Specialized Assessment.

BACKGROUND: Many health systems are interested in increasing the number of uncomplicated and typical dementia diagnoses that are made in primary care, but the comparative accuracy of tests is unknown. OBJECTIVE: Calculate diagnostic accuracy of brief cognitive tests in primary care. METHODS: We did a diagnostic test accuracy study in general practice, in people over 70 years who had consulted their GP with cognitive symptoms but had no prior diagnosis of dementia. The reference standard was specialist assessment, adjudicated for difficult cases, according to ICD-10. We assessed 16 index tests at a research clinic, and additionally analyzed referring GPs clinical judgement. RESULTS: 240 participants had a median age of 80 years, of whom 126 were men and 132 had dementia. Sensitivity of individual tests at the recommended thresholds ranged from 56% for GP judgement (specificity 89%) to 100% for MoCA (specificity 16%). Specificity of individual tests ranged from 4% for Sniffin' sticks (sensitivity 100%) to 91% for Timed Up and Go (sensitivity 23%). The 95% centile of test duration in people with dementia ranged from 3 minutes for 6CIT and Time and Change, to 16 minutes for MoCA. Combining tests with GP judgement increased test specificity and decreased sensitivity: e.g., MoCA with GP Judgement had specificity 87% and sensitivity 55%. CONCLUSIONS: Using GP judgement to inform selection of tests was an efficient strategy. Using IQCODE in people who GPs judge as having dementia and 6CIT in people who GPs judge as having no dementia, would be a time-efficient and accurate diagnostic assessment.The original protocol for the study is available at https://bmcfampract.biomedcentral.com/articles/10.1186/s12875-016-0475-2.

Decline in Cognition from Mid-Life Improves Specificity of Mini-Mental State Examination: Diagnostic Test Accuracy in Caerphilly Prospective Study (CaPs).

BACKGROUND: The merit of using baseline cognitive assessments in mid-life to help interpret cross-sectional cognitive tests scores in later life is uncertain. OBJECTIVE: Evaluate how accuracy for diagnosing dementia is enhanced by comparing cross-sectional results to a midlife measure. METHODS: Cohort study of 2,512 men with repeated measures of Mini-Mental State Examination (MMSE) over approximately 10 years. Index test MMSE at threshold of 24 indicating normal, as a cross-sectional measure and in combination with decline in MMSE score from mid-life. Reference standard consensus clinical diagnosis of dementia by two clinicians according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). RESULTS: 1,150 men participated at phase 4 of whom 75 had dementia. A cross-sectional MMSE alone produced a sensitivity of 60% (50% to 70%) and specificity 95% (94% to 97%) with a threshold of≥24 points indicating normal. For lower-scoring men in late life, with cross sectional scores of < 22, combining cross-sectional AND a three-point or more decline over time had a sensitivity of 52% (39% to 64%) and specificity 99% (99% to 100%). For higher-scoring men in later life, with cross sectional scores < 26 combining cross-sectional OR decline of at least three points had a sensitivity of 98% (92% to 100%) and specificity 38% (32% to 44%). CONCLUSION: It may be helpful in practice to formally evaluate cognition in mid-life as a baseline to compare with if problems develop in future, as this may enhance diagnostic accuracy and classification of people in later life.

Clinical judgment of GPs for the diagnosis of dementia: a diagnostic test accuracy study.

BACKGROUND: GPs often report using clinical judgment to diagnose dementia. AIM: To investigate the accuracy of GPs' clinical judgment for the diagnosis of dementia. DESIGN & SETTING: Diagnostic test accuracy study, recruiting from 21 practices around Bristol, UK. METHOD: The clinical judgment of the treating GP (index test) was based on the information immediately available at their initial consultation with a person aged ≥70 years who had cognitive symptoms. The reference standard was an assessment by a specialist clinician, based on a standardised clinical examination and made according to the 10th revision of the International Classification of Diseases (ICD-10) criteria for dementia. RESULTS: A total of 240 people were recruited, with a median age of 80 years (interquartile range [IQR] 75-84 years), of whom 126 (53%) were men and 132 (55%) had dementia. The median duration of symptoms was 24 months (IQR 12-36 months) and the median Addenbrooke's Cognitive Examination III (ACE-III) score was 75 (IQR 65-87). GP clinical judgment had sensitivity 56% (95% confidence interval [CI] = 47% to 65%) and specificity 89% (95% CI = 81% to 94%). Positive likelihood ratio was higher in people aged 70-79 years (6.5, 95% CI = 2.9 to 15) compared with people aged ≥80 years (3.6, 95% CI = 1.7 to 7.6), and in women (10.4, 95% CI = 3.4 to 31.7) compared with men (3.2, 95% CI = 1.7 to 6.2), whereas the negative likelihood ratio was similar in all groups. CONCLUSION: A GP clinical judgment of dementia is specific, but confirmatory testing is needed to exclude dementia in symptomatic people whom GPs judge as not having dementia.

Skull base aspergillosis in an immunocompetent elderly man with early response to steroid.

We report the case of a previously well 80-year-old man who presented with subacute bilateral painful optic neuropathy with initial response to corticosteroids but ultimately progressed to a fatal skull base syndrome. Initial presentation of steroid-responsive painful bilateral posterior optic neuropathy, preliminary normal enhanced MRI, normal cerebrospinal fluid and inflammatory markers indicated atypical optic neuritis. However, this progressed to a bilateral orbital apex syndrome with ophthalmoplegia and evidence of abnormal skull base enhancement on subsequent MRI. Biopsy of radiologically abnormal dura was non-diagnostic and negative for fungal stains. He deteriorated and died 8 months after initial presentation. At postmortem, fungal skull base infection was diagnosed. This case demonstrates that chronic skull base fungal infection can: (1) present in elderly immunocompetent patients, (2) show initial improvement with corticosteroids and (3) evade diagnosis on biopsy. We encourage a high index of suspicion for fungal skull base infection in similar cases.

Towards improving diagnosis of memory loss in general practice: TIMeLi diagnostic test accuracy study protocol.

BACKGROUND: People with cognitive problems, and their families, report distress and uncertainty whilst undergoing evaluation for dementia and perceive that traditional diagnostic evaluation in secondary care is insufficiently patient centred. The James Lind Alliance has prioritised research to investigate the role of primary care in supporting a more effective diagnostic pathway, and the topic is also of interest to health commissioners. However, there are very few studies that investigate the accuracy of diagnostic tests for dementia in primary care. METHODS: We will conduct a prospective diagnostic test accuracy study to evaluate the accuracy of a range of simple tests for diagnosing all-cause-dementia in symptomatic people aged over 70 years who have consulted with their general practitioner (GP). We will invite eligible people to attend a research clinic where they will undergo a range of index tests that a GP could perform in the surgery and also be assessed by a specialist in memory disorders at the same appointment. Participating GPs will request neuroimaging and blood tests and otherwise manage patients in line with their usual clinical practice. The reference standard will be the consensus judgement of three experts (neurologist, psychiatrist and geriatrician) based on information from the specialist assessment, GP records and investigations, but not including items in the index test battery. The target condition will be all-cause dementia but we will also investigate diagnostic accuracy for sub-types where possible. We will use qualitative interviews with patients and focus groups with clinicians to help us understand the acceptability and feasibility of diagnosing dementia in primary care using the tests that we are investigating. DISCUSSION: Our results will help clinicians decide on which tests to perform in someone where there is concern about possible dementia and inform commissioning of diagnostic pathways.

Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the combined blood expression of neuromuscular and inflammatory biomarkers as predictors of disease progression and prognosis in amyotrophic lateral sclerosis (ALS). METHODS: Logistic regression adjusted for markers of the systemic inflammatory state and principal component analysis were carried out on plasma levels of creatine kinase (CK), ferritin, and 11 cytokines measured in 95 patients with ALS and 88 healthy controls. Levels of circulating biomarkers were used to study survival by Cox regression analysis and correlated with disease progression and neurofilament light chain (NfL) levels available from a previous study. Cytokines expression was also tested in blood samples longitudinally collected for up to 4 years from 59 patients with ALS. RESULTS: Significantly higher levels of CK, ferritin, tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß, IL-2, IL-8, IL-12p70, IL-4, IL-5, IL-10, and IL-13 and lower levels of interferon (IFN)-γ were found in plasma samples from patients with ALS compared to controls. IL-6, TNF-α, and IFN-γ were the most highly regulated markers when all explanatory variables were jointly analyzed. High ferritin and IL-2 levels were predictors of poor survival. IL-5 levels were positively correlated with CK, as was TNF-α with NfL. IL-6 was strongly associated with CRP levels and was the only marker showing increasing expression towards end-stage disease in the longitudinal analysis. CONCLUSIONS: Neuromuscular pathology in ALS involves the systemic regulation of inflammatory markers mostly active on T-cell immune responses. Disease stratification based on the prognostic value of circulating inflammatory markers could improve clinical trials design in ALS.

Clinical history for diagnosis of dementia in men: Caerphilly Prospective Study.

BACKGROUND: Diagnosis of dementia often requires specialist referral and detailed, time-consuming assessments. AIM: To investigate the utility of simple clinical items that non-specialist clinicians could use, in addition to routine practice, to diagnose all-cause dementia syndrome. DESIGN AND SETTING: Cross-sectional diagnostic test accuracy study. Participants were identified from the electoral roll and general practice lists in Caerphilly and adjoining villages in South Wales, UK. METHOD: Participants (1225 men aged 45-59 years) were screened for cognitive impairment using the Cambridge Cognitive Examination, CAMCOG, at phase 5 of the Caerphilly Prospective Study (CaPS). Index tests were a standardised clinical evaluation, neurological examination, and individual items on the Informant Questionnaire for Cognitive Disorders in the Elderly (IQCODE). RESULTS: Two-hundred and five men who screened positive (68%) and 45 (4.8%) who screened negative were seen, with 59 diagnosed with dementia. The model comprising problems with personal finance and planning had an area under the curve (AUC) of 0.92 (95% confidence interval [CI] = 0.86 to 0.97), positive likelihood ratio (LR+) of 23.7 (95% CI = 5.88 to 95.6), negative likelihood ratio (LR-) of 0.41 (95% CI = 0.27 to 0.62). The best single item for ruling out was no problems learning to use new gadgets (LR- of 0.22, 95% CI = 0.11 to 0.43). CONCLUSION: This study found that three simple questions have high utility for diagnosing dementia in men who are cognitively screened. If confirmed, this could lead to less burdensome assessment where clinical assessment suggests possible dementia.

Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis.

OBJECTIVE: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). CONCLUSION: Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. CLASSIFICATION OF EVIDENCE: This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls.

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

OBJECTIVE: To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. RESULTS: Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. CONCLUSIONS: Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression. TRAIL REGISTRATION NUMBER: NIHRID6160.

The role of IGF-I, IGF-II, and IGFBP-3 in male cognitive aging and dementia risk: the Caerphilly Prospective Study.

