Cristian E. Leyton

Subtypes of progressive aphasia: application of the international consensus criteria and validation using β-amyloid imaging

Primary progressive aphasia comprises a heterogeneous group of neurodegenerative conditions with diverse clinical profiles and underlying pathological substrates. A major development has been the publication of the recent International Consensus Criteria for the three major variants namely: semantic, non-fluent/agrammatic and logopenic. The logopenic variant is assumed to represent an atypical presentation of Alzheimer pathology although evidence for this is, at present, limited. The semantic and non-fluent/agrammatic variants are largely associated with frontotemporal lobar degeneration with TDP-43 and tau pathology, respectively. The applicability of the International Consensus Criteria to an unselected clinical sample is unknown and no agreed clinical evaluation scale on which to derive the diagnosis exists. We assessed 47 consecutive cases of primary progressive aphasic seen over a 3-year period in a specialist centre, using a newly developed progressive aphasia language scale. A subgroup of 30 cases underwent (11)C-labelled Pittsburgh Compound B positron emission tomography imaging, a putative biomarker of Alzheimers disease that detects β-amyloid accumulation, and they were compared with an age-matched group (n = 10) with typical, predominately amnestic Alzheimers disease. The application of an algorithm based on four key speech and language variables (motor speech disorders, agrammatism, single-word comprehension and sentence repetition) classified 45 of 47 (96%) of patients and showed high concordance with the gold standard expert clinical diagnosis based on the International Consensus Criteria. The level of neocortical β-amyloid burden varied considerably across aphasic variants. Of 13 logopenic patients, 12 (92%) had positive β-amyloid uptake. In contrast, one of nine (11%) semantic variant and two of eight (25%) non-fluent/agrammatic cases were positive. The distribution of β-amyloid across cortical regions of interest was identical in cases with the logopenic variant to that of patients with typical Alzheimers disease although the total load was lower in the aphasic cases. Impairments of sentence repetition and sentence comprehension were positively correlated with neocortical burden of β-amyloid, whereas impaired single-word comprehension showed a negative correlation. The International Consensus Criteria can be applied to the majority of cases with primary progressive aphasic using a simple speech and language assessment scale based upon four key variables. β-amyloid imaging confirms the higher rate of Alzheimer pathology in the logopenic variant and, in turn, the low rates in the other two variants. The study offers insight into the biological basis of clinical manifestations of Alzheimers disease, which appear topographically independent of β-amyloid load.

New criteria for frontotemporal dementia syndromes: clinical and pathological diagnostic implications

Objective To assess the impact of new clinical diagnostic criteria for frontotemporal dementia (FTD) syndromes, including primary progressive aphasias (PPA), on prior clinical diagnosis and to explore clinicopathological correlations. Methods 178 consecutive neuropathologically ascertained cases initially diagnosed with a FTD syndrome were collected through specialist programmes: the Cambridge Brain Bank, UK, and Sydney Brain Bank, Australia. 135 cases were reclassified using the revised diagnostic criteria into behavioural variant (bvFTD), semantic variant PPA (sv-PPA), non-fluent/agrammatic variant PPA (nfv-PPA) and logopenic variant PPA (lv-PPA). Pathological diagnoses included FTLD-tau, FTLD-TDP, FTLD-FUS, FTLD-UPS, FLTD-ni and Alzheimers disease (AD). Statistical analyses included χ2 tests, analyses of variance and discriminant statistics. Results Comparison of the original and revised diagnosis revealed no change in 90% of bvFTD and sv-PPA cases. By contrast, 51% of nfv-PPA cases were reclassified as lv-PPA, with apraxia of speech and sentence repetition assisting in differentiation. Previous patterns of pathology were confirmed, although more AD cases occurred in FTD syndromes (10% bvFTD, ∼15% sv-PPA and ∼30% nfv-PPA) than expected. AD was the dominant pathology (77%) of lv-PPA. Discriminant analyses revealed that object agnosia, phonological errors and neuropsychiatric features differentiated AD from FTLD. Conclusions This study provides pathological validation that the new criteria assist with separating PPA cases with AD pathology into the new lv-PPA syndrome and found that a number of diagnostic clinical features (disinhibition, food preferences and naming) did not assist in discriminating the different FTD syndromes.

Cognitive decline in logopenic aphasia: more than losing words.

Objective: To track cognitive and language changes over time in patients with logopenic (lv-PPA) and semantic (sv-PPA) variants of primary progressive aphasia (PPA). Methods: Thirteen consecutive patients with lv-PPA and 11 patients with sv-PPA underwent yearly evaluation for a mean of 3 years. Nineteen patients (11 lv-PPA, 8 sv-PPA) had Pittsburgh compound B PET scans. Outcome variables included the Mini-Mental State Examination, Addenbrookes Cognitive Examination–revised (ACE-R) with its 5 cognitive subscores, and 3 language tasks based on single word processing. Mixed-models regressions were used to estimate the differential rate of decline between cohorts. Results: Despite equivalent level of baseline impairment, the lv-PPA cohort showed more rapid and generalized cognitive decline that involved nonverbal domains, with the majority of cases meeting criteria for dementia within 12 months. By contrast, cognitive changes in the sv-PPA cohort were slower and remained confined to verbally mediated tasks. Conclusions: Patients with lv-PPA are on the cusp of global dementia that typically develops quite rapidly, contrasting with the long period of circumscribed semantic impairment seen in patients with sv-PPA. The ACE-R appears capable of monitoring decline, which is relevant to therapeutic trials.

