Kuven Moodley

The Hippocampus in Neurodegenerative Disease

AD is the commonest neurodegenerative disorder resulting ultimately in dementia, a stage during which there is a loss of previously acquired intellectual skill and independent occupational and social function. Neurodegenerative changes within the hippocampus and an extended neuronal network involving the medial temporal and medial parietal lobe result in the archetypal memory impairment seen in Alzheimers disease (AD). As attention focuses increasingly on early diagnosis and treatment of dementia, this understanding of the hippocampal involvement in AD has helped to develop diagnostic tools for use in early disease. However, hippocampal damage is also a common feature among non-AD neurodegenerative dementias. Neuroimaging techniques, in conjunction with behavioral and pathological techniques, can be used to determine the involvement of the hippocampus in AD and other neurodegenerative diseases.

Diagnostic differentiation of mild cognitive impairment due to Alzheimer's disease using a hippocampus-dependent test of spatial memory.

The hippocampus is one of the earliest brain regions affected in Alzheimers disease (AD) and tests of hippocampal function have the potential to detect AD in its earliest stages. Given that the hippocampus is critically involved in allocentric spatial memory, this study applied a short test of spatial memory, the 4 Mountains Test (4MT), to determine whether test performance can differentiate mild cognitive impairment (MCI) patients with and without CSF biomarker evidence of underlying AD and whether the test can distinguish patients with MCI and mild AD dementia when applied in different cultural settings. Healthy controls (HC), patients with MCI, and mild AD dementia were recruited from study sites in UK and Italy. Study numbers were: HC (UK 20, Italy 10), MCI (UK 21, Italy 14), and AD (UK 11, Italy 9). Nineteen UK MCI patients were grouped into CSF biomarker‐positive (MCI+, n = 10) and biomarker‐negative (MCI–, n = 9) subgroups. Behavioral data were correlated with hippocampal volume and cortical thickness of the precuneus and posterior cingulate gyrus. Spatial memory was impaired in both UK and Italy MCI and AD patients. Test performance additionally differentiated between MCI+ and MCI– subgroups (P = 0.001). A 4MT score of ≤8/15 was associated with 100% sensitivity and 90% specificity for detection of early AD (MCI+ and mild AD dementia) in the UK population, and with 100% sensitivity and 50% specificity for detection of MCI and AD in the Italy sample. 4MT performance correlated with hippocampal volume in the UK population and cortical thickness of the precuneus in both study populations. In conclusion, performance on a hippocampus‐sensitive test of spatial memory differentiates MCI due to AD with high diagnostic sensitivity and specificity. The observation that similar diagnostic sensitivity was obtained in two separate study populations, allied to the scalability and usability of the test in community memory clinics, supports future application of the 4MT in the diagnosis of pre‐dementia due to AD.

Fifty Percent Prevalence of extracampine hallucinations in Parkinson's Disease Patients

Extracampine hallucinations (EH), the sense of a presence or fleeting movement in the absence of an associated visual percept, have been reported in Parkinson’s disease (PD) patients but their prevalence, characteristics, and temporal relationship to visual hallucinations (VH) remain unclear. Given that, VH are predictive of cognitive impairment in PD, improved understanding of EH may have significant prognostic implications. The objective of this study is to evaluate the prevalence and characteristics of EH in a large unselected population with PD and to assess the temporal relationship between EH, VH, and memory decline. Cross-sectional data were collected from 414 PD patients using a questionnaire circulated via an online patient community. Data were obtained regarding the occurrence, timing, and characteristics of VH and EH and symptoms of PD, disease duration, disease severity, and medication history. About 50.4% of respondents reported EH and 15.5% reported VH. EH were typically experienced alongside, rather than behind, the individual (p < 0.001) without clear lateralization (p = 0.438) and were more likely to be of unfamiliar presences (p < 0.001). The occurrence of EH was associated with Hoehn and Yahr score (p = 0.002) but not disease duration (p = 0.158). EH onset was associated with VH onset (p = 0.046) and occurred after the onset of anosmia (p < 0.001), cognitive decline (p = 0.002), and sleep disturbance (p = 0.002). The reported prevalence of EH in PD patients was threefold greater than that of VH, with similar timings of onset, suggesting that EH are under-recognized and under-reported. Further work is needed to determine whether EH are predictive of cognitive decline.

