Lucy L. Russell

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.

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.

Plasma tau is increased in frontotemporal dementia

Background Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations in GRN, MAPT and C9orf72 being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life. Methods This study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in either MAPT (n=12), GRN (n=9) or C9orf72 (n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression. Results Higher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only the MAPT group had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration. Conclusion Plasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only in MAPT mutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.

Cardiac responses to viewing facial emotion differentiate frontotemporal dementias

To establish proof‐of‐principle for the use of heart rate responses as objective measures of degraded emotional reactivity across the frontotemporal dementia spectrum, and to demonstrate specific relationships between cardiac autonomic responses and anatomical patterns of neurodegeneration.

Auditory conflict and congruence in frontotemporal dementia.

ABSTRACT Impaired analysis of signal conflict and congruence may contribute to diverse socio‐emotional symptoms in frontotemporal dementias, however the underlying mechanisms have not been defined. Here we addressed this issue in patients with behavioural variant frontotemporal dementia (bvFTD; n = 19) and semantic dementia (SD; n = 10) relative to healthy older individuals (n = 20). We created auditory scenes in which semantic and emotional congruity of constituent sounds were independently probed; associated tasks controlled for auditory perceptual similarity, scene parsing and semantic competence. Neuroanatomical correlates of auditory congruity processing were assessed using voxel‐based morphometry. Relative to healthy controls, both the bvFTD and SD groups had impaired semantic and emotional congruity processing (after taking auditory control task performance into account) and reduced affective integration of sounds into scenes. Grey matter correlates of auditory semantic congruity processing were identified in distributed regions encompassing prefrontal, parieto‐temporal and insular areas and correlates of auditory emotional congruity in partly overlapping temporal, insular and striatal regions. Our findings suggest that decoding of auditory signal relatedness may probe a generic cognitive mechanism and neural architecture underpinning frontotemporal dementia syndromes. HIGHLIGHTSSocioemotional changes in frontotemporal dementia may reflect altered signal decoding.To address this, we varied semantic and emotional signal relatedness in sound scenes.Frontotemporal dementia patients had impaired semantic and emotional scene decoding.These deficits correlated with atrophy of distributed cortico‐subcortical regions.Signal processing approaches may help deconstruct complex dementia phenotypes.

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.

Retained capacity for perceptual learning of degraded speech in primary progressive aphasia and Alzheimer’s disease

BackgroundProcessing of degraded speech is a promising model for understanding communication under challenging listening conditions, core auditory deficits and residual capacity for perceptual learning and cerebral plasticity in major dementias.MethodsWe compared the processing of sine-wave-degraded speech in 26 patients with primary progressive aphasia (non-fluent, semantic, and logopenic variants), 10 patients with typical Alzheimer’s disease and 17 healthy control subjects. Participants were required to identify sine-wave words that were more predictable (three-digit numbers) or less predictable (place names). The change in identification performance within each session indexed perceptual learning. Neuroanatomical associations of degraded speech processing were assessed using voxel-based morphometry.ResultsPatients with non-fluent and logopenic progressive aphasia and typical Alzheimer’s disease showed impaired identification of sine-wave numbers, whereas all syndromic groups showed impaired identification of sine-wave place names. A significant overall identification advantage for numbers over place names was shown by patients with typical Alzheimer’s disease, patients with semantic progressive aphasia and healthy control participants. All syndromic groups showed spontaneous perceptual learning effects for sine-wave numbers. For the combined patient cohort, grey matter correlates were identified across a distributed left hemisphere network extending beyond classical speech-processing cortices.ConclusionsThese findings demonstrate resilience of auditory perceptual learning capacity across dementia syndromes, despite variably impaired perceptual decoding of degraded speech and reduced predictive integration of semantic knowledge. This work has implications for the neurobiology of dynamic sensory processing and plasticity in neurodegenerative diseases and for development of novel biomarkers and therapeutic interventions.