Mark Fish

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.

Does anxiety affect risk of dementia? Findings from the Caerphilly Prospective Study

Objective: To examine the association of anxiety with incident dementia and cognitive impairment not dementia (CIND). Methods: We conducted a prospective study of men aged 48 to 67 years at baseline anxiety assessment; we measured cognition 17 years later. We studied 1481 men who were either eligible for examination or were known to have dementia. Trait Anxiety was assessed using the Spielberger State Trait Anxiety Inventory. Psychological distress was assessed using the 30-item general health questionnaire. Cognitive screening was followed by a clinical examination. Medical notes and death certificates of those not seen were also examined. Outcomes were CIND and Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) dementia. Results: Of 1160 men who were cognitively screened, 174 cases of CIND and 69 cases of dementia were identified. A further 21 cases of dementia were identified from medical records. After adjustment for age, vascular risk factors and premorbid cognitive function associations with higher anxiety (31st–95th centile) were for CIND odds ratio (OR) 2.31 (95% Confidence Interval (CI) = 1.20–4.44) and for dementia OR 2.37 (95% CI = 0.98–5.71). These associations were slightly stronger for nonvascular (OR = 2.45; 95% CI = 1.28–4.68) than for vascular impairment (OR = 1.94; 95% CI = 0.77–4.89). Analyses of change in cognitive performance, assessed by the Cambridge Cognitive Examination of the Elderly subscales found some evidence for decline in learning memory with higher anxiety score (bage adj = −0.291 (−0.551, −0.032), but not for any other subscale. Conclusions: Anxiety is a risk factor for CIND and dementia. The extent to which the association is independent of depression and whether or not it is causal requires further study. BMI = body mass index; CAMCOG = Cambridge Cognitive Examination of the Elderly; CaPS = Caerphilly Prospective Study; CIND = cognitive impairment not dementia; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; GHQ30 = 30-item general health questionnaire; GP = general practice; Lowess = locally weighted least squares; NINDS-AIREN = National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l’Enseignement en Neurosciences; STAI = Spielberger State Trait Anxiety Inventory.

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 ratio0.5 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.

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.

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 1225 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.

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.

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.

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)–1β, 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.

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 β 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.

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.