Non-verbal episodic memory deficits in primary progressive aphasias are highly predictive of underlying amyloid pathology

Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer’s disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases

Naming treatment in semantic and logopenic variant PPA

Primary progressive aphasia (PPA) is an acquired impairment of language caused by neurodegenerative disease affecting language regions in the brain. Unlike aphasia caused by stroke, the language impairments in PPA gradually worsen over time as atrophy spreads. Current consensus criteria for diagnosis identify three clinical variants, each of which is associated with a different pathological entity: a semantic variant, with verbal and nonverbal semantic deficits; a logopenic variant, with anomia and phonological working memory problems; and a nonfluent variant, with agrammatism and/or apraxia of speech (Gorno-Tempini et al., 2011; Gorno-Tempini et al., 2004)

Divergent longitudinal propagation of white matter degradation in logopenic and semantic variants of primary progressive aphasia

Background: Clinico-pathological distinction of primary progressive aphasia (PPA) can be challenging at clinic presentation. In particular, cross-sectional neuroimaging signatures across the logopenic (lvPPA) and semantic (svPPA) variants are difficult to establish, with longitudinal profiles showing greater divergence. Objective: Assess longitudinal propagation of white matter degradation in lvPPA and svPPA to determine disease progression over time, and whether this reflects distinct underlying pathology. Method: A cohort of 27 patients with dementia (12 lvPPA; 15 svPPA) and 12 healthy controls were assessed at baseline and 1-year follow-up on the Addenbrooke’s Cognitive Examination-Revised and Sydney Language Battery. Diffusion weighted images were collected at both time-points and analyzed for longitudinal white matter change using DTI-TK and TBSS. Results: LvPPA patients showed a significant decline in naming and repetition, over 1 year, while svPPA patients declined in naming and comprehension. Longitudinal imaging revealed widespread bilateral degradation of white matter tracts in lvPPA over a 1-year period with early involvement of the left posterior inferior longitudinal fasciculus (ILF). SvPPA demonstrated focal left lateralized white matter degradation involving the uncinate fasciculus (UF) and anterior ILF, propagating to the right UF with disease progression. Conclusions: LvPPA and svPPA cohorts showed distinct longitudinal cognitive and white matter profiles. We propose differences in multi-centric and focal white matter dysfunction in lvPPA and svPPA, respectively, reflect underlying pathological differences. The clinical relevance of white matter degradation and mechanisms underlying disease propagation are discussed

Clinical, anatomical and pathological features in the three variants of primary progressive aphasia : a review

Primary progressive aphasias (PPA) are neurodegenerative diseases clinically characterized by an early and relatively isolated language impairment. Three main clinical variants, namely the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA) have been described, each with specific linguistic/cognitive deficits, corresponding anatomical and most probable pathological features. Since the discovery and the development of diagnostic criteria for the PPA variants by the experts in the field, significant progress has been made in the understanding of these diseases. This review aims to provide an overview of the literature on each of the PPA variant in terms of their clinical, anatomical and pathological features, with a specific focus on recent findings. In terms of clinical advancements, recent studies have allowed a better characterization and differentiation of PPA patients based on both their linguistic and non-linguistic profiles. In terms of neuroimaging, techniques such as diffusion imaging and resting-state fMRI have allowed a deeper understanding of the impact of PPA on structural and functional connectivity alterations beyond the well-defined pattern of regional gray matter atrophy. Finally, in terms of pathology, despite significant advances, clinico-pathological correspondence in PPA remains far from absolute. Nonetheless, the improved characterization of PPA has the potential to have a positive impact on the management of patients. Improved reliability of diagnoses and the development of reliable in vivo biomarkers for underlying neuropathology will also be increasingly important in the future as trials for etiology-specific treatments become available

The neural correlates of verbal and nonverbal semantic processing deficits in neurodegenerative disease

Objective—To investigate the neural correlates of verbal and non-verbal semantic processing in neurodegenerative disease. Background—Semantic memory is often impaired in neurodegenerative disease. Neuropsychological and functional neuroimaging studies suggest that the semantic processing of verbal and non-verbal stimuli may depend on partially distinct brain networks. Methods—We examined this possibility using voxel-based morphometry to correlate performance on verbal and non-verbal versions of a semantic association task with regional gray matter atrophy in 144 individuals with a variety of neurodegenerative diseases. Results—Results showed that, regardless of stimulus type, semantic processing correlated with atrophy in both temporal lobes. In addition, material-specific correlations were found in left temporal regions for verbal stimuli and the right fusiform gyrus for non-verbal stimuli. Conclusions—These results provide evidence for a differential role of the left and right hemispheres in the extraction of semantic information from verbal and pictorial representations. Areas in the right inferior temporal lobe may be necessary to access structural descriptions of visually presented object