Tracking the progression of social cognition in neurodegenerative disorders

Background and purpose Behavioural-variant frontotemporal dementia (bvFTD) and Alzheimers disease (AD) patients experience behavioural and emotion recognition alterations, yet understanding of how socioemotional processing is affected with disease progression is minimal. Additionally, evidence suggests that bvFTD patients with limited brain atrophy on neuroimaging at presentation (bvFTD-la) have a more benign course than those with marked atrophy (bvFTD-ma). Longitudinal investigation of these patients, however, is lacking. Methods We investigated general cognition, emotion recognition and sarcasm detection in 20 bvFTD (8 with limited brain atrophy) and 17 AD patients longitudinally and used mixed models analyses to determine the level and rates of decline across groups over time. Results At baseline, all patient groups performed worse than controls on general cognition and emotion recognition measures. The bvFTD-ma group showed significant impairment on the sarcasm detection task compared with controls. Longitudinally, an overall effect of time was present for general cognition (p<0.001); however, the rate of decline did not differ across groups. Trends for interactions between time and diagnosis were observed for both emotion recognition tasks (p=0.055; p=0.062), with the bvFTD-ma group declining more rapidly than AD or bvFTD-la groups. On the sarcasm detection task, the bvFTD-ma and AD patients declined, whereas bvFTD-la patients remained stable over time (p=0.002). Conclusions Tasks of sarcasm detection represent a clinically useful tool to differentiate between bvFTD and AD at baseline. Furthermore, tasks of socioemotional functioning can track progression within bvFTD and identify bvFTD patients more likely to show a faster rate of decline.

Logopenic and Nonfluent Variants of Primary Progressive Aphasia Are Differentiated by Acoustic Measures of Speech Production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r 2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA.

Degradation of emotion processing ability in corticobasal syndrome and Alzheimer’s disease

Disturbed emotion processing and difficulty with social interactions are present to variable degrees in dementia. They are characteristic features of frontotemporal dementia, whereas these deficits tend to be mild in Alzheimers disease, reflecting the different patterns of neurodegeneration seen in these disorders. Corticobasal syndrome is an atypical parkinsonian disorder clinically and pathologically related to frontotemporal dementia. Corticobasal syndrome typically presents as a motor disturbance, although cognitive and behavioural changes are now recognized. Pathological changes are found in frontoparietal cortical regions and in the basal ganglia; regions that are heavily involved in emotion processing. Despite the overlap with frontotemporal dementia and the observed regions of brain atrophy, emotion processing has not been systematically explored in corticobasal syndrome. This study aimed to (i) comprehensively examine emotion processing in corticobasal syndrome in comparison to Alzheimers disease, to determine whether emotion processing deficits exist in this syndrome, beyond those seen in Alzheimers disease; and (ii) identify the neural correlates underlying emotion processing in corticobasal syndrome and Alzheimers disease. Sixteen patients with corticobasal syndrome, 18 patients with Alzheimers disease and 22 matched healthy control subjects were assessed on a comprehensive battery of face and emotion processing tasks. Behavioural analyses revealed deficits in both basic face processing and high-level emotion processing tasks in patients with corticobasal syndrome. Notably, the emotion processing disturbance persisted even after controlling for face processing deficits. In contrast, patients with Alzheimers disease were impaired on high-level complex and cognitively demanding emotion recognition tasks (Ekman 60, The Awareness of Social Inference Test) only. Neuroimaging analyses using FreeSurfer revealed that emotion processing deficits in corticobasal syndrome were associated with basal ganglia volume loss as well as cortical thinning of the left paracentral gyrus/precuneus region. In Alzheimers disease, however, emotion processing deficits were associated with atrophy in a different set of brain regions, including the right cingulate and the bilateral insulae, as well as the hippocampi, right amygdala and nucleus accumbens bilaterally. Our results demonstrate that patients with corticobasal syndrome experience widespread deficits in emotion processing, and these deficits are related to changes in brain regions known to be crucial for emotion processing. These findings have important clinical implications for the treatment and management of these patients.

