Effect of donepezil on transcranial magnetic stimulation parameters in Alzheimer's disease

INTRODUCTION: There is a need for a reliable, noninvasive biomarker for Alzheimer's disease (AD). We assessed whether short-latency afferent inhibition (SAI), a transcranial magnetic stimulation paradigm that assesses cholinergic circuits of the brain, could become such a biomarker. METHODS: Nineteen patients with AD underwent four SAI testing sessions. The timing of their usual donepezil dose was altered to create different cholinergic states for each session. This was compared to the SAI results from 20 healthy subjects. RESULTS: SAI was not able to distinguish the different cholinergic states assessed in our study. There appeared to be a diurnal variation in cholinergic function in the control group, which was not present in the AD cohort. DISCUSSION: SAI does not appear to have a role in diagnosis and assessment of AD patients. The loss of diurnal variation, however, warrants further investigation as it may provide further biochemical insights about AD

A cross-sectional study of memory and executive functions in patients with sporadic inclusion body myositis

INTRODUCTION: Sporadic inclusion body myositis (IBM) is a degenerative and inflammatory acquired myopathy characterised by muscle deposition of various proteins typically associated with Alzheimer's disease and other neurodegenerative diseases. While cognitive impairment is not noted as a clinical feature of IBM, evidence is lacking. We aimed to investigate whether cognitive performance of patients with IBM differs from population norms, focussing on cognitive domains affected in early Alzheimer's disease (memory, executive function), and to test whether disease duration and the level of disability of IBM are associated with cognitive function. METHODS: Twenty-four patients with IBM (mean [SD] age 62.0 [7.2] years; disease duration 9.6 [4.8] years) were assessed cross-sectionally on neuropsychological tests covering multiple cognitive domains, including the Preclinical Alzheimer Cognitive Composite (PACC). Performance was compared to published normative data adjusted for age, sex and education (National Alzheimer's Coordinating Center; N = 3268). Associations were examined between PACC score, disease duration and level of disability (assessed using the IBM Functional Rating Scale [IBMFRS]). RESULTS: Across all cognitive tests, group performance was within ±1SD of the normative mean. There was no evidence of associations between PACC score and either disease duration (ρ = -0.04, p = 0.87) or IBMFRS total score (ρ = 0.14, p = 0.52). DISCUSSION: Memory and executive function in patients with IBM did not differ from normative data, and we observed no evidence of associations between the cognitive composite and disease duration or level of disability. This addresses a question frequently asked by patients, and will be of value for clinicians and patients alike. This article is protected by copyright. All rights reserved

Human herpesvirus infections and dementia or mild cognitive impairment: a systematic review and meta-analysis

Interest is growing in the role of infectious agents in the pathogenesis of dementia, but current evidence is limited. We conducted a systematic review and meta-analysis to investigate the effect of any of eight human herpesviruses on development of dementia or mild cognitive impairment (MCI). We searched the Cochrane Library, Embase, Global Health, Medline, PsycINFO, Scopus, Web of Science, clinical trials registers and grey literature sources from inception to December 2017 for observational studies with cohort, case control or self-controlled designs, or randomised controlled trials of interventions against herpesviruses. Pooled effect estimates and 95% confidence intervals (CIs) were generated through random effects meta-analyses across studies with the same design, outcome, and virus type, method and site of measurement. We included 57 studies across various geographic settings. Past infection with herpesviruses, measured by IgG seropositivity, was generally not associated with dementia risk. A single cohort study rated moderate quality showed an association between varicella zoster virus reactivation (ophthalmic zoster) and incident dementia (HR 2.97; 95%CI, 1.89 to 4.66). Recent infection with, or reactivation of, herpes simplex virus type 1 or type 1/2 unspecified, cytomegalovirus and human herpes virus-6 measured by serum IgM, high titre IgG or clinical disease may be associated with dementia or MCI, though results were inconsistent across studies and overall evidence rated very low quality. Longitudinal population studies with robust repeated virus measurements taken sufficiently proximal to dementia onset are needed to establish whether, when and among whom herpesviruses affect dementia risk

Aβ₄₂/Aβ₄₀ and Aβ₄₂/Aβ₃₈ Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer’s Disease: A Pilot Study

Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer’s disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ₄₂/Aβ₄₀ and Aβ₄₂/Aβ₃₈ correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aβ₄₀ and Aβ₃₈ but not Aβ₄₂. The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ₄₀ and Aβ₃₈) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency

CSF and Brain Structural Imaging Markers of the Alzheimer's Pathological Cascade

10.1371/journal.pone.0047406PLoS ONE712

High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline

Calculating Stage Duration Statistics in Multistage Diseases

Many human diseases are characterized by multiple stages of progression. While the typical sequence of disease progression can be identified, there may be large individual variations among patients. Identifying mean stage durations and their variations is critical for statistical hypothesis testing needed to determine if treatment is having a significant effect on the progression, or if a new therapy is showing a delay of progression through a multistage disease. In this paper we focus on two methods for extracting stage duration statistics from longitudinal datasets: an extension of the linear regression technique, and a counting algorithm. Both are non-iterative, non-parametric and computationally cheap methods, which makes them invaluable tools for studying the epidemiology of diseases, with a goal of identifying different patterns of progression by using bioinformatics methodologies. Here we show that the regression method performs well for calculating the mean stage durations under a wide variety of assumptions, however, its generalization to variance calculations fails under realistic assumptions about the data collection procedure. On the other hand, the counting method yields reliable estimations for both means and variances of stage durations. Applications to Alzheimer disease progression are discussed

Longitudinal neuroanatomical and cognitive progression of posterior cortical atrophy

Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy of posterior brain regions. With the majority of cases attributable to Alzheimer’s disease and recent evidence for genetic risk factors specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer’s disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer’s disease were recruited from three centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical Alzheimer’s disease using differential equation models. We compared and contrasted the order in which regional brain volumes become abnormal within posterior cortical atrophy and typical Alzheimer’s disease using event-based models. We also examined trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models. Temporally aligned trajectories for eight regions of interest revealed distinct (P5 0.002) patterns of progression in posterior cortical atrophy and typical Alzheimer’s disease. Patients with posterior cortical atrophy showed early occipital and parietal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent of posterior cortical involvement. Patients with typical Alzheimer’s disease showed early hippocampal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction declined earlier in posterior cortical atrophy than typical Alzheimer’s disease whilst tests sensitive to working memory impairment declined earlier in typical Alzheimer’s disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy and typical Alzheimer’s disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy