Progressive Aphasia Research Articles

A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia (MAINSTREAM): A Study Protocol.

Primary Progressive Aphasia (PPA) is a syndrome due to different neurodegenerative disorders selectively disrupting language functions. PPA specialist care is underdeveloped. There are very few specialists (neurologists, psychiatrists, neuropsychologists, and speech therapists) and few hospital- or community-based services dedicated to the diagnosis and continuing care of people with PPA. Currently, healthcare systems struggle to provide adequate coverage of care that is too often fragmented, uncoordinated, and unresponsive to the needs of people with PPA and their families. Recently, attention has been gained by non-invasive brain stimulation techniques that allow a personalized treatment approach, such as transcranial Direct Current Stimulation (tDCS). The MAINSTREAM trial looks forward to introducing and evaluating therapeutic innovations such as tDCS coupled with language therapy in rehabilitation settings. A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia, MAINSTREAM (ID: 3430931) was registered in the clinicaltrials.gov database (identifier: NCT05730023) on 15 February 2023.

Expressive Prosody in Patients With Focal Anterior Temporal Neurodegeneration.

Progressive focal anterior temporal lobe (ATL) neurodegeneration has been historically called semantic dementia. More recently, semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) have been linked with predominant left and right ATL neurodegeneration, respectively. Nonetheless, clinical tools for an accurate diagnosis of sbvFTD are still lacking. Expressive prosody refers to the modulation of pitch, loudness, tempo, and quality of voice used to convey emotional and linguistic information and has been linked to bilateral but right-predominant frontotemporal functioning. Changes in expressive prosody can be detected with semiautomated methods and could represent a useful diagnostic marker of socioemotional functioning in sbvFTD. Participants underwent a comprehensive neuropsychological and language evaluation and a 3T MRI at the University of California San Francisco. Each participant provided a verbal description of the picnic scene from the Western Aphasia Battery. The fundamental frequency (f0) range, an acoustic measure of pitch variability, was extracted for each participant. We compared the f0 range between groups and investigated associations with an informant-rated measure of empathy, a facial emotion labeling task, and gray matter (GM) volumes using voxel-based morphometry. Twenty-eight patients with svPPA, 18 with sbvFTD, and 18 healthy controls (HCs) were included. f0 range was significantly different across groups: patients with sbvFTD showed reduced f0 range in comparison with both patients with svPPA (mean difference of -1.4 ± 2.4 semitones; 95% CI -2.4 to -0.4]; p < 0.005) and HCs (mean difference of -1.9 ± 3.0 semitones; 95% CI -3.0 to -0.7]; p < 0.001). A higher f0 range was correlated with a greater informant-rated empathy (r = 0.355; p ≤ 0.05), but not facial emotion labeling. Finally, the lower f0 range was correlated with lower GM volume in the right superior temporal gyrus, encompassing anterior and posterior portions (p < 0.05 FWE cluster corrected). Expressive prosody may be a useful clinical marker of sbvFTD. Reduced empathy is a core symptom in sbvFTD; the present results extend this to prosody, a core component of social interaction, at the intersection of speech and emotion. They also inform the long-standing debate on the lateralization of expressive prosody in the brain, highlighting the critical role of the right superior temporal lobe.

Perspective of Speech and Language Therapists in Turkey on Primary Progressive Aphasia

Primary progressive aphasia (PPA) is a neurodegenerative disease characterized by the insidious and progressive loss of speech and language skills. However, there is no standardized intervention method applied in patients with PPA. It was conducted a virtual survey of SLTs across Turkey, to collect information about the assessment, intervention and management of patients with PPA. A total of 285 SLTs participated the survey; 76.8% ( n = 219) of the respondents were female, 58.9% ( n = 168) were 1 to 2 years post graduation, 62.8% ( n = 179) of them were master’s degree, and 46% ( n = 131) were working in a rehabilitation center. All 285 participants included in the study stated that they did not create a therapy process for their clients with PPA and they performed the therapy processes applied in the classical aphasia treatment. Two hundred sixty-eight participants stated that they had more than six sessions with their clients, and 280 respondents. It is very important for all participants to plan functional interventions that require joint participation with the patient and their family/caregiver or friends, which will support communication and language and communication-oriented intervention. However, there is a need to develop specific evidence-based care pathways for people with PPA so that more efficient interventions can be made. Raising awareness among SLTs and other clinical service providers that rehabilitation is effective can increase the accessibility of interventions for individuals with PPA and lead to a more robust support system for individuals affected by PPA.

