Alexander J.M. Foulkes

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.

Music Perception in Dementia.

Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimers disease (AD, n = 16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n = 5), and progressive nonfluent aphasia (PNFA; n = 9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. Taking working memory performance into account, no specific deficits of musical temporal processing, timbre processing, musical scene analysis, or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation.

Do cerebrospinal fluid transfer methods affect measured amyloid β42, total tau, and phosphorylated tau in clinical practice?

Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimers disease. Several preanalytical factors may alter the CSF concentrations of amyloid β 1–42 (Aβ1–42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory.

Effect of age at onset on cortical thickness and cognition in posterior cortical atrophy

Age at onset (AAO) has been shown to influence the phenotype of Alzheimer’s disease (AD), but how it affects atypical presentations of AD remains unknown. Posterior cortical atrophy (PCA) is the most common form of atypical AD. In this study, we aimed to investigate the effect of AAO on cortical thickness and cognitive function in 98 PCA patients. We used Freesurfer (v5.3.0) to compare cortical thickness with AAO both as a continuous variable, and by dichotomizing the groups based on median age (58 years). In both the continuous and dichotomized analyses, we found a pattern suggestive of thinner cortex in precuneus and parietal areas in earlier-onset PCA, and lower cortical thickness in anterior cingulate and prefrontal cortex in later-onset PCA. These cortical thickness differences between PCA subgroups were consistent with earlier-onset PCA patients performing worse on cognitive tests involving parietal functions. Our results provide a suggestion that AAO may not only affect the clinico-anatomical characteristics in AD but may also affect atrophy patterns and cognition within atypical AD phenotypes.

Cortical microstructure in young onset Alzheimer's disease using neurite orientation dispersion and density imaging

Alzheimers disease (AD) is associated with extensive alterations in grey matter microstructure, but our ability to quantify this in vivo is limited. Neurite orientation dispersion and density imaging (NODDI) is a multi‐shell diffusion MRI technique that estimates neuritic microstructure in the form of orientation dispersion and neurite density indices (ODI/NDI). Mean values for cortical thickness, ODI, and NDI were extracted from predefined regions of interest in the cortical grey matter of 38 patients with young onset AD and 22 healthy controls. Five cortical regions associated with early atrophy in AD (entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, fusiform gyrus, and precuneus) and one region relatively spared from atrophy in AD (precentral gyrus) were investigated. ODI, NDI, and cortical thickness values were compared between controls and patients for each region, and their associations with MMSE score were assessed. NDI values of all regions were significantly lower in patients. Cortical thickness measurements were significantly lower in patients in regions associated with early atrophy in AD, but not in the precentral gyrus. Decreased ODI was evident in patients in the inferior and middle temporal gyri, fusiform gyrus, and precuneus. The majority of AD‐related decreases in cortical ODI and NDI persisted following adjustment for cortical thickness, as well as each other. There was evidence in the patient group that cortical NDI was associated with MMSE performance. These data suggest distinct differences in cortical NDI and ODI occur in AD and these metrics provide pathologically relevant information beyond that of cortical thinning.

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.

Navigational cue effects in Alzheimer's disease and posterior cortical atrophy

Deficits in spatial navigation are characteristic and disabling features of typical Alzheimers disease (tAD) and posterior cortical atrophy (PCA). Visual cues have been proposed to mitigate such deficits; however, there is currently little empirical evidence for their use.

DIFFERENTIAL HIPPOCAMPAL SUBFIELD LOSS IN DIFFERENT PHENOTYPES OF YOUNG ONSET ALZHEIMER’S DISEASE

to controls. Connections were predominantly impaired in frontal and occipital junctions. There was a graduation from controls to MCI and from MCI to AD. CSF markers differed not between AD and MCI. For all subjects a low correlation was observed for MMSE and CSF tau and a number of connections including fronto-parietal and fronto-occipital. Conclusions: In this investigation with an rs-fNIRS it was demonstrated a good feasibility of the method. Moreover it turned out to be sufficient to detect substantial differences between controls andMCI subjects, and AD patients, respectively. For further longitudinal studies it may be worth to explore whether rs-fNIRS has the capability to predict thoseMCI subjects that convert into AD.

LONGITUDINAL CORTICAL THICKNESS IN SPORADIC YOUNG ONSET ALZHEIMER’S DISEASE

MRI from 1713 ADNI subjects; 11593 T1-MRI from 5389 Rotterdam-Study-Scan (Ikram et al, 2015) aging subjects; 244 T1-MRI from 64 PPMS subjects of the Institute of Neurology-UCL; we analyzed 24 T1-MRI and DTI of HCP subjects to estimate an average structural connectome. Results: The mechanistic profile identified by our model (Fig 2) agrees with current results that identify transneuronal spread from and to hubs as the principal mechanism underlying neurodegeneration in AD (Cope et al, 2018). Interestingly, the model points out that we can’t neglect the component of neurodegeneration due to nodal stress – vulnerability of hubs due to increased metabolic demand. The proximity mechanism identified in HA suggests a more uniform brain-loss, while the presence of an un-explained term indicates that the hypothetical mechanisms utilized are not sufficient to fully explain the aging process. In PPMS the profile is a combination of apparently discordant (nodal stress and trophic failure) mechanisms: it is possible that the focal inflammatory component of MS, although not strong in our progressive cohort, plays a role in complicating the patterns of neurodegeneration. Conclusions:Our results suggest that neurodegeneration in AD and PPMS is not simply an acceleration of the aging process: the two diseases have distinct spreading mechanisms underlying neurodegeneration.

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.