Kirsty Macpherson

Serum neurofilament light in familial Alzheimer disease: A marker of early neurodegeneration

Objectives: To investigate whether serum neurofilament light (NfL) concentration is increased in familial Alzheimer disease (FAD), both pre and post symptom onset, and whether it is associated with markers of disease stage and severity. Methods: We recruited 48 individuals from families with PSEN1 or APP mutations to a cross-sectional study: 18 had symptomatic Alzheimer disease (AD) and 30 were asymptomatic but at 50% risk of carrying a mutation. Serum NfL was measured using an ultrasensitive immunoassay on the single molecule array (Simoa) platform. Cognitive testing and MRI were performed; 33 participants had serial MRI, allowing calculation of atrophy rates. Genetic testing established mutation status. A generalized least squares regression model was used to compare serum NfL among symptomatic mutation carriers, presymptomatic carriers, and noncarriers, adjusting for age and sex. Spearman coefficients assessed associations between serum NfL and (1) estimated years to/from symptom onset (EYO), (2) cognitive measures, and (3) MRI measures of atrophy. Results: Nineteen of the asymptomatic participants were mutation carriers (mean EYO −9.6); 11 were noncarriers. Compared with noncarriers, serum NfL concentration was higher in both symptomatic (p < 0.0001) and presymptomatic mutation carriers (p = 0.007). Across all mutation carriers, serum NfL correlated with EYO (ρ = 0.81, p < 0.0001) and multiple cognitive and imaging measures, including Mini-Mental State Examination (ρ = −0.62, p = 0.0001), Clinical Dementia Rating Scale sum of boxes (ρ = 0.79, p < 0.0001), baseline brain volume (ρ = −0.62, p = 0.0002), and whole-brain atrophy rate (ρ = 0.53, p = 0.01). Conclusions: Serum NfL concentration is increased in FAD prior to symptom onset and correlates with measures of disease stage and severity. Serum NfL may thus be a feasible biomarker of early AD-related neurodegeneration.

Altered Sense of Humor in Dementia

Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer’s disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications.

Presymptomatic cortical thinning in familial Alzheimer disease A longitudinal MRI study

Objective: To identify a cortical signature pattern of cortical thinning in familial Alzheimer disease (FAD) and assess its utility in detecting and tracking presymptomatic neurodegeneration. Methods: We recruited 43 FAD mutation carriers—36 PSEN1, 7 APP (20 symptomatic, 23 presymptomatic)—and 42 healthy controls to a longitudinal clinical and MRI study. T1-weighted MRI scans were acquired at baseline in all participants; 55 individuals (33 mutation carriers; 22 controls) had multiple (mean 2.9) follow-up scans approximately annually. Cortical thickness was measured using FreeSurfer. A cortical thinning signature was identified from symptomatic FAD participants. We then examined cortical thickness changes in this signature region in presymptomatic carriers and assessed associations with cognitive performance. Results: The cortical signature included 6 regions: entorhinal cortex, inferior parietal cortex, precuneus, superior parietal cortex, superior frontal cortex, and supramarginal gyrus. There were significant differences in mean cortical signature thickness between mutation carriers and controls 3 years before predicted symptom onset. The earliest significant difference in a single region, detectable 4 years preonset, was in the precuneus. Rate of change in cortical thickness became significantly different in the cortical signature at 5 years before predicted onset, and in the precuneus at 8 years preonset. Baseline mean signature thickness predicted rate of subsequent thinning and correlated with presymptomatic cognitive change. Conclusions: The FAD cortical signature appears to be similar to that described for sporadic AD. All component regions showed significant presymptomatic thinning. A composite signature may provide more robust results than a single region and have utility as an outcome measure in presymptomatic trials.

ApoE influences regional white-matter axonal density loss in Alzheimer's disease

Mechanisms underlying phenotypic heterogeneity in young onset Alzheimer disease (YOAD) are poorly understood. We used diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI) with tract-based spatial statistics to investigate apolipoprotein (APOE) ε4 modulation of white-matter damage in 37 patients with YOAD (22, 59% APOE ε4 positive) and 23 age-matched controls. Correlation between neurite density index (NDI) and neuropsychological performance was assessed in 4 white-matter regions of interest. White-matter disruption was more widespread in ε4+ individuals but more focal (posterior predominant) in the absence of an ε4 allele. NODDI metrics indicate fractional anisotropy changes are underpinned by combinations of axonal loss and morphological change. Regional NDI in parieto-occipital white matter correlated with visual object and spatial perception battery performance (right and left, both p = 0.02), and performance (nonverbal) intelligence (WASI matrices, right, p = 0.04). NODDI provides tissue-specific microstructural metrics of white-matter tract damage in YOAD, including NDI which correlates with focal cognitive deficits, and APOEε4 status is associated with different patterns of white-matter neurodegeneration.