Automated analysis of written language in the three variants of primary progressive aphasia.

Despite the important role of written language in everyday life, abnormalities in functional written communication have been sparsely investigated in primary progressive aphasia. Prior studies have analysed written language separately in each of the three variants of primary progressive aphasia-but have rarely compared them to each other or to spoken language. Manual analysis of written language can be a time-consuming process. We therefore developed a program that quantifies content units and total units in written or transcribed language samples. We analysed written and spoken descriptions of the Western Aphasia Battery picnic scene, based on a predefined content unit corpus. We calculated the ratio of content units to units as a measure of content density. Our cohort included 115 participants (20 controls for written, 20 controls for spoken, 28 participants with nonfluent variant primary progressive aphasia, 30 for logopenic variant and 17 for semantic variant). Our program identified content units with a validity of 99.7% (95%CI 99.5-99.8). All patients wrote fewer units than controls (P < 0.001). Patients with the logopenic variant (P = 0.013) and the semantic variant (0.004) wrote fewer content units than controls. The content unit-to-unit ratio was higher in the nonfluent and semantic variants than controls (P = 0.019), but no difference in the logopenic variant (P = 0.962). Participants with the logopenic (P < 0.001) and semantic (P = 0.04) variants produced fewer content units in written compared to spoken descriptions. All variants produced fewer units in written samples compared to spoken (P < 0.001). However, due to a relatively smaller decrease in written content units, we observed a larger content unit-to-unit ratio in writing over speech (P < 0.001). Written and spoken content units (r = 0.5, P = 0.009) and total units (r = 0.64, P < 0.001) were significantly correlated in patients with nonfluent variant, but this was not the case for logopenic or semantic. Considering all patients with primary progressive aphasia, fewer content units were produced in those with greater aphasia severity (Progressive Aphasia Severity Scale Sum of Boxes, r = -0.24, P = 0.04) and dementia severity (Clinical Dementia Rating scale Sum of Boxes, r = -0.34, P = 0.004). In conclusion, we observed reduced written content in patients with primary progressive aphasia compared to controls, with a preference for content over non-content units in patients with the nonfluent and semantic variants. We observed a similar 'telegraphic' style in both language modalities in patients with the nonfluent variant. Lastly, we show how our program provides a time-efficient tool, which could enable feedback and tracking of writing as an important feature of language and cognition.

“I felt like I had been put on the shelf and forgotten about” – lasting lessons about the impact of COVID-19 on people affected by rarer dementias

BackgroundThe public health measures imposed in many countries to contain the spread of COVID-19 resulted in significant suspensions in the provision of support and care for people with dementia. The negative effects of these measures have been extensively reported. However, little is known about the specific impact on people with young onset, non-memory-led and inherited dementias. This group may have experienced different challenges compared to those with late onset dementia given their non-memory phenotypes and younger age. We explored the impact of the first COVID-19 lockdown on people living with familial Alzheimer’s disease, behavioural variant frontotemporal dementia, familial frontotemporal dementia, dementia with Lewy bodies, posterior cortical atrophy and primary progressive aphasia and their carers in the UK and their self-reported strategies for coping.MethodsThis was a mixed methods study. An online survey was administered to people with dementia and family carers recruited via Rare Dementia Support. Free-text responses were analysed using framework analysis to identify key issues and themes.Results184 carers and 24 people with dementia completed the survey. Overall, people with dementia experienced worsening of cognitive symptoms (70%), ability to do things (62%), well-being (57%) and changes to medication (26%) during lockdown. Carers reported a reduction in the support they received (55%) which impacted their own mental health negatively. Qualitative analysis of free-text responses shed light on how the disruption to routines, changes to roles and responsibilities, and widespread disconnection from friends, family and health and social care support varied according to phenotype. These impacts were exacerbated by a more general sense that precious time was being lost, given the progressive nature of dementia. Despite significant challenges, respondents demonstrated resilience and resourcefulness in reporting unexpected positives and strategies for adapting to confinement.ConclusionsThis study has highlighted the specific impacts of the COVID-19 restrictions on people with young onset, non-memory-led and inherited dementias, including behavioural variant frontotemporal dementia, primary progressive aphasia and posterior cortical atrophy, and their carers. The specific challenges faced according to diagnosis and the self-reported strategies speak to the importance of – and may inform the development of – tailored support for these underrepresented groups more generally.Visual abstract

