This thesis focused on cognitive and MRI measures of early change and progression in Huntington's disease (HD). HD is clinically heterogeneous and previous findings about the location of brain atrophy in the early stages, and its relation to cognition, are equivocal. A pilot study assessed the practicality of using serial volumetric MRI in early HD and the usefulness of cognitive tasks in longitudinal assessment. A larger study investigated cross-sectional and longitudinal aspects of these domains in premanifest and early HD. Global and regional cerebral volumes were investigated using manual volumetry and voxel-based morphometry (VBM). The work describes the application of the Brain Boundary Shift Integral (BBSI) to measure of whole-brain atrophy rate. Preparatory technical work included choice of templates for optimum scan alignment and segmentation in VBM, and adjustment of BBSI parameters to obtain maximum agreement between it and manual measures. Cognitive ability was assessed using a wide-ranging battery of tests, some standard and some novel. Atrophy in early HD was found to be more extensive than previously reported, involving widespread extra-striatal loss, and not all functional deficits could be attributed to striatal damage. Emotion recognition deficits were broad and associated with striatal and extra-striatal brain regions. Executive function and memory tasks demonstrated decline over one year. Whole-brain atrophy rates were increased in early HD and associated with decline in cognition and CAG repeat length. This work elucidates the extent of, and associations of, atrophy and cognitive impairment in HD, and adds weight to the suggestion that variability in progression rates is partly explained by genetic factors. The suggestion that motor learning might be impaired even in very far-from-onset gene carriers, and that tasks other than those tapping executive function were sensitive to decline, should motivate further work aimed at detecting the very earliest signs of change in this disease.
Despite growing clinical and neurobiological interest in the brain mechanisms that process emotion in music, these mechanisms remain incompletely understood. Patients with frontotemporal lobar degeneration (FTLD) frequently exhibit clinical syndromes that illustrate the effects of breakdown in emotional and social functioning. Here we investigated the neuroanatomical substrate for recognition of musical emotion in a cohort of 26 patients with FTLD (16 with behavioural variant frontotemporal dementia, bvFTD, 10 with semantic dementia, SemD) using voxel-based morphometry. On neuropsychological evaluation, patients with FTLD showed deficient recognition of canonical emotions (happiness, sadness, anger and fear) from music as well as faces and voices compared with healthy control subjects. Impaired recognition of emotions from music was specifically associated with grey matter loss in a distributed cerebral network including insula, orbitofrontal cortex, anterior cingulate and medial prefrontal cortex, anterior temporal and more posterior temporal and parietal cortices, amygdala and the subcortical mesolimbic system. This network constitutes an essential brain substrate for recognition of musical emotion that overlaps with brain regions previously implicated in coding emotional value, behavioural context, conceptual knowledge and theory of mind. Musical emotion recognition may probe the interface of these processes, delineating a profile of brain damage that is essential for the abstraction of complex social emotions.
Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration.However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined.Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29) and semantic variant primary progressive aphasia (svPPA; n = 15), relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification.Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry.The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere.The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification).DTI associations of impaired social cognition were more consistent than corresponding grey matter associations.These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes.The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.
The authors measured the rate of whole-brain atrophy over 6 months in 13 patients with early Huntington disease (HD) and seven matched controls. Patients with early HD had significantly increased rates of whole-brain atrophy vs controls (mean [SD] HD, 1.10 [0.88]%/year; controls, 0.26 [0.54]%/year). The measurement of cerebral change over short time periods (e.g., 6 months) may be relevant for trials designed to assess effects on neurodegeneration or atrophy.