BACKGROUND: The increasing incidence of cognitive impairment and dementia in an aging population poses a significant burden on healthcare. Consequently, identifying modifiable physiological factors which may influence the onset of cognitive decline are becoming increasingly important. Previous studies have suggested an association between levels of insulin-like growth factors and cognitive function. OBJECTIVE: To investigate whether low IGF-I, IGF-II, and IGF molar ratio is associated with greater cognitive decline and increased risk of dementia. METHODS: We examined prospective associations between IGF-I, IGF-II, and IGFBP-3 and cognitive function in the Caerphilly Prospective Study (CaPS) (n = 746 men) from samples obtained around 1986, with assessment in around 2003 for clinical diagnosis of cognitive impairment but no dementia (CIND) or dementia, as well as with CAMCOG scores at three phases. RESULTS: A one standard deviation increase in IGF-II was associated with a reduced odds ratio for CIND (0.76, 95% CI 0.60, 0.96) which hardly altered after further adjustment for confounders. A one standard deviation increase in IGFBP-3 among participants without dementia or CIND was associated with greater decline in cognition (p = 0.002) equivalent to 2.4 years difference in age. All the associations between IGF-I and our outcomes were consistent with chance. CONCLUSION: In this study of men, we found that both IGF-II and IGFBP-3 are associated with normal age-related cognitive decline and clinical pathology associated with CIND, but we failed to replicate previous associations with IGF-I. Assuming these findings are replicated, they may provide new insights into potential biological mechanisms that underlie age-related cognitive changes and development of dementia.

Auditory threshold, phonologic demand, and incident dementia.

OBJECTIVE: This study was undertaken to investigate the association of auditory threshold with cognitive decline and dementia. METHODS: The 1,057 surviving men of the Caerphilly cohort with audiometric data at baseline were followed for 17 years for cognitive outcomes. Pure-tone unaided audiometric threshold was assessed at 0.5, 1, 2, and 4 KHz at baseline and after 9 years. Incident dementia was assessed according to DSM-IV criteria, including standard criteria for vascular dementia and for Alzheimer disease. Cognitive decline was assessed by repeat administration of a cognitive test battery. RESULTS: Mean age-adjusted auditory threshold across both time points was associated with incident dementia and cognitive decline. After adjustment for premorbid cognitive function, the association with dementia was retained (odds ratio(0.5 KHz) = 2.67; 95% confidence interval, 1.38-5.18; p = 0.004). Stronger associations with cognitive decline were found for tests administered by interview than for those administered by computer. CONCLUSIONS: This study has found an association of auditory threshold with dementia and cognitive decline over a 17-year period. The mechanisms underlying this association are unclear and may include a prodromal effect of dementia on auditory threshold, an effect of auditory threshold on cognitive assessment, an effect of auditory threshold on cognitive loss, or a shared etiologic pathway between both.

Physical activity in middle-age and dementia in later life: findings from a prospective cohort of men in Caerphilly, South Wales and a meta-analysis.

Previous studies suggest that physical activity may be protective for dementia and cognitive impairment. We report findings comparing leisure-time and work-related physical activity from the Caerphilly Prospective study (CaPS) with dementia and cognitive impairment not dementia (CIND) after around 16 years of follow-up. We synthesized our results with a meta-analysis specifically testing if length of follow-up was associated with the size of any association. Age-adjusted models found no real association with dementia, and if anything increased risk for CIND (odds ratio (OR) highest versus lowest tertile 2.61, 95% CI 1.58 to 4.31), though this was attenuated after adjustment for other confounders (OR highest versus lowest tertile 1.38, 95% CI 0.78 to 2.44). There was no evidence that this differed by type (vascular versus non-vascular) of cognitive disease. Meta-analysis of other published effect estimates showed a protective effect of physical activity on cognitive impairment (OR 0.66, 95% CI 0.52 to 0.85) but with significant heterogeneity which was partially explained by length of follow up (p = 0.03). A protective association was also seen for dementia (OR 0.78, 95% CI 0.65, 0.94), which did not appear to be related to follow-up length but there was evidence of small study bias (p = 0.002) suggesting an absence of small null studies. The apparent protective effects of physical activity on cognitive health may partially reflect reverse causation and current estimates may be overly optimistic in terms of cognitive benefits.

High caloric intake, poor cognition and dementia: the Caerphilly Prospective Study.