Simultaneous PET/MRI in frontotemporal dementia

A 64-year-old woman presented with a 3-year history of apathy, emotional blunting and hyperorality. Initial MRI and neuropsychometric data were consistent with a diagnosis of behavioural variant frontotemporal dementia (bv-FTD) [1]. The images presented are sagittal (top) and axial (bottom) views of 3-T MRI and FDG PET scans acquired simultaneously on an integrated PET/ MRI scanner. The combined images show colocalized atrophy and hypometabolism in the frontal lobe (top right) as well as parietal hypometabolism without atrophy (bottom right), possibly reflecting disruption of the frontoparietal connections in bv-FTD.

The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease

This protocol describes the administration of the 4 Mountains Test (4MT), a short test of spatial memory, in which memory for the topographical layout of four mountains within a computer-generated landscape is tested using a delayed match-to-sample paradigm. Allocentric spatial memory is assessed by altering the viewpoint, colors and textures between the initially presented and target images. Allocentric spatial memory is a key function of the hippocampus, one of the earliest brain regions to be affected in Alzheimers disease (AD) and impairment of hippocampal function predates the onset of dementia. It was hypothesized that performance on the 4MT would aid the diagnosis of predementia AD, which manifests clinically as Mild Cognitive Impairment (MCI). The 4MT was applied to patients with MCI, stratified further based on cerebrospinal fluid (CSF) AD biomarker status (10 MCI biomarker positive, 9 MCI biomarker negative), and with mild AD dementia, as well as healthy controls. Comparator tests included tests of episodic memory and attention widely accepted as sensitive measures of early AD. Behavioral data were correlated with quantitative MRI measures of the hippocampus, precuneus and posterior cingulate gyrus. 4MT scores were significantly different between the two MCI groups (p = 0.001), with a test score of ≤8/15 associated with 100% sensitivity and 78% specificity for the classification of MCI with positive AD biomarkers, i.e., predementia AD. 4MT test scores correlated with hippocampal volume (r = 0.42) and cortical thickness of the precuneus (r = 0.55). In conclusion, the 4MT is effective in identifying the early stages of AD. The short duration, easy application and scoring, and favorable psychometric properties of the 4MT fulfil the need for a simple but accurate diagnostic test for predementia AD.

Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer's Disease and Frontotemporal Dementia: An Extended Case Series

BACKGROUND Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. OBJECTIVES The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimers disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. METHOD PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohens kappa. RESULTS Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0-0.25 for PCA to 0.29-0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. CONCLUSION The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice.

Slowly progressive behavioural presentation in two UK cases with the R406W MAPT mutation.

Mutations in the gene encoding microtubule-associated protein tau (MAPT) are associated with neurodegeneration characterized by the accumulation of taupositive intracellular inclusion bodies and manifest clinically as frontotemporal dementia (FTD), with variations in clinical phenotype arising due to differences in the location of the mutation (eg intronic versus exonic) and the topographical distribution of the associated neuronal loss. The R406W MAPT mutation is typically associated with a slowly progressive memory decline clinically similar to that associated with typical Alzheimer’s disease [1-8] with symmetrical frontotemporal atrophy observed on MRI [9]. Here we report the first UK cases of the R406W mutation in two unrelated patients with familial FTD, who present with a hitherto-undescribed clinico-radiological phenotype in the form of a slowly progressive behavioural disorder associated with predominantly rightsided temporal lobe atrophy.