ABSTRACT Objectives: Depression, anxiety, and apathy are the most commonly reported neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD). Understanding their prevalence in rarer dementias such as frontotemporal dementia (FTD), primary progressive aphasia (PPA), posterior cortical atrophy (PCA), young-onset AD (YOAD), and inherited dementias has implications for both clinical practice and research. In this study, we aimed to examine the current state of knowledge of the prevalence of these three NPS in less prevalent dementias. Design: We conducted a systematic review based on searches of EMBASE, PsycINFO, and PubMed up to September 2019. Results: 47 articles meeting inclusion criteria were identified. Depression, anxiety, and apathy were commonly reported across the phenotypes studied but their prevalence showed large variation between studies. Apathy showed the highest reported frequency in FTD (50–100% across studies), behavioral variant frontotemporal dementia (bvFTD) (73–100%), and YOAD (44–100%). Anxiety was frequently reported in FTD (0–100%) and bvFTD (19–63%). Depression showed the highest prevalence in FTD (7–69%) and YOAD (11–55%). Among the three variants of PPA, sv-PPA is the one most investigated (seven articles). Three or fewer articles were identified examining NPS in the remaining PPA variants, PCA, familial AD, and familial FTD. Inconsistency in the tools used to measure symptoms and small sample sizes were common methodological limitations. Conclusions: Future studies should consider the inclusion of larger sample sizes (e.g. through multicenter collaborations) and the use of harmonized protocols that include the combination of caregiver and patient-derived measures and symptom-specific questionnaires. More research is needed on the phenotype-specific barriers and facilitators for people living with dementia to successfully engage in self-reports of NPS.
Posterior Cortical Atrophy (PCA) involves deterioration of visual processing in contrast to relatively spared episodic memory function and insight. One form of early visual processing deficit that may be particularly prominent in PCA is visual crowding. Crowding involves the diminishing effect of nearby stimuli (‘flankers’) on identification of a target stimulus. Crowding effects are exacerbated by target-flanker proximity and visual similarity, and are reduced with target and flankers of opposite polarity. Under normal conditions, crowding is only detectable in normal peripheral vision. This study aimed to establish whether PCA patients exhibit prominent crowding even with centrally-presented flanked letter stimuli. 26 PCA, 17 typical AD and 14 healthy control participants were asked to name target letters presented in isolation or flanked by letters, shapes, numbers, and letters in same/reverse polarity. In each flanking condition, target letter identification was probed under two spatial conditions, condensed and spaced. There was no significant difference in naming accuracy between PCA, typical AD or controls for letters presented in isolation. However, PCA patients were consistently worse than both tAD patients and controls in terms of both naming accuracy and latency for flanked letter stimuli. The accuracy of tAD patients was not significantly different from that of controls in any flanker condition (see Table 1). Consistent with observations of crowding in normal peripheral vision, PCA performance was primarily determined by spacing but not flanker type, with condensed flankers leading to reduced speed and accuracy. Another characteristic of crowding observed in PCA task performance was an ameliorating effect of reverse polarity flankers on flanked letter identification. Voxel-based-morphometry analysis of the occipital region found an association between crowding performance and grey matter volume in the right collateral sulcus (see Figure 1). These findings demonstrate a grave inhibitory effect in the spatial vision of PCA patients that is of qualitative similarity to crowding. Future investigations might reveal how emerging crowding effects relate to visual dysfunction and particularly reading impairment in PCA.
Abstract Background Accelerated Forgetting (AF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). AF has been observed in presymptomatic carriers of mutations causing familial Alzheimer’s disease (AD) (doi:10.1016/S1474‐4422(17)30434‐9). To our knowledge, no studies have investigated whether AF is sensitive to preclinical AD pathology in cognitively‐normal older adults. Method Participants in the Insight 46 study, a sub‐study of the British 1946 birth cohort, completed baseline cognitive and neuroimaging assessments at age 69‐71. For the follow‐up visits (∼29 months later), we complemented the clinic visit assessments of Complex Figure Drawing and the Face‐Name test (FNAME‐12) with a 7‐day delay version administered by telephone (Figure 1). AF scores were calculated as the percentage of material retained after 7 days, relative to retention after 30 minutes. Cerebral atrophy between baseline and follow‐up was quantified from T1‐weighted MRI using the Brain Boundary Shift Integral (BBSI). β‐amyloid status at baseline (positive / negative) was determined from 18 F‐Florbetapir‐PET. As follow‐up assessments are still underway, preliminary interim analyses have been conducted based on 195 cognitively‐normal individuals with complete neuroimaging data (see Table 1 for characteristics). Multivariable regression models were used to investigate the effects of β‐amyloid status and BBSI on AF, and to explore interactions between these two predictors, adjusting for potential confounders including prospectively‐collected measures of childhood cognitive ability and education. Result Despite no statistically‐significant differences after a 30‐minute delay, β‐amyloid‐positive participants retained a lower percentage of Complex Figure material over 7 days (71.8% vs. 80.7%, p =0.010) and a trend to a lower percentage of FNAME‐12 material (69.4% vs. 77.2%, p = 0.083) (Table 2, Figure 2). Higher education predicted better retention of the Complex Figure. Among β‐amyloid‐positive participants only, greater cerebral atrophy predicted poorer retention of the Complex Figure (Table 2, Figure 3). Conclusion These results provide novel evidence of AF in cognitively‐normal β‐amyloid‐positive 72‐year‐olds. AF may be a sensitive outcome measure for therapeutic trials in preclinical AD, as it may reveal subtle memory decline at an earlier stage than traditional assessments. The interaction between β‐amyloid pathology and cerebral atrophy merits longitudinal investigation.