To examine the hypothesis that caloric intake in mid-life is associated with later dementia or cognitive impairment not dementia (CIND). A prospective cohort study was conducted in Caerphilly, South Wales, United Kingdom. Men aged 45-59 years were identified from the electoral roll and general practice. 2,512 men were examined between July 1979 until September 1983. Four follow-up examinations were conducted every 4-5 years until 2004. Participants were categorized on the basis of their average daily caloric intake over each of the first three phases. Outcomes were CIND and dementia ascertained at phase five (2004). 192 men (15% of 1,248 participants at phase five) had CIND and 100 (8%) dementia. Age adjusted odds ratios demonstrated strongest associations between average energy consumption and vascular CIND or dementia (OR 1.62 95% CI 1.25-2.10). Adjustment for nutritional factors, vascular disease, diabetes, smoking, BP and BMI if anything increased the association (OR 1.64, 95% CI 1.03-2.60). After adjusting for social class, associations were attenuated and consistent with chance (OR 1.48, 95% CI 0.92-2.38). When adjusted for social class, the previously observed association between caloric intake and cognitive outcomes is modest, consistent with chance, and may be due to residual confounding.

Benzodiazepine use and risk of dementia: evidence from the Caerphilly Prospective Study (CaPS).

BACKGROUND: Benzodiazepine use is widespread in older people, although its benefit is uncertain. AIM: To investigate the long-term effect of benzodiazepine use upon dementia risk. METHODS: A prospective cohort of men seen on five occasions over 22 years with full medication histories, repeat measures of cognitive function and a clinical diagnosis of dementia. RESULTS: Of 1134 men with complete data, 103 (9.1%) had been taking benzodiazepines regularly at one or more phases. These men showed a marked increased incidence of dementia (OR=3.50, 95% CI 1.57 to 7.79, p=0.002), which persisted despite adjustment for psychological distress and other covariates. Men exposed in earlier phases showed a greater association than more recent exposure, counter to what one would expect if this was due to reverse causation, though we failed to demonstrate a dose-response effect with drug duration. CONCLUSION: The taking of benzodiazepines is associated with an increased risk of dementia.

Metabolic syndrome, diabetes, poor cognition, and dementia in the Caerphilly prospective study.

We have examined whether metabolic syndrome is associated with intermediate risk of impaired cognition between people with and without diabetes. Men aged 45 to 59 years were identified from Caerphilly in South Wales, United Kingdom. Participation rate was 89% (41% of the original cohort) and 2,512 men were examined in phase one from July 1979 until September 1983. Follow-up examinations occurred at four intervals until 2004 when 1,225 men participated. Participants were categorized on the basis of their exposure to metabolic syndrome not diabetes (MSND) and diabetes (with or without metabolic syndrome) at each of the first three phases. Neuropsychological outcomes and clinical diagnosis of cognitive impairment not dementia (CIND) and dementia were assessed at phase five. The prevalence of MSND increased from 1% to 5% and for diabetes from 3% to 9% between phase one and phase three. 15% of participants had CIND and 8% dementia. People with diabetes, but not those with MSND, at phases one, two, or three had poorer cognition at phase five (adjusted ß coefficient AH4 -4.3 95% CI -7.9, -0.7; phase two: -2.5 95% CI -4.7, -0.3; phase three: -2.3 95% CI -4.2, -0.5). The adjusted odds ratio (phase one) for diabetes and CIND was 4.0 (95% CI 1.4, 11.5) and dementia 0.61 (95% CI 0.07, 5.37). After adjustment, higher systolic blood pressure was the only component of the metabolic syndrome associated with worse cognitive outcomes. Diabetes in mid-life, but not MSND, is associated with impaired cognition and increased odds of CIND in later life.

Dynamics in insulin resistance and plasma levels of adipokines in patients with acute decompensated and chronic stable heart failure.

