Chris J.D. Hardy

Hearing and dementia.

Hearing deficits associated with cognitive impairment have attracted much recent interest, motivated by emerging evidence that impaired hearing is a risk factor for cognitive decline. However, dementia and hearing impairment present immense challenges in their own right, and their intersection in the auditory brain remains poorly understood and difficult to assess. Here, we outline a clinically oriented, symptom-based approach to the assessment of hearing in dementias, informed by recent progress in the clinical auditory neuroscience of these diseases. We consider the significance and interpretation of hearing loss and symptoms that point to a disorder of auditory cognition in patients with dementia. We identify key auditory characteristics of some important dementias and conclude with a bedside approach to assessing and managing auditory dysfunction in dementia.

The Language Profile of Behavioral Variant Frontotemporal Dementia

Background The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. Objective We aimed to quantify the extent of language deficits in this patient group. Methods We assessed a cohort of patients with bvFTD (n=24) in relation to patents with semantic variant primary progressive aphasia (svPPA; n=14), nonfluent variant primary progressive aphasia (nfvPPA; n=18) and healthy age-matched individuals (n=24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients’ brain magnetic resonance images. Results Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. Conclusions bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.

Primary progressive aphasia: a clinical approach

The primary progressive aphasias are a heterogeneous group of focal ‘language-led’ dementias that pose substantial challenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including ‘clinical pearls’ that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic ‘roadmap’. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers.

Functional neuroanatomy of speech signal decoding in primary progressive aphasias

The pathophysiology of primary progressive aphasias remains poorly understood. Here, we addressed this issue using activation fMRI in a cohort of 27 patients with primary progressive aphasia (nonfluent, semantic, and logopenic variants) versus 15 healthy controls. Participants listened passively to sequences of spoken syllables in which we manipulated 3-key auditory speech signal characteristics: temporal regularity, phonemic spectral structure, and pitch sequence entropy. Relative to healthy controls, nonfluent variant patients showed reduced activation of medial Heschls gyrus in response to any auditory stimulation and reduced activation of anterior cingulate to temporal irregularity. Semantic variant patients had relatively reduced activation of caudate and anterior cingulate in response to increased entropy. Logopenic variant patients showed reduced activation of posterior superior temporal cortex to phonemic spectral structure. Taken together, our findings suggest that impaired processing of core speech signal attributes may drive particular progressive aphasia syndromes and could index a generic physiological mechanism of reduced computational efficiency relevant to all these syndromes, with implications for development of new biomarkers and therapeutic interventions.

Donepezil enhances understanding of degraded speech in Alzheimer's disease.

Auditory dysfunction under complex, dynamic listening conditions is a clinical hallmark of Alzheimers disease (AD) but challenging to measure and manage. Here, we assessed understanding of sinewave speech (a paradigm of degraded speech perception) and general cognitive abilities in 17 AD patients, before and following a 10 mg dose of donepezil. Relative to healthy older individuals, patients had impaired sinewave speech comprehension that was selectively ameliorated by donepezil. Our findings demonstrate impaired perception of degraded speech in AD but retained perceptual learning capacity that can be harnessed by acetylcholinesterase inhibition, with implications for designing communication interventions and acoustic environments in dementia.

Impaired Interoceptive Accuracy in Semantic Variant Primary Progressive Aphasia

Background Interoception (the perception of internal bodily sensations) is strongly linked to emotional experience and sensitivity to the emotions of others in healthy subjects. Interoceptive impairment may contribute to the profound socioemotional symptoms that characterize frontotemporal dementia (FTD) syndromes, but remains poorly defined. Methods Patients representing all major FTD syndromes and healthy age-matched controls performed a heartbeat counting task as a measure of interoceptive accuracy. In addition, patients had volumetric MRI for voxel-based morphometric analysis, and their caregivers completed a questionnaire assessing patients’ daily-life sensitivity to the emotions of others. Results Interoceptive accuracy was impaired in patients with semantic variant primary progressive aphasia relative to healthy age-matched individuals, but not in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Impaired interoceptive accuracy correlated with reduced daily-life emotional sensitivity across the patient cohort, and with atrophy of right insula, cingulate, and amygdala on voxel-based morphometry in the impaired semantic variant group, delineating a network previously shown to support interoceptive processing in the healthy brain. Conclusion Interoception is a promising novel paradigm for defining mechanisms of reduced emotional reactivity, empathy, and self-awareness in neurodegenerative syndromes and may yield objective measures for these complex symptoms.

