Retinal phenotyping of variants of Alzheimer's disease using ultra-widefield retinal images

Background: Posterior cortical atrophy (PCA) is the most common atypical variant of Alzheimer's disease (AD). Changes associated with PCA in the brain affect the visual cortex, but little is known about retinal changes in PCA. In this study, we explored retinal phenotypic variations in typical AD (tAD) and PCA. Methods: Retinal phenotyping was carried out on ultra-widefield (UWF) images of 69 control, 24 tAD, and 25 PCA participants. Results: Individuals with tAD (odds ratio [OR] = 2.76 [confidence interval (CI):1.24 to 6.10], P = .012) and PCA (OR = 3.40 [CI:1.25 to 9.22], P = .016) were more likely phenotyped as hard drusen. tAD (OR = 0.34 [CI:0.12 to 0.92], P = .035) were less likely to have soft drusen compared to control. Almost 3-fold increase in reticular pseudodrusen formation in tAD (OR = 2.93 [CI:1.10 to 7.76], P = .030) compared to control was estimated. Discussion: Studying the peripheral retina may contribute to a better understanding of differences in retinal phenotypes of different AD variants

Disease Knowledge Transfer across Neurodegenerative Diseases

We introduce Disease Knowledge Transfer (DKT), a novel technique for transferring biomarker information between related neurodegenerative diseases. DKT infers robust multimodal biomarker trajectories in rare neurodegenerative diseases even when only limited, unimodal data is available, by transferring information from larger multimodal datasets from common neurodegenerative diseases. DKT is a joint-disease generative model of biomarker progressions, which exploits biomarker relationships that are shared across diseases. Our proposed method allows, for the first time, the estimation of plausible, multimodal biomarker trajectories in Posterior Cortical Atrophy (PCA), a rare neurodegenerative disease where only unimodal MRI data is available. For this we train DKT on a combined dataset containing subjects with two distinct diseases and sizes of data available: 1) a larger, multimodal typical AD (tAD) dataset from the TADPOLE Challenge, and 2) a smaller unimodal Posterior Cortical Atrophy (PCA) dataset from the Dementia Research Centre (DRC), for which only a limited number of Magnetic Resonance Imaging (MRI) scans are available. Although validation is challenging due to lack of data in PCA, we validate DKT on synthetic data and two patient datasets (TADPOLE and PCA cohorts), showing it can estimate the ground truth parameters in the simulation and predict unseen biomarkers on the two patient datasets. While we demonstrated DKT on Alzheimer's variants, we note DKT is generalisable to other forms of related neurodegenerative diseases. Source code for DKT is available online: https://github.com/mrazvan22/dkt.Comment: accepted at MICCAI 2019, 13 pages, 5 figures, 2 table

Functional neuroanatomy of spatial sound processing in Alzheimer's disease.

Deficits of auditory scene analysis accompany Alzheimer's disease (AD). However, the functional neuroanatomy of spatial sound processing has not been defined in AD. We addressed this using a "sparse" fMRI virtual auditory spatial paradigm in 14 patients with typical AD in relation to 16 healthy age-matched individuals. Sound stimulus sequences discretely varied perceived spatial location and pitch of the sound source in a factorial design. AD was associated with loss of differentiated cortical profiles of auditory location and pitch processing at the prescribed threshold, and significant group differences were identified for processing auditory spatial variation in posterior cingulate cortex (controls > AD) and the interaction of pitch and spatial variation in posterior insula (AD > controls). These findings build on emerging evidence for altered brain mechanisms of auditory scene analysis and suggest complex dysfunction of network hubs governing the interface of internal milieu and external environment in AD. Auditory spatial processing may be a sensitive probe of this interface and contribute to characterization of brain network failure in AD and other neurodegenerative syndromes

Developing poetry as a research methodology with rarer forms of dementia: Four research protocols

People living with rarer forms of dementia tend to have progressive cognitive symptoms affecting skills other than memory and/ or onset before the age of 65 years. They are often misdiagnosed and due to symptom profile or age of onset, do not usually fit well with care pathways designed for older people with typical Alzheimer’s disease or vascular dementia. Although the arts have been increasingly used as interventions to support people with dementia, there is very little attention given to rarer dementia forms in arts and health research or practice. The objective of the present international study seeks to systematically explore four diverse forms of poetry writing within this population through virtual and in-person small and large group formats. Our approach includes investigating poetic processes as methodology through the lens of an arts-based methodological approach in order to explore how poems construct knowledge and a felt experience. We will also use more traditional qualitative approaches to understand the experience of writing, reading and listening to poetry as an intervention that can be used with different rarer forms of dementia. To the best of our knowledge, this will be the first study to explore poetry using multiple research protocols. The results will have implications for methodology development, co-constructed poetic inquiry and multiple opportunities for involving poetry in supporting people with dementia and family members