BACKGROUND: Patients with heart failure (HF) develop metabolic derangements including increased adipokine levels, insulin resistance, inflammation and progressive catabolism. It is not known whether metabolic dysfunction and adipocyte activation worsen in the setting of acute clinical decompensation, or conversely, improve with clinical recovery. METHODS AND RESULTS: We assessed insulin resistance using homeostasis model assessment of insulin resistance (HOMA-IR), and measured plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), adiponectin, visfatin, resistin, leptin, and tumor necrosis factor (TNF) α in 44 patients with acute decompensated HF (ADHF) due to left ventricular (LV) systolic dysfunction and again early (<1 wk) and late (> 6 mo) after clinical recovery, in 26 patients with chronic stable HF, and in 21 patients without HF. NT-proBNP was not increased in control subjects, mildly elevated in patients with stable HF, markedly elevated in patients with ADHF, and decreased progressively early and late after treatment. Compared to control subjects, plasma adiponectin, visfatin, leptin, resistin, and TNF-α were elevated in patients with chronic stable HF and increased further in patients with ADHF. Likewise, HOMA-IR was increased in chronic stable HF and increased further during ADHF. Adiponectin, visfatin, and HOMA-IR remained elevated at the time of discharge from the hospital, but returned to chronic stable HF levels. Adipokine levels were not related to body mass index in HF patients. HOMA-IR correlated positively with adipokines and TNF-α in HF patients. CONCLUSIONS: ADHF is associated with worsening of insulin resistance and elevations of adipokines and TNF-α, indicative of adipocyte activation. These metabolic abnormalities are reversible, but they temporally lag behind the clinical resolution of decompensated HF.

Sleep disturbance and daytime sleepiness predict vascular dementia.

BACKGROUND: Disturbed sleep is common throughout the community and is associated with an increase in daytime sleepiness, both of which, in turn are associated with an increased risk of ischaemic vascular disease. The hypothesis that sleep disturbances are predictive of dementia, and in particular vascular dementia was tested in a large community-based cohort of older men. METHODS: A questionnaire on sleep disturbances was administered to 1986 men aged 55-69 years in the Caerphilly Cohort Study and 10 years later the men were examined clinically for evidence of dementia or cognitive impairment with no dementia (CIND). FINDINGS: Approximately 20% of the men reported disturbed sleep and 30% reported 'severe' daytime sleepiness. Ten years later 1,225 men (75% of the surviving men in the cohort) were tested and 268 (22%) were found to be cognitively impaired with 93 (7.6%) showing clear evidence of dementia and the remaining 175 (14.3%) showing evidence of CIND. After adjustment for possible confounding, including cognitive function and the taking of sleeping tablets at baseline, sleep disturbances appeared to be predictive of dementia and CIND of vascular origin, while there was no suggestion of prediction of non-vascular cognitive impairment by sleep. Prediction of vascular dementia appeared to be particularly strong for daytime sleepiness, with an adjusted OR of 4.44 (95% CI 2.05 to 9.61). Further adjustments for psychological distress at baseline reduced the size of the relationships, but the ORs remain large, consistent with a direct positive effect of sleep disturbance on vascular dementia. INTERPRETATION: Sleep disturbances, and in particular severe daytime sleepiness, appear to be strongly predictive of vascular dementia, but have no predictive power for non vascular dementia.

Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure.

Perry syndrome is a rare form of autosomal dominant Parkinsonism with respiratory failure recently defined as being due to mutations in the DCTN1 gene. We describe a new family carrying a G71R mutation in the DCTN1 gene. The proband displayed a series of distinctive features not previously described in Perry syndrome: a disorder of vertical downward saccades accompanied by progressive midbrain atrophy, predominant nonmotor symptoms responsive to levodopa, distinctive craniocervical levodopa induced dyskinesias, and a good response to high-dose levodopa therapy and respiratory support. The family was initially thought to have autosomal dominant behavioral variant frontotemporal dementia with Parkinsonism. This report expands the clinical definition of this distinctive syndrome.