Composite Indices of the Color-Picture Version of Boston Naming Test Have Better Discriminatory Power: Reliability and Validity in a Chinese Sample with Diverse Neurodegenerative Diseases.

The Boston Naming Test (BNT) is the most widely used measure to assess anomia. However, it has been criticized for failing to differentiate the underlying cognitive process of anomia. We validated the color-picture version of BNT (CP-BNT) in a sample with diverse neurodegenerative dementia diseases (NDDs). We also verified the differential ability of the composite indices of CP-BNT across NDDs groups. The present study included Alzheimer's disease (n = 132), semantic variant primary progressive aphasia (svPPA, n = 53), non-svPPA (n = 33), posterior cortical atrophy (PCA, n = 35), and normal controls (n = 110). We evaluated psychometric properties of CP-BNT for the spontaneous naming (SN), the percentage of correct responses on semantic cuing and word recognition cuing (% SC, % WR). Receiver operating characteristic analysis was used to examine the discriminatory power of SN alone and the composite indices (SN, % SC, and % WR). The CP-BNT had sufficient internal consistency, good convergent, divergent validity, and criterion validity. Different indices of CP-BNT demonstrated distinct cognitive underpinnings. Category fluency was the strongest predictor of SN (β= 0.46, p < 0.001). Auditory comprehension tests highly associated with % WR (Sentence comprehension: β= 0.22, p = 0.001; Word comprehension: β= 0.20, p = 0.001), whereas a lower visuospatial score predicted % SC (β= -0.2, p = 0.001). Composite indices had better predictability than the SN alone when differentiating between NDDs, especially for PCA versus non-svPPA (area under the curve increased from 63.9% to 81.2%). The CP-BNT is a highly linguistically relevant test with sufficient reliability and validity. Composite indices could provide more differential information beyond SN and should be used in clinical practice.

Atypical forms of Alzheimer's disease: patients not to forget.

The aim of this paper is to summarize the latest work on neuroimaging in atypical Alzheimer's disease (AD) patients and to emphasize innovative aspects in the clinic and research. The paper will mostly cover language (logopenic variant of primary progressive aphasia; lvPPA), visual (posterior cortical atrophy; PCA), behavioral (bvAD) and dysexecutive (dAD) variants of AD. MRI and PET can detect and differentiate typical and atypical AD variants, and novel imaging markers like brain iron deposition, white matter hyperintensities (WMH), cortical mean diffusivity, and brain total creatine can also contribute. Together, these approaches have helped to characterize variant-specific distinct imaging profiles. Even within each variant, various subtypes that capture the heterogeneity of cases have been revealed. Finally, in-vivo pathology markers have led to significant advances in the atypical AD neuroimaging field. Overall, the recent neuroimaging literature on atypical AD variants contribute to increase knowledge of these lesser-known AD variants and are key to generate atypical variant-specific clinical trial endpoints, which are required for inclusion of these patients in clinical trials assessing treatments. In return, studying these patients can inform the neurobiology of various cognitive functions, such as language, executive, memory, and visuospatial abilities.