Purpose: There is limited research on the psychological impact of cancer for teenagers and young adults (TYAs) and the role of protective factors such as resilience. This study investigated associations between resilience and psychosocial outcomes in this group. Methods: Data were collected from TYAs (aged 16–24) who attended the TYA cancer clinic at Guy's Hospital between 2013 and 2021. Participants (N = 63) completed psychosocial questionnaires within 4 weeks of their treatment start date (T1) and again between 9 and 15 months later (T2). We used separate multivariable linear regression models to analyze associations of resilience (Brief Resilience Questionnaire) with outcomes measured at T2, including symptoms of depression (Patient Health Questionnaire [PHQ]-9), anxiety (Generalized Anxiety Disorder [GAD]-7), and subjective quality of life. Models were adjusted for age, gender, ethnicity, and T1 outcome assessments. Results: Higher resilience at T1 was associated with increased anxiety (β = 1.68; bootstrapped confidence interval [95% CI −0.28 to 3.19]), depression (β = 1.24; [−0.85 to 2.90]), and quality of life (5.76; [−0.88 to 15.60]). In contrast, an increase in resilience over time was associated with decreases in the same period in anxiety (β = −3.16; [−5.22 to −1.47]) and depression (β = −2.36, [−4.41 to −0.58]), and an increase in quality of life (β = 9.82, [−0.24 to 21.13]). Conclusion: Increases in resilience during cancer treatment were associated with reduced symptoms of depression and anxiety in TYAs. We discuss factors likely to influence these outcomes, the implications for psychosocial interventions in this population, and identify further research to explore the impact of other factors such as diagnosis and treatment type.
Abstract Background Age is the biggest risk factor for dementia, yet human brains do not age uniformly. The British 1946 birth cohort, the world’s longest continuously running birth cohort, provides a unique opportunity to assess these variations in biological ageing. So‐called ‘brain age’ is a biomarker of brain ageing, derived from machine‐learning analysis trained on a large sample of healthy brains (N=2001). Brain age has previously been related to cognitive ageing, physiological ageing and mortality risk (DOI: 10.1038/mp.2017.62), supporting the validity of this approach for assessing biological ageing. Method 502 participants in the Insight 46 study, all born during one week in 1946, completed baseline cognitive and neuroimaging assessments at age 69‐71. 468 underwent combined 18 florbetapir PET‐MRI scans, from which amyloid status (positive/negative), whole brain volume (WBV), total intracranial volume (TIV) and hippocampal volumes (HV) were derived. The T1‐weighted sequence was passed through the Brain‐age algorithm (https://github.com/james‐cole/brainageR), deriving brain predicted‐age (BPA) and brain‐predicted age difference (brain‐PAD; BPA minus chronological age). Serum neurofilament light (NFL) concentration was measured via Simoa immunoassay. A Preclinical Alzheimer’s Cognitive Composite Score (PACC) was calculated as a mean of z‐scores of the Mini‐mental state exam (MMSE), logical memory delayed recall, digit symbol substitution score and the Face‐Name test. Life course metrics (childhood cognitive scores, education level and Framingham Risk scores) were obtained from previous cohort assessments. Multivariate regression models were used to investigate whether life course metrics predict BPA, as well as whether NFL levels, brain volumes, or cognitive scores correlated with BPA, adjusting for chronological age. Result There was a significant difference between the 229 females assessed (mean BPA 65.2 years) compared with the 239 males assessed (mean BPA 70.7). BPA was independently associated with serum NFL concentration (p = 0.071) and inversely with whole brain volume (p < 0.001). Life course factors did not predict brain age. Conclusion The results showed a significant association of BPA, a cross‐sectional imaging metric, with a biochemical marker of neuronal damage (NFL) and sex. BPA has utility as an imaging metric that can integrate multiple modalities contributing to biological age, with potential as a predictive biomarker of cognitive decline.
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