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

A clinical test for visual crowding

Crowding is a major limitation of visual perception. Because of crowding, a simple object, like a letter, can only be recognized if clutter is a certain critical spacing away. Crowding is only weakly associated with acuity. The critical spacing of crowding is lowest in the normal fovea, and grows with increasing eccentricity in peripheral vision. Foveal crowding is more prominent in certain patient groups, including those with strabismic amblyopia and apperceptive agnosia. Crowding may lessen with age during childhood as reading speed increases. The range of crowding predicts much of the slowness of reading in children with developmental dyslexia. There is tantalizing evidence suggesting that the critical spacing of crowding indicates neural density (participating neurons per square deg) in the visual cortex. Thus, for basic and applied reasons, it would be very interesting to measure foveal crowding clinically in children and adults with normal and impaired vision, and to track the development of crowding during childhood. While many labs routinely measure peripheral crowding as part of their basic research in visual perception, current tests are not well suited to routine clinical testing because they take too much time, require good fixation, and are mostly not applicable to foveal vision. Here we report a new test for clinical measurement of crowding in the fovea. It is quick and accurate, works well with children and adults, and we expect it to work well with dementia patients as well. The task is to identify a numerical digit, 1-9, using a new “Pelli” font that is identifiable at tiny width (0.02 deg, about 1 minarc, in normal adult fovea). This allows quick measurement of the very small (0.05 deg) critical spacing in the normal adult fovea, as well as with other groups that have higher critical spacing. Preliminary results from healthy adults and children are presented

Phonemic restoration in Alzheimer's disease and semantic dementia: a preliminary investigation

Phonemic restoration—perceiving speech sounds that are actually missing—is a fundamental perceptual process that ‘repairs’ interrupted spoken messages during noisy everyday listening. As a dynamic, integrative process, phonemic restoration is potentially affected by neurodegenerative pathologies, but this has not been clarified. Here, we studied this phenomenon in 5 patients with typical Alzheimer’s disease and 4 patients with semantic dementia, relative to 22 age-matched healthy controls. Participants heard isolated sounds, spoken real words and pseudowords in which noise bursts either overlaid a consonant or replaced it; a tendency to hear replaced (missing) speech sounds as present signified phonemic restoration. All groups perceived isolated noises normally and showed phonemic restoration of real words, most marked in Alzheimer’s patients. For pseudowords, healthy controls showed no phonemic restoration, while Alzheimer’s patients showed marked suppression of phonemic restoration and patients with semantic dementia contrastingly showed phonemic restoration comparable to real words. Our findings provide the first evidence that phonemic restoration is preserved or even enhanced in neurodegenerative diseases, with distinct syndromic profiles that may reflect the relative integrity of bottom-up phonological representation and top-down lexical disambiguation mechanisms in different diseases. This work has theoretical implications for predictive coding models of language and neurodegenerative disease and for understanding cognitive ‘repair’ processes in dementia. Future research should expand on these preliminary observations with larger cohorts

Misdiagnosed and misunderstood’: Insights into rarer forms of dementia through a stepwise approach to co-constructed research poetry

This study investigated co-constructed research poetry as a way to understand the lived experiences of people affected by rarer dementia and as a means to use poetry to convey those experiences to healthcare professionals. Using mixed methods, 71 people living with rarer dementia and care-partners (stakeholders) contributed to co-constructing 27 poems with professional poets; stakeholders’ verbatim words were analysed with descriptive qualitative analysis. Stakeholders were also surveyed and interviewed about their participation. Healthcare professionals (n = 93) were surveyed to elicit their responses to learning through poetry and its acceptability as a learning tool. Poems conveyed a shared narrative of different aspects of lived experience, often owing to atypical symptoms, misunderstandings by professionals, lack of support pathways, and a continuous struggle to adapt. Stakeholder surveys indicated it was a valuable experience to both co-create and respond to the poems, whilst group interviews revealed people’s experiences of the research poetry were characterised by reflection on lived experience, curiosity and exploration. Healthcare professionals’ responses reinforced poetry’s capacity to stimulate cognitive and affective learning specific to rare dementia support and prompt both empathy and critical thinking in practice. As the largest poetry-based study that we are aware of, this novel accessible approach of creating group poems yielded substantial information about the experiences and needs of those affected by rarer dementia and how poetry can contribute to healthcare education and training

Music models aberrant rule decoding and reward valuation in dementia.

Aberrant rule- and reward-based processes underpin abnormalities of socio-emotional behaviour in major dementias. However, these processes remain poorly characterized. Here we used music to probe rule decoding and reward valuation in patients with frontotemporal dementia (FTD) syndromes and Alzheimer's disease (AD) relative to healthy age-matched individuals. We created short melodies that were either harmonically resolved ('finished') or unresolved ('unfinished'); the task was to classify each melody as finished or unfinished (rule processing) and rate its subjective pleasantness (reward valuation). Results were adjusted for elementary pitch and executive processing; neuroanatomical correlates were assessed using voxel-based morphometry. Relative to healthy older controls, patients with behavioural variant FTD showed impairments of both musical rule decoding and reward valuation, while patients with semantic dementia showed impaired reward valuation but intact rule decoding, patients with AD showed impaired rule decoding but intact reward valuation and patients with progressive non-fluent aphasia performed comparably to healthy controls. Grey matter associations with task performance were identified in anterior temporal, medial and lateral orbitofrontal cortices, previously implicated in computing diverse biological and non-biological rules and rewards. The processing of musical rules and reward distils cognitive and neuroanatomical mechanisms relevant to complex socio-emotional dysfunction in major dementias

Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer’s disease

Amyloid imaging studies of presymptomatic familial Alzheimer’s disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer’s disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical grey matter regions of interest, with increased fractional anisotropy in bilateral putamen. We propose that axonal injury may be an early event in presymptomatic Alzheimer’s disease, causing an initial fall in axial and mean diffusivity, which then increases with loss of axonal density. The selective degeneration of long-coursing white matter tracts, with relative preservation of short interneurons, may account for the increase in fractional anisotropy that is seen in the thalamus and caudate presymptomatically. It may be owing to their dense connectivity that imaging changes are seen first in the thalamus and striatum, which then progress to involve other regions in a vulnerable neuronal network