Processing of Self versus Non-Self in Alzheimer’s Disease

Despite considerable evidence for abnormalities of self-awareness in Alzheimer’s disease (AD), the cognitive mechanisms of altered self-processing in AD have not been fully defined. Here we addressed this issue in a detailed analysis of self/non-self-processing in three patients with AD. We designed a novel neuropsychological battery comprising tests of tactile body schema coding, attribution of tactile events to self versus external agents, and memory for self- versus non-self-generated vocal information, administered in conjunction with a daily life measure of self/non-self-processing (the Interpersonal Reactivity Index). Three male AD patients (aged 54–68 years; one with a pathogenic mutation in the Presenilin 1 gene, one with a pathogenic mutation in the Amyloid Precursor Protein gene, and one with a CSF protein profile supporting underlying AD pathology) were studied in relation to a group of eight healthy older male individuals (aged 58–74 years). Compared to healthy controls, all patients had relatively intact tactile body schema processing. In contrast, all patients showed impaired memory for words previously presented using the patient’s own voice whereas memory for words presented in other voices was less consistently affected. Two patients showed increased levels of emotional contagion and reduced perspective taking on the Interpersonal Reactivity Index. Our findings suggest that AD may be associated with deficient self/non-self differentiation over time despite a relatively intact body image: this profile of altered self-processing contrasts with the deficit of tactile body schema previously described in frontotemporal dementia associated with C9orf72 mutations. We present these findings as a preliminary rationale to direct future systematic study in larger patient cohorts.

Eyetracking Metrics in Young Onset Alzheimer’s Disease: A Window into Cognitive Visual Functions

Young onset Alzheimer’s disease (YOAD) is defined as symptom onset before the age of 65 years and is particularly associated with phenotypic heterogeneity. Atypical presentations, such as the clinic-radiological visual syndrome posterior cortical atrophy (PCA), often lead to delays in accurate diagnosis. Eyetracking has been used to demonstrate basic oculomotor impairments in individuals with dementia. In the present study, we aim to explore the relationship between eyetracking metrics and standard tests of visual cognition in individuals with YOAD. Fifty-seven participants were included: 36 individuals with YOAD (n = 26 typical AD; n = 10 PCA) and 21 age-matched healthy controls. Participants completed three eyetracking experiments: fixation, pro-saccade, and smooth pursuit tasks. Summary metrics were used as outcome measures and their predictive value explored looking at correlations with visuoperceptual and visuospatial metrics. Significant correlations between eyetracking metrics and standard visual cognitive estimates are reported. A machine-learning approach using a classification method based on the smooth pursuit raw eyetracking data discriminates with approximately 95% accuracy patients and controls in cross-validation tests. Results suggest that the eyetracking paradigms of a relatively simple and specific nature provide measures not only reflecting basic oculomotor characteristics but also predicting higher order visuospatial and visuoperceptual impairments. Eyetracking measures can represent extremely useful markers during the diagnostic phase and may be exploited as potential outcome measures for clinical trials.

ACCELERATED LONG-TERM FORGETTING IN PRESYMPTOMATIC FAMILIAL ALZHEIMER’S DISEASE

O2-04-05 ACCELERATED LONG-TERM FORGETTING IN PRESYMPTOMATIC FAMILIAL ALZHEIMER’S DISEASE Philip S. J. Weston, Susie M. D. Henley, Yuying Liang, Jennifer Nicholas, Natalie S. Ryan, Kirsty MacPherson, Elizabeth Donnachie, Jon M. Schott, Martin N. Rossor, Sebastian J. Crutch, Christopher R. Butler, Adam Z. Zeman, Nick C. Fox, UCL Institute of Neurology, London, United Kingdom; London School of Hygiene and Tropical Medicine, London, United Kingdom; 3 University of Oxford, Oxford, United Kingdom; 4 University of Exeter Medical School, Exeter, United Kingdom. Contact e-mail: philip. weston.11@ucl.ac.uk