Behavioural and neuroanatomical correlates of auditory speech analysis in primary progressive aphasias

BackgroundNon-verbal auditory impairment is increasingly recognised in the primary progressive aphasias (PPAs) but its relationship to speech processing and brain substrates has not been defined. Here we addressed these issues in patients representing the non-fluent variant (nfvPPA) and semantic variant (svPPA) syndromes of PPA.MethodsWe studied 19 patients with PPA in relation to 19 healthy older individuals. We manipulated three key auditory parameters—temporal regularity, phonemic spectral structure and prosodic predictability (an index of fundamental information content, or entropy)—in sequences of spoken syllables. The ability of participants to process these parameters was assessed using two-alternative, forced-choice tasks and neuroanatomical associations of task performance were assessed using voxel-based morphometry of patients’ brain magnetic resonance images.ResultsRelative to healthy controls, both the nfvPPA and svPPA groups had impaired processing of phonemic spectral structure and signal predictability while the nfvPPA group additionally had impaired processing of temporal regularity in speech signals. Task performance correlated with standard disease severity and neurolinguistic measures. Across the patient cohort, performance on the temporal regularity task was associated with grey matter in the left supplementary motor area and right caudate, performance on the phoneme processing task was associated with grey matter in the left supramarginal gyrus, and performance on the prosodic predictability task was associated with grey matter in the right putamen.ConclusionsOur findings suggest that PPA syndromes may be underpinned by more generic deficits of auditory signal analysis, with a distributed cortico-subcortical neuraoanatomical substrate extending beyond the canonical language network. This has implications for syndrome classification and biomarker development.

Profiles in paint: contrasting responses to a common artistic exercise by people with different dementias

Abstract Paintings could offer insight into the varied experiences of people with different dementias. In this project, a single exercise – the painting of a group of objects in still-life – was used to capture artistic production in four artists with different diagnoses of dementia and four healthy artists. Whilst quantitative studies provide important insights into the neuroanatomical supports for artistic actions, autonomous art exercises may yield deeper understanding of the individual creative experience in the context of neurodegenerative disease.

Agnosia for bird calls

ABSTRACT The cognitive organisation of nonverbal auditory knowledge remains poorly defined. Deficits of environmental sound as well as word and visual object knowledge are well‐recognised in semantic dementia. However, it is unclear how auditory cognition breaks down in this disorder and how this relates to deficits in other knowledge modalities. We had the opportunity to study a patient with a typical syndrome of semantic dementia who had extensive premorbid knowledge of birds, allowing us to assess the impact of the disease on the processing of auditory in relation to visual and verbal attributes of this specific knowledge category. We designed a novel neuropsychological test to probe knowledge of particular avian characteristics (size, behaviour [migratory or nonmigratory], habitat [whether or not primarily water‐dwelling]) in the nonverbal auditory, visual and verbal modalities, based on a uniform two‐alternative‐forced‐choice procedure. The patients performance was compared to healthy older individuals of similar birding experience. We further compared his performance on this test of bird knowledge with his knowledge of familiar human voices and faces. Relative to healthy birder controls, the patient showed marked deficits of bird call and bird name knowledge but relatively preserved knowledge of avian visual attributes and retained knowledge of human voices and faces. In both the auditory and visual modalities, his knowledge of the avian characteristics of size and behaviour was intact whereas his knowledge of the associated characteristic of habitat was deficient. This case provides further evidence that nonverbal auditory knowledge has a fractionated organisation that can be differentially targeted in semantic dementia. HIGHLIGHTSThe cognitive organisation of auditory semantics is poorly understood.We assessed multimodal avian knowledge in a birder with semantic dementia.The patient had auditory (but not visual) agnosia for birds versus healthy birders.Auditory knowledge of avian attributes and human voices were differentially affected.This case illuminates the fractionated organisation of nonverbal auditory knowledge.

CAN EYETRACKING METRICS PROVIDE INSIGHT INTO THE DIAGNOSIS OF DIFFERENT DEMENTIA TYPES? A SPATIAL ANTICIPATION TASK

BDNF polymorphisms on the net change in Memory (Tab 1). In particular, subjects with Tallele of SOD2 and subjects with A allele of BDNF showed a lower decrease of visuospatial and memory domains respectively. SNPs and development of dementia and cognitive impairment: Bivariate analysis showed that among the 176 subjects APOE4 carriers, 14 (8%) developed dementia, and among the 789 non-carriers 35 (4,4%) developed dementia ( p1⁄40.055). Similarly, among the 576 subjects in the BDNF-GG group, 36 (6.3%) developed dementia, and among the 389 subject with BDNF-A allele, 13 (3.3%) developed dementia (p1⁄40.044). Logistic regression showed an increased likelihood of AD for APOE4, whereas the allele A of BDNF decreased the probability of overall dementia and non-aMCI. Conclusions: We found two SNPs (SOD2RS4880-T and BDNF-A) known to be less favorable to gene expression associated with less decline on specific cognitive domains. It has been postulated an age-modulated effect that can reverse the meaning of val/met polymorphism of BDNF (Erickson et al. 2008). APOE4 confirmed its role in development of AD.More epidemiological and experimental studies are needed to better understand the real meaning of these polymorphisms.