Phonological processing in primary progressive aphasia

Primary progressive aphasia (PPA) is a debilitating condition wherein speech and language deteriorate as a result of neurodegenerative disease. Three variants of PPA are now recognized, each of which shows a unique constellation of speech-language deficits and pattern of underlying atrophy in the brain (Gorno-Tempini et al., 2011). The variants include a nonfluent/agrammatic type (nfvPPA), characterized by syntactic and motor speech deficits and fronto-insular atrophy in the left hemisphere. The semantic variant (svPPA) shows degradation of semantic knowledge in the context of anterior and inferior temporal lobe atrophy (left hemisphere greater than right). Finally, the more recently characterized logopenic variant (lvPPA) shows impairments in naming and repetition that are thought to be phonological in nature. This variant, associated with atrophy of temporoparietal regions in the left hemisphere, has also been referred to as the “phonological” variant of PPA due to observed deficits on tasks that require phonological storage (i.e., the “phonological loop”) and to the presence of phonological paraphasias in connected speech (Gorno-Tempini et al., 2008). Impaired phonological processing has been considered a unique feature of the logopenic variant of PPA, however, phonological skills have not been thoroughly characterized across the three variants. Recent models of the functional neuroanatomy of language propose two pathways by which speech is processed in the brain (Hickok & Poeppel, 2007). A dorsal pathway involving temporoparietal and posterior frontal structures is thought to be involved in mapping phonological representations onto articulatory representations. A ventral pathway located in the middle and inferior temporal lobes is considered crucial for mapping phonological representations onto lexical-semantic representations. Both the dorsal and ventral streams emanate from a common cortical region in posterior, superior temporal cortex/sulcus that appears critical to the mental representation of phonology. We investigated phonological processing in PPA, with the goal of identifying whether patterns of performance in the different variants support this functional-anatomical framework. Based on our knowledge of the locus of anatomical damage in the subtypes of PPA, we hypothesized that patients with damage to dorsal route structures (nonfluent and logopenic variants) would show greater impairment on phonological processing tasks, whereas patients with damage to ventral route structures (semantic variant) would show relative preservation of phonological abilities

Detecting clinical change with the CDR-FTLD:differences between FTLD and AD dementia

Objective: To investigate the psychometric properties of the Clinical Dementia Scale—frontotemporal lobar degeneration (CDR-FTLD) psychometric properties using Rasch analysis and its sensitivity distinguishing disease progression between FTLD and Alzheimer's disease (AD).  Methods: Of 603 consecutive patients from the National Alzheimer Coordinating Center dataset (FTLD = 350; AD = 253), 120 FTLDs were included in a Rasch analysis to verify CDR-FTLD psychometric properties; 483 (FTLD = 230; AD = 253) were included to analyse disease progression, with 195 (FTLD = 82; AD = 113) followed-up (24 months).  Results: The CDR-FTLD demonstrated good consistency, construct and concurrent validity and correlated well with mini-mental state examination (MMSE) and disease duration (ps < 0.05). At baseline, FTLD showed greater dementia severity than AD after matched for MMSE and disease duration (p < 0.001). Independent Rasch analyses demonstrated different patterns of progression for FTLD and AD in terms of the domains initially and then subsequently affected with disease progression. At follow-up, although MMSE showed significant changes (p < 0.05), these were greater on the CDR-FTLD (p < 0.001).  Conclusion: The CDR-FTLD satisfactorily measures dementia severity and change in FTLD, distinguishing disease progression between FTLD and AD, with clear implications for care, prognosis and future clinical trials. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd

Interpersonal prosodic correlation in frontotemporal dementia.

Communication accommodation describes how individuals adjust their communicative style to that of their conversational partner. We predicted that interpersonal prosodic correlation related to pitch and timing would be decreased in behavioral variant frontotemporal dementia (bvFTD). We predicted that the interpersonal correlation in a timing measure and a pitch measure would be increased in right temporal FTD (rtFTD) due to sparing of the neural substrate for speech timing and pitch modulation but loss of social semantics. We found no significant effects in bvFTD, but conversations including rtFTD demonstrated higher interpersonal correlations in speech rate than healthy controls

Findings of Impaired Hearing in Patients With Nonfluent/Agrammatic Variant Primary Progressive Aphasia.