EXPLORING THE POPULATION PREVALENCE OF β-AMYLOID BURDEN: AN ANALYSIS OF 250 INDIVIDUALS BORN IN MAINLAND BRITAIN IN THE SAME WEEK IN 1946

that is associated with frontal lobe change. Traditional neuropsychological tests examining frontal dysfunction, such as the Stroop and the Trail Making tests, measure individual’s top-down control ability by comparing the time taken to complete the task in control condition and the interference condition. Trial-by-trial intra-individual reaction time (RT) variability in cognitive control tasks, however, could also be a sensitive measure of frontal integrity, since it has been shown that frontal involvement is critical in maintaining cognitive stability by minimizing fluctuation of cognitive performance. In this study, we purported to investigate the neural correlates of intra-individual RT variability in an experimental cognitive control task, namely the Multi-Source Interference Task (MSIT).Methods:Utilizing functional magnetic resonance imaging (fMRI), we investigated the brain regions activated when healthy older adults (n1⁄452) performed the MSIT, which consists of interference and control conditions. Regional activation that was significantly different in the interference condition compared to the control condition was examined to find brain regions involved in inhibitory control. Within the regions found to be involved in inhibitory control, we identified regions that were specifically associated with the intra-individual RT variability. Results: Inhibitory success was correlated with smaller intra-individual variability of RT, while themagnitude of the variability was reflected in the activation of the frontal regions, such as the left middle and left inferior frontal gyri, as well as the left supramarginal gyrus. Conclusions: Individuals with greater intra-individual variability during the MSIT activated the inhibitory control network to a greater magnitude, possibly reflecting the increased demand for cognitive control network due to their less efficient inhibitory control system. This is consistent with previous findings that showed greater intra-individual variability in dementia patients with frontal involvement compared to those with Alzheimer’s disease. Increase in intra-individual variability of RT has also been shown to be observed in people with MCI, suggesting the measure as a promising behavioral index that reflects frontal or frontoparietal integrity.

CAN EYETRACKING METRICS RELATE TO PERFORMANCE ON VISUAL COGNITIVE TESTS OF INDIVIDUALS WITH YOUNG-ONSET ALZHEIMER’S DISEASE?

compare AD patients with and without confabulations. Methods: 37 healthy control (HC) and 35 individuals with mild to moderate AD were recruited at the Piti e-Salpêtri ere University Hospital. All participants were evaluated on Dalla Barba’s Confabulation Battery to determine their tendency to produce provoked confabulations. Thus, among AD patients, we distinguish between those who produced episodic confabulations, and those who didn’t. Accordingly 27 AD patients were considered free of confabulations (ADC-), and 8 as confabulators (ADC+) (none HC met the criteria). Then, all participants were assessed on a comprehensive neuropsychological battery which evaluate notably episodic memory, language, executive functioning and working memory. Participants also went through a structural MRI to determine whether ADCand ADC+ are similar. Results:Statistical analyses showed a significant difference between HC participants and the two groups of AD patients, in almost all cognitive domains assessed in our battery. However when comparing the two AD groups, they didn’t demonstrate distinct profiles. Regarding the neuroimaging data, and particularly hippocampal subfields volumes, the results showed the same pattern. Conclusions: In demonstrating that there is no cognitive differences between patients with and without confabulations, our results put in doubt some confabulation models supposing a unique and sufficient cognitive (e.g. executive) process underlying the onset of confabulations.

SERUM NEUROFILAMENT LIGHT CONCENTRATION IN FAMILIAL ALZHEIMER’S DISEASE AND ASSOCIATION WITH MARKERS OF DISEASE STAGE AND SEVERITY

O4-02-04 SERUM NEUROFILAMENT LIGHT CONCENTRATION IN FAMILIAL ALZHEIMER’S DISEASE AND ASSOCIATION WITH MARKERS OF DISEASE STAGE AND SEVERITY Philip S. J. Weston, Teresa Poole, Natalie S. Ryan, Akshay Nair, Yuying Liang, Kirsty Macpherson, Ronald Druyeh, Ian B. Malone, R. Laila Ahsan, Hugh Pemberton, Jana Klimova, Simon Mead, Kaj Blennow, Martin N. Rossor, Jonathan M. Schott, Henrik Zetterberg, Nick C. Fox, UCL Institute of Neurology, London, United Kingdom; London School of Hygiene and Tropical Medicine, London, United Kingdom; Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom; University College London, Institute of Neurology, London, United Kingdom; Institute of Neurology, University College London, London, United Kingdom; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M€olndal, Sweden. Contact e-mail: philip.weston.11@ucl.ac.uk