Rare exonic variant affects GRN splicing and contributes to frontotemporal lobar degeneration

Heterozygous loss-of-function (LOF) mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. For most missense mutations, the contribution to FTLD is however unclear. We studied the pathogenicity of rare GRN missense mutations using patient biomaterials. We identified a new mutation in GRN, c.1178 A>C, in a patient with a diagnosis of primary progressive aphasia. Neuropathological examination of autopsied brain showed FTLD with TAR DNA-binding protein 43 (FTLD-TDP) type A pathology with concomitant Alzheimer’s disease pathology. Serum progranulin protein levels were reduced to levels comparable to known LOF mutations. The mutation is in the last codon of exon 10, in the splice donor sequence. Our data provide evidence that the mutation leads to aberrant splicing, resulting in a frameshift (p.(Glu393AlafsTer31)) and consequently nonsense-mediated mRNA decay. Our finding demonstrates that carefully examining sequencing data around splice sites is needed since this mutation was annotated as a missense mutation. Unraveling the pathogenicity of variants of unknown significance is important for clinical diagnosis and genetic counseling.

Potamkin Prize Winner Elucidates the Underpinnings of Both Primary Progressive Aphasia and Dyslexia

Potamkin Prize Winner Elucidates the Underpinnings of Both Primary Progressive Aphasia and Dyslexia

Altered within- and between-network functional connectivity in atypical Alzheimer's disease.

Posterior cortical atrophy and logopenic progressive aphasia are atypical clinical presentations of Alzheimer's disease. Resting-state functional connectivity studies have shown functional network disruptions in both phenotypes, particularly involving the language network in logopenic progressive aphasia and the visual network in posterior cortical atrophy. However, little is known about how connectivity differs both within and between brain networks in these atypical Alzheimer's disease phenotypes. A cohort of 144 patients was recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, USA, and underwent structural and resting-state functional MRI. Spatially preprocessed data were analysed to explore the default mode network and the salience, sensorimotor, language, visual and memory networks. The data were analysed at the voxel and network levels. Bayesian hierarchical linear models adjusted for age and sex were used to analyse within- and between-network connectivity. Reduced within-network connectivity was observed in the language network in both phenotypes, with stronger evidence of reductions in logopenic progressive aphasia compared to controls. Only posterior cortical atrophy showed reduced within-network connectivity in the visual network compared to controls. Both phenotypes showed reduced within-network connectivity in the default mode and sensorimotor networks. No significant change was noted in the memory network, but a slight increase in the salience within-network connectivity was seen in both phenotypes compared to controls. Between-network analysis in posterior cortical atrophy showed evidence of reduced visual-to-language network connectivity, with reduced visual-to-salience network connectivity, compared to controls. An increase in visual-to-default mode network connectivity was noted in posterior cortical atrophy compared to controls. Between-network analysis in logopenic progressive aphasia showed evidence of reduced language-to-visual network connectivity and an increase in language-to-salience network connectivity compared to controls. Findings from the voxel-level and network-level analysis were in line with the Bayesian hierarchical linear model analysis, showing reduced connectivity in the dominant network based on diagnosis and more crosstalk between networks in general compared to controls. The atypical Alzheimer's disease phenotypes were associated with disruptions in connectivity, both within and between brain networks. Phenotype-specific differences in connectivity patterns were noted in the visual network for posterior cortical atrophy and the language network for logopenic progressive aphasia.

Network anatomy in logopenic variant of primary progressive aphasia.

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.

Predicting Confrontation Naming in the Logopenic Variant of Primary Progressive Aphasia

