Jennifer M. Nicholas

R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia

Rare TREM2 variants are significant risk factors for Alzheimers disease (AD).

Recent HbA1c Values and Mortality Risk in Type 2 Diabetes. Population-Based Case-Control Study

This study aimed to evaluate mortality within 365 days of HbA1c values of <6.5% or >9.0% in participants with clinical type 2 diabetes mellitus. A matched nested case-control study was implemented, within a cohort of participants with type 2 diabetes from 2000 to 2008. Conditional logistic regression was used to model the odds ratio for mortality adjusting for comorbidity and drug utilisation. There were 97,450 participants with type 2 diabetes; 16,585 cases that died during follow up were matched to 16,585 controls. The most recent HbA1c value was <6.5% (48 mmol/mol) for 22.2% of cases and 24.2% of controls, the HbA1c was >9.0% for 9.0% of cases and 7.7% of controls. In a complete case analysis, the adjusted odds ratio (AOR) for mortality associated with most recent HbA1c <6.5% was 1.31 (95% confidence interval (CI): 1.21,1.42). After multiple imputation of missing HbA1c values the AOR was 1.20 (CI: 1.12,1.28). The complete case analysis gave an AOR for HbA1c >9.0% of 1.51 (CI: 1.33, 1.70), in the multiple imputation analysis this was 1.29 (1.17,1.41). The risk associated with HbA1c <6.5% was age dependent. In the multiple imputation analysis the AOR was 1.53 (CI: 0.84 to 2.79) at age<55 years but 1.04 (CI: 0.92, 1.17) at age 85 years and over. In non-randomised data, values of HbA1c that are either <6.5% or >9.0% may be associated with increased mortality within one year in clinical type 2 diabetes. Relative risks may be higher at younger ages.

Identification of an important potential confound in CSF AD studies: aliquot volume

Abstract Background: Cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42), total tau (T-tau) and phosphorylated tau181 (P-tau) are finding increasing utility as biomarkers of Alzheimer’s disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by aliquot storage volume and whether addition of detergent-containing buffer mitigates any observed effects. Methods: AD and control CSF was distributed into polypropylene tubes in aliquots of different volumes (50–1500 μL). Aβ1-42, T-tau and P-tau were measured with and without addition of Tween 20 (0.05%). Results: Measured concentrations of Aβ1-42 increased two-fold with aliquot storage volume. A volume increase of 10 µL caused an Aβ1-42 increase of 0.95 pg/mL [95% confidence interval (CI) 0.36–1.50, p=0.02] in controls, and 0.60 pg/mL (CI 0.23–0.98 pg/mL, p=0.003) in AD samples. Following addition of Tween 20, the positive relationship between Aβ1-42 and aliquot volume disappeared. T-tau and P-tau were not significantly affected. Conclusions: CSF aliquot storage volume has a significant impact on the measured concentration of Aβ1-42. The introduction of a buffer detergent at the initial aliquoting stage may be an effective solution to this problem.

Longitudinal diffusion tensor imaging in frontotemporal dementia.

Novel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD).

Auditory spatial processing in Alzheimer’s disease

Auditory spatial processing is vulnerable in dementia. Golden et al. show that patients with typical Alzheimer’s disease or posterior cortical atrophy are impaired relative to controls in detecting the movement and location of sounds. The deficits have anatomical correlates in right parietal cortex, with implications for studies of network degeneration.

Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease.

Familial Alzheimers disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD.

Humour processing in frontotemporal lobar degeneration: A behavioural and neuroanatomical analysis

Humour is a complex cognitive and emotional construct that is vulnerable in neurodegenerative diseases, notably the frontotemporal lobar degenerations. However, humour processing in these diseases has been little studied. Here we assessed humour processing in patients with behavioural variant frontotemporal dementia (n = 22, mean age 67 years, four female) and semantic dementia (n = 11, mean age 67 years, five female) relative to healthy individuals (n = 21, mean age 66 years, 11 female), using a joint cognitive and neuroanatomical approach. We created a novel neuropsychological test requiring a decision about the humorous intent of nonverbal cartoons, in which we manipulated orthogonally humour content and familiarity of depicted scenarios. Structural neuroanatomical correlates of humour detection were assessed using voxel-based morphometry. Assessing performance in a signal detection framework and after adjusting for standard measures of cognitive function, both patient groups showed impaired accuracy of humour detection in familiar and novel scenarios relative to healthy older controls (p < .001). Patient groups showed similar overall performance profiles; however the behavioural variant frontotemporal dementia group alone showed a significant advantage for detection of humour in familiar relative to novel scenarios (p = .045), suggesting that the behavioural variant syndrome may lead to particular difficulty decoding novel situations for humour, while semantic dementia produces a more general deficit of humour detection that extends to stock comedic situations. Humour detection accuracy was associated with grey matter volume in a distributed network including temporo-parietal junctional and anterior superior temporal cortices, with predominantly left-sided correlates of processing humour in familiar scenarios and right-sided correlates of processing novel humour. The findings quantify deficits of core cognitive operations underpinning humour processing in frontotemporal lobar degenerations and suggest a candidate brain substrate in cortical hub regions processing incongruity and semantic associations. Humour is a promising candidate tool with which to assess complex social signal processing in neurodegenerative disease.

Physiological phenotyping of dementias using emotional sounds.

Emotional behavioral disturbances are hallmarks of many dementias but their pathophysiology is poorly understood. Here we addressed this issue using the paradigm of emotionally salient sounds.

Dementias show differential physiological responses to salient sounds

Abnormal responsiveness to salient sensory signals is often a prominent feature of dementia diseases, particularly the frontotemporal lobar degenerations, but has been little studied. Here we assessed processing of one important class of salient signals, looming sounds, in canonical dementia syndromes. We manipulated tones using intensity cues to create percepts of salient approaching (“looming”) or less salient withdrawing sounds. Pupil dilatation responses and behavioral rating responses to these stimuli were compared in patients fulfilling consensus criteria for dementia syndromes (semantic dementia, n = 10; behavioral variant frontotemporal dementia, n = 16, progressive nonfluent aphasia, n = 12; amnestic Alzheimers disease, n = 10) and a cohort of 26 healthy age-matched individuals. Approaching sounds were rated as more salient than withdrawing sounds by healthy older individuals but this behavioral response to salience did not differentiate healthy individuals from patients with dementia syndromes. Pupil responses to approaching sounds were greater than responses to withdrawing sounds in healthy older individuals and in patients with semantic dementia: this differential pupil response was reduced in patients with progressive nonfluent aphasia and Alzheimers disease relative both to the healthy control and semantic dementia groups, and did not correlate with nonverbal auditory semantic function. Autonomic responses to auditory salience are differentially affected by dementias and may constitute a novel biomarker of these diseases.

Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial

Summary Background In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures. Methods We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348. Findings Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6–7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8–8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2–2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3–4·8; p=0·028). A treatment effect was not noted for any other outcomes. Interpretation To our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials. Funding The Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a personal contribution from A W Pidgley CBE, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London.