Allocentric Spatial Memory Testing Predicts Conversion from Mild Cognitive Impairment to Dementia: An Initial Proof-of-Concept Study

The hippocampus is one of the first regions to exhibit neurodegeneration in Alzheimer’s disease (AD), and knowledge of its role in allocentric spatial memory may therefore aid early diagnosis of AD. The 4 Mountains Test (4MT) is a short and easily administered test of spatial memory based on the cognitive map theory of hippocampal function as derived from rodent single cell and behavioral studies. The 4MT has been shown in previous cross-sectional studies to be sensitive and specific for mild cognitive impairment (MCI) due to AD. This report describes the initial results of a longitudinal study testing the hypothesis that allocentric spatial memory is predictive of conversion from MCI to dementia. Fifteen patients with MCI underwent baseline testing on the 4MT in addition to CSF amyloid/tau biomarker studies, volumetric MRI and neuropsychological assessment including the Rey Auditory Verbal Learning Test (RAVLT) and Trail Making Test “B” (TMT-B). At 24 months, 9/15 patients had converted to AD dementia. The 4MT predicted conversion to AD with 93% accuracy (Cohen’s d = 2.52). The predictive accuracies of the comparator measures were as follows: CSF tau/β-amyloid1–42 ratio 92% (d = 1.81), RAVLT 64% (d = 0.41), TMT-B 78% (d = 1.56), and hippocampal volume 77% (d = 0.65). CSF tau levels were strongly negatively correlated with 4MT scores (r = −0.71). This proof-of-concept study provides initial support for the hypothesis that allocentric spatial memory testing is a predictive cognitive marker of hippocampal neurodegeneration in pre-dementia AD. The 4MT is a brief, non-invasive, straightforward spatial memory test and is therefore ideally suited for use in routine clinical diagnostic practice. This is of particular importance given the current unmet need for simple accurate diagnostic tests for early AD and the ongoing development of potential disease-modifying therapeutic agents, which may be more efficacious when given earlier in the disease course. By applying a test based on studies of hippocampal function in rodents to patient populations, this work represents the first step in the development of translatable biomarkers of hippocampal involvement in early AD for use in both animal models and human subjects.

Autoimmune limbic encephalitis presenting as relapsing psychosis

A 34-year-old woman with a history of relapsing psychosis presented with a 15-month history of impassivity and social withdrawal associated with cognitive impairment. The subsequent recurrence of psychomotor agitation, auditory hallucinations and delusional thinking resulted in an emergency admission under psychiatric services. Initial investigations, including MRI of the brain and cerebrospinal fluid studies were unremarkable and she was treated for a primary psychiatric disorder. The diagnosis of autoimmune limbic encephalitis was established after further investigations revealed the presence of antibodies to the NR1 subunit of the N-Methyl-d-aspartate receptor (NMDAR). Immunotherapy resulted in rapid resolution of psychosis and marked improvement in cognitive and social function. This case underlines the importance of considering anti-NMDAR encephalitis within the differential diagnosis of psychosis associated with cognitive impairment even in those with an apparent previous psychiatric history and response to antipsychotics.

High-resolution, graph-based analysis reveals pervasive functional disconnection in mild cognitive impairment

pre-scan diagnosis was 84.3% for PIB and 82.1% for FDG. The primary diagnosis was changed after PET in 13/140 patients (9.3%): 12/13 changes were concordant with PIB and 8/13 with FDG results. When examined independently, both discordant PIB and discordant FDG were associated with a change in diagnosis (p<0.0001). However, multivariate analysis revealed that changes in diagnosis were associated with discordant PIB (p1⁄40.00013) but not discordant FDG (p1⁄40.087) (LRadditional covariates: clinical dilemmas pre -PET, gender, age at PET, baseline diagnosis, new patient (follow up before PET of less than 1 year) and CDR <1) 35% of patients had a change in AD therapy post-PET (initiating or discontinuing acetycholinesterase inhibitors or memantine). In the entire population changes in treatment were not associated with discordant PIB or discordant FDG (p>0.05 in LR model); however discordant PIB did affect treatment in of patients with non-Ab pre-PET diagnoses (p1⁄40.028), driven by the initiation of acetycholinesterase inhibitors in patients who were unexpectedly PIB-positive. Conclusions: Overall concordance of PET amyloid and FDG results with clinical diagnosis was high and changes in diagnosis were uncommon. Discordant PIB had a greater effect on diagnostic changes than discordant FDG. Impact on treatment was more modest than on diagnosis and limited to Ab negative patients.