ABSTRACT Background Naming difficulties are prominent and pervasive in the logopenic variant of primary progressive aphasia (lvPPA) and may reflect its underlying deficits in phonological processing. Importantly, some words appear to be more vulnerable to deterioration than others. We hypothesize that these differences can be explained, in part, by the unique psycholinguistic properties of words. Aims Our study investigated the role of psycholinguistic properties of words, along with their underlying psycholinguistic factors, in predicting confrontation naming performance in individuals with lvPPA. Methods & Procedures Naming accuracy data were collected from 14 individuals with lvPPA using the Boston Naming Test (BNT). For each test item, values were extracted for frequency, age of acquisition (AoA), familiarity, word length, phonological neighborhood density (PND), semantic neighborhood density (SND), arousal, and valence. We examined the effects of these psycholinguistic properties on naming accuracy using logistic regression analyses at the individual level and multiple linear regression analysis at the group level. Further, we performed mediation analyses to examine the mediating contributions of related psycholinguistic properties on naming accuracy. Finally, principal component analysis (PCA) was performed to extract fundamental factors of the psycholinguistic properties. These factor scores were entered into regression analyses to investigate their relative contribution to naming accuracy in lvPPA. Outcomes & Results Age of acquisition emerged as the strongest psycholinguistic predictor of naming accuracy in lvPPA at both the individual and group levels. The influence of AoA on naming accuracy was only partially mediated by frequency. Three principal psycholinguistic factors were extracted from the PCA. These were interpreted as “lexical-semantic usage”, “phonological complexity”, and “emotional intensity”. Results indicated that “lexical-semantic usage” and “emotional intensity” predicted naming performance at both the individual and group levels. Conclusions Age of acquisition has been associated with the phonological level in models of word naming. The observed psycholinguistic effects on naming accuracy are discussed in the context of phonological deficits in lvPPA and models of word naming.

Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

ObjectiveTo identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. ConclusionsLanguage deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials.

Distinct and shared neuropsychiatric phenotypes in FTLD-tauopathies.

Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau) commonly causes dementia syndromes that include primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD). Cognitive decline in PPA and bvFTD is often accompanied by debilitating neuropsychiatric symptoms. In 44 participants with PPA or bvFTD due to autopsy-confirmed FTLD-tau, we characterized neuropsychiatric symptoms at early and late disease stages and determined whether the presence of certain symptoms predicted a specific underlying FTLD-tauopathy. Participants completed annual research visits at the Northwestern University Alzheimer's Disease Research Center. All participants had an initial Global Clinical Dementia Rating (CDR) Scale score ≤ 2, and neuropsychiatric symptoms were evaluated via the Neuropsychiatric Inventory-Questionnaire (NPI-Q). We assessed the frequency of neuropsychiatric symptoms across all participants at their initial and final visits and performed logistic regression to determine whether symptoms predicted a specific FTLD-tau pathologic diagnosis. Across the FTLD-tau cohort, irritability and apathy were most frequently endorsed at initial and final visits, respectively, whereas psychosis was highly uncommon at both timepoints. Irritability at initial visit predicted greater odds of a 4-repeat compared to a 3-repeat tauopathy (OR = 3.95, 95% CI = 1.10-15.83, p < 0.05). Initial sleep disturbance predicted greater odds of progressive supranuclear palsy (PSP) compared to other FTLD-tau subtypes (OR = 10.68, 95% CI = 2.05-72.40, p < 0.01). Appetite disturbance at final evaluation predicted lower odds of PSP (OR = 0.15, 95% CI = 0.02-0.74, p < 0.05). Our findings suggest that characterization of neuropsychiatric symptoms can aid in the prediction of underlying FTLD-tauopathies. Given considerable pathologic heterogeneity underlying dementias, neuropsychiatric symptoms may be useful for differential diagnosis and treatment planning.

Apraxia of Speech in the Spontaneous Speech of Nonfluent/Agrammatic Primary Progressive Aphasia.

Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated. To assess the frequency of features of AOS in the spontaneous, connected speech of individuals with naPPA and to evaluate whether these features are associated with an underlying motor disorder such as corticobasal syndrome or progressive supranuclear palsy. We examined features of AOS in 30 patients with naPPA using a picture description task. We compared these patients to 22 individuals with behavioral variant frontotemporal dementia and 30 healthy controls. Each speech sample was evaluated perceptually for lengthened speech segments and quantitatively for speech sound distortions, pauses between and within words, and articulatory groping. We compared subgroups of naPPA with and without at least two features of AOS to assess the possible contribution of a motor impairment to speech production deficits. naPPA patients produced both speech sound distortions and other speech sound errors. Speech segmentation was found in 27/30 (90%) of individuals. Distortions were identified in 8/30 (27%) of individuals, and other speech sound errors occurred in 18/30 (60%) of individuals. Frequent articulatory groping was observed in 6/30 (20%) of individuals. Lengthened segments were observed rarely. There were no differences in