Importance: Despite being characterized as a disorder of language production, nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) is frequently associated with auditory symptoms. However, to our knowledge, peripheral auditory function has not been defined in this condition. Objective: To assess peripheral hearing function in individuals with nfvPPA compared with healthy older individuals and patients with Alzheimer disease (AD). Design, Setting, and Participants: This cross-sectional single-center study was conducted at the Dementia Research Centre of University College London between August 2015 and July 2018. A consecutive cohort of patients with nfvPPA and patients with AD were compared with healthy control participants. No participant had substantial otological or cerebrovascular disease; all eligible patients fulfilling diagnostic criteria and able to comply with audiometry were included. Main Outcomes and Measures: We measured mean threshold sound levels required to detect pure tones at frequencies of 500, 1000, 2000, 4000, and 6000 Hz in the left and right ears separately; these were used to generate better-ear mean and worse-ear mean composite hearing threshold scores and interaural difference scores for each participant. All analyses were adjusted for participant age. Results: We studied 19 patients with nfvPPA (9 female; mean [SD] age, 70.3 [9.0] years), 20 patients with AD (9 female; mean [SD] age, 69.4 [8.1] years) and 34 control participants (15 female; mean [SD] age, 66.7 [6.3] years). The patients with nfvPPA had significantly higher scores than control participants on better-ear mean scores (patients with nfvPPA: mean [SD], 36.3 [9.4] decibels [dB]; control participants: 28.9 [7.3] dB; age-adjusted difference, 5.7 [95% CI, 1.4-10.0] dB; P = .01) and worse-ear mean scores (patients with nfvPPA: 42.2 [11.5] dB; control participants: 31.7 [8.1] dB; age-adjusted difference, 8.5 [95% CI, 3.6-13.4] dB; P = .001). The patients with nfvPPA also had significantly higher better-ear mean scores than patients with AD (patients with AD: mean [SD] 31.1 [7.5] dB; age-adjusted difference, 4.8 [95% CI, 0.0-9.6] dB; P = .048) and worse-ear mean scores (patients with AD: mean [SD], 33.8 [8.2] dB; age-adjusted difference, 7.8 [95% CI, 2.4-13.2] dB; P = .005). The difference scores (worse-ear mean minus better-ear mean) were significantly higher in the patients with nfvPPA (mean [SD], 5.9 [5.2] dB) than control participants (mean [SD], 2.8 [2.2] dB; age-adjusted difference, 2.8 [95% CI, 0.9-4.7] dB; P = .004) and patients with AD (mean [SD], 2.8 [2.1] dB; age-adjusted difference, 3.0 [95% CI, 0.9-5.1] dB; P = .005). Conclusions and Relevance: In this study, patients with nfvPPA performed worse on pure-tone audiometry than healthy older individuals or patients with AD, and the difference was not attributable to age or general disease factors. Cases of nfvPPA were additionally associated with increased functional interaural audiometric asymmetry. These findings suggest conjoint peripheral afferent and more central regulatory auditory dysfunction in individuals with nfvPPA.The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the Alzheimer’s Society (grant AS-PG-16-007 [Dr Warren]), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, the University College London Leonard Wolfson Experimental Neurology Centre (grant PR/ylr/18575), an Action on Hearing Loss–Dunhill Medical Trust Pauline Ashley Fellowship (grant PA23_Hardy [Dr Hardy]), a Medical Research Council PhD Studentship (Ms Bond), a Medical Research Council Clinician Scientist Fellowship (Dr Rohrer), an Association of British Neurologists Clinical Research Training Fellowship (Dr Johnson), Wolfson Foundation Clinical Research Fellowships (Drs Marshall and Sivasathiaseelan), and the Wellcome Trust (grant 091673/Z/10/Z [Dr Warren])

Multimodal Cuing of Autobiographical Memory in Semantic Dementia

OBJECTIVE: Individuals with semantic dementia (SD) have impaired autobiographical memory (AM), but the extent of the impairment has been controversial. According to one report (Westmacott, Leach, Freedman, & Moscovitch, 2001), patient performance was better when visual cues were used instead of verbal cues; however, the visual cues used in that study (family photographs) provided more retrieval support than do the word cues that are typically used in AM studies. In the present study, we sought to disentangle the effects of retrieval support and cue modality. METHOD: We cued AMs of 5 patients with SD and 5 controls with words, simple pictures, and odors. Memories were elicited from childhood, early adulthood, and recent adulthood; they were scored for level of detail and episodic specificity. RESULTS: The patients were impaired across all time periods and stimulus modalities. Within the patient group, words and pictures were equally effective as cues (Friedman test; χ² = 0.25, p = .61), whereas odors were less effective than both words and pictures (for words vs. odors, χ² = 7.83, p = .005; for pictures vs. odors, χ² = 6.18, p = .01). There was no evidence of a temporal gradient in either group (for patients with SD, χ² = 0.24, p = .89; for controls, χ² \u3c 2.07, p = .35). CONCLUSIONS: Once the effect of retrieval support is equated across stimulus modalities, there is no evidence for an advantage of visual cues over verbal cues. The greater impairment for olfactory cues presumably reflects degeneration of anterior temporal regions that support olfactory memory