Phonologic errors as a clinical marker of the logopenic variant of PPA

Objective: To disentangle the clinical heterogeneity of nonsemantic variants of primary progressive aphasia (PPA) and to identify a coherent linguistic-anatomical marker for the logopenic variant of PPA (lv-PPA). Methods: Key speech and language features of 14 cases of lv-PPA and 18 cases of nonfluent/agrammatic variant of PPA were systematically evaluated and scored by an independent rater blinded to diagnosis. Every case underwent a structural MRI and a Pittsburgh compound B (PiB)-PET scan, a putative biomarker of Alzheimer disease. Key speech and language features that showed association with the PiB-PET status were entered into a hierarchical cluster analysis. The linguistic features and patterns of cortical thinning in each resultant cluster were analyzed. Results: The cluster analysis revealed 3 coherent clinical groups, each of which was linked to a specific PiB-PET status. The first cluster was linked to high PiB retention and characterized by phonologic errors and cortical thinning focused on the left superior temporal gyrus. The second and third clusters were characterized by grammatical production errors and motor speech disorders, respectively, and were associated with low PiB brain retention. A fourth cluster, however, demonstrated nonspecific language deficits and unpredictable PiB-PET status. Conclusions: These findings suggest that despite the clinical and pathologic heterogeneity of nonsemantic variants, discrete clinical syndromes can be distinguished and linked to specific likelihood of PiB-PET status. Phonologic errors seem to be highly predictive of high amyloid burden in PPA and can provide a specific clinical marker for lv-PPA.

The Neural Basis of Logopenic Progressive Aphasia

Logopenic progressive aphasia (LPA) is defined clinically by impairments of naming and sentence repetition. The relationship between these impairments and their neural basis has, however, not yet been determined. We aimed to localize cortical thinning associated with naming and repetition deficits using cortical thickness measurements. Consecutive LPA cases (n = 15) were matched with healthy controls (n = 16). All LPA cases underwent general cognitive testing and language assessment using the progressive aphasia language scale. Word retrieval and verbal short-term memory, the core cognitive processes involved in LPA, were assessed using visual confrontation naming and forward digit-span tasks. Cortical thickness was estimated vertex-by-vertex using Freesurfer. The pattern of cortical thinning for the LPA group as well as the location of cortical thinning linked to the impairment of each core cognitive process was estimated using general linear models. LPA cases showed extensive left-sided cortical thinning in which the temporo-parietal junction had the greatest involvement. Impaired naming was associated with cortical thinning of the supramarginal gyrus (BA 40), while reduced digit-span score, regarded as a surrogate marker for sentence repetition, was correlated with thinning of the left superior temporal gyrus (BA 22 and 42). These results suggest that the core manifestations of LPA emerge from the damage to segregated and non-overlapping cortical regions typically affected in this focal presentation of Alzheimers disease.

Application of Addenbrooke’s Cognitive Examination to Diagnosis and Monitoring of Progressive Primary Aphasia

Background/Aims: Primary progressive aphasia (PPA) comprises 2 main variants: semantic dementia (SD) and progressive nonfluent aphasia (PNFA). Addenbrooke’s Cognitive Examination (ACE) has become widely used for the diagnosis of dementias. Less information, however, is available about its ability to detect and monitor changes in cognition in PPA. We aimed to analyse the sensitivity and longitudinal changes of ACE scores in 2 subforms of PPA. Methods: We included 63 SD and 45 PNFA cases, all of whom had at least 2 assessments. Sensitivity levels, annualised rates of change and difference in scores over time on repeated ACE measurements were calculated. Results: A cut-off of 88 points detected 95% of the PNFA and SD cases. Longitudinal analysis showed an average annual decline of 10 points per year, with no significant difference between groups. Conclusion: The ACE is a useful tool for detecting and tracking the evolution of PPA.

Disease-specific patterns of cortical and subcortical degeneration in a longitudinal study of Alzheimer's disease and behavioural-variant frontotemporal dementia.

Background: Clinical differentiation between Alzheimers disease (AD) and behavioural‐variant frontotemporal dementia (bvFTD) is challenging due to overlapping clinical features at presentation. Whilst diagnostic criteria for both disorders incorporate evidence of frontal and temporal cortical atrophy, understanding of the progression of atrophy in these disorders is limited. This study aimed to elucidate common and disease‐specific progressive changes in cortical and subcortical brain structures in AD and bvFTD. Methods: Forty‐one AD, 37 bvFTD and 33 healthy controls underwent baseline MRI and of these longitudinal follow‐up was obtained for 20 AD and 20 bvFTD (1 to 4 years). A total of 87 AD and 70 bvFTD consecutive scans were included in the study. The trajectories of progression in cortical and subcortical structures were identified with FreeSurfer and linear mixed effect modelling. Results: The results uncovered cortical and subcortical disease‐specific trajectories of neurodegeneration in AD and bvFTD. Specifically, direct comparisons between patient groups revealed that over time AD showed greater cortical atrophy in the inferior parietal and posterior cingulate cortex than bvFTD. Conversely, bvFTD patients showed greater atrophy in the striatum than AD over time. Conclusions: These results indicate that atrophy in the posterior cingulate and the striatum diverges with disease progression in these dementia syndromes and may represent a potential diagnostic biomarker for tracking rates of progression of AD and bvFTD. These findings may help inform future drug trials by identifying appropriate outcome measures to quantify drug efficacy and their ability to modulate disease progression over time. HighlightsWe report divergent patterns of cortical and subcortical involvement in AD and bvFTD with disease progression.AD show more atrophy in cortical regions (e.g., posterior cingulate) than in subcortical structures over time.The reverse pattern is seen in bvFTD, with greater involvement of subcortical striatal structures with disease progression.This paper demonstrates the utility of linear mixed effects models to examine disease‐specific patterns of neurodegeneration.