Kirsi M. Kinnunen

Profiles of White Matter Tract Pathology in Frontotemporal Dementia

Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template‐based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimers disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimers disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimers disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co‐localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies. Hum Brain Mapp 35:4163–4179, 2014.

The pattern of atrophy in familial Alzheimer disease Volumetric MRI results from the DIAN study

Objective: To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers. Methods: A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume. Results: Significant differences in gray matter (p < 0.05, family-wise error–corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers. Conclusions: Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.

Degradation of cognitive timing mechanisms in behavioural variant frontotemporal dementia.

The current study examined motor timing in frontotemporal dementia (FTD), which manifests as progressive deterioration in social, behavioural and cognitive functions. Twenty-patients fulfilling consensus clinical criteria for behavioural variant FTD (bvFTD), 11 patients fulfilling consensus clinical criteria for semantic-variant primary progressive aphasia (svPPA), four patients fulfilling criteria for nonfluent/agrammatic primary progressive aphasia (naPPA), eight patients fulfilling criteria for Alzheimer׳s disease (AD), and 31 controls were assessed on both an externally- and self-paced finger-tapping task requiring maintenance of a regular, 1500 ms beat over 50 taps. Grey and white matter correlates of deficits in motor timing were examined using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). bvFTD patients exhibited significant deficits in aspects of both externally- and self-paced tapping. Increased mean inter-response interval (faster than target tap time) in the self-paced task was associated with reduced grey matter volume in the cerebellum bilaterally, right middle temporal gyrus, and with increased axial diffusivity in the right superior longitudinal fasciculus, regions and tracts which have been suggested to be involved in a subcortical–cortical network of structures underlying timing abilities. This suggests that such structures can be affected in bvFTD, and that impaired motor timing may underlie some characteristics of the bvFTD phenotype.

Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing

Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimers disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimers disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimers disease from the Dominantly Inherited Alzheimers Network (DIAN), an Alzheimers disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimers disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimers disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimers disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimers disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimers disease pathology (preclinical Alzheimers disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimers disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimers disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimers disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimers disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimers disease and ageing add to prior work arguing against Alzheimers disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimers disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimers disease pathology within targeted neural networks.

Brain imaging evidence of early involvement of subcortical regions in familial and sporadic Alzheimer's disease

Recent brain imaging studies have found changes in subcortical regions in presymptomatic autosomal dominant Alzheimers disease (ADAD). These regions are also affected in sporadic Alzheimers disease (sAD), but whether such changes are seen in early-stage disease is still uncertain. In this review, we discuss imaging studies published in the past 12 years that have found evidence of subcortical involvement in early-stage ADAD and/or sAD. Several papers have reported amyloid deposition in the striatum of presymptomatic ADAD mutation carriers, prior to amyloid deposition elsewhere. Altered caudate volume has also been implicated in early-stage ADAD, but findings have been variable. Less is known about subcortical involvement in sAD: the thalamus and striatum have been found to be atrophied in symptomatic patients, but their involvement in the preclinical phase remains unclear, in part due to the difficulties of studying this stage in sporadic disease. Longitudinal imaging studies comparing ADAD mutation carriers with individuals at high-risk for sAD may be needed to elucidate the significance of subcortical involvement in different AD clinical stages.

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

Identifying at what point atrophy rates first change in Alzheimers disease is important for informing design of presymptomatic trials.

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study.

Identifying at what point atrophy rates first change in Alzheimers disease is important for informing design of presymptomatic trials.

A FEASIBILITY AND ACCEPTABILITY RANDOMISED CONTROLLED TRIAL OF A MANUAL BASED INTERVENTION FOR SLEEP DIFFICULTIES IN PEOPLE LIVING WITH DEMENTIA (DREAMS-START)

brain, completed 5.860.6 24-hour periods of wrist actigraphy, the Mini-Mental State Examination (MMSE), and the Center for Epidemiological Studies Depression Scale (CES-D). Using functional principal component (fPC) analysis, we identified 10 uncorrelated patterns (fPCs) accounting for 90% of variability in actigraphic RARs. Participants’ fPC scores were included simultaneously in models as primary predictors. Outcomes were volumes of gray matter, white matter, ventricles, inferior temporal gyrus, hippocampus, and parahippocampal gyrus, all normalized to intracranial volume. We adjusted for age, sex, race, education, CES-D and MMSE. Results were rounded to the nearest 30 minutes. Results: Participants were aged 72.9 611.5 years, 56.0% women, and 28.7% racial/ethnic minorities. fPC1 represented the average 24-hour RAR pattern across all subjects, in which activity sharply increased at 6am, peaked at 8:30am, then slowly decreased until 9pm, when it decreased sharply until 6am. Participants with higher fPC1 scores had greater white matter volume (p1⁄40.009) and smaller ventricles (p1⁄40.005). Other patterns were linked to lower brain volumes. For example, higher fPC4 (reflecting higher activity from 4:30-8am and lower activity from 8-12:30pm) and higher fPC8 scores (representing an “ultradian” pattern, with repeated cycles of high-to-low activity within a day) were linked to lower inferior temporal gyrus volume (p<0.008 for both); fPC4 was also linked to lower hippocampal volume (p1⁄40.047). Finally, higher fPC10 scores (representing an ultradian pattern distinct from fPC8) were associated with lower parahippocampal gyrus (p1⁄40.023) and greater ventricular volume (p1⁄40.001). Conclusions: In cognitively normal older adults, atypical RARs are associated with lower brain volumes, including in regions affected early in AD. Further research is needed on RARs as modifiable contributors to, or markers and predictors of preclinical neurodegeneration.

RESEARCHING DEMENTIA-RELATED SLEEP PROBLEMS USING ACTI-WATCHES: PRELIMINARY INSIGHTS FROM THE DREAMS START STUDY

Very mild Mild Moderate Severe Age range 60-69 70-79 80-89 90+ SLEEP PROBLEMS USING ACTIWATCHES: PRELIMINARY INSIGHTS FROM THE DREAMS START STUDY Brendan Hallam*, Kirsi M. Kinnunen*, Lucy A. Webster, Penny Rapaport, Claudia Cooper, Julie Barber, Rossana Horsley, James Pickett, Simon D. Kyle, Colin A. Espie, Gill Livingston, Division of Psychiatry, Faculty of Brain Sciences, University College London, London, United Kingdom; Department of Statistical Sciences, Faculty of Mathematical & Physical Sciences, University College London, United Kingdom; Alzheimer’s Society Volunteer Network, London, United Kingdom; Alzheimer’s Society, London, United Kingdom; Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. *equal contributions. Contact e-mail: b.hallam@ucl.ac.uk

[Accepted Manuscript] Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study.

Identifying at what point atrophy rates first change in Alzheimers disease is important for informing design of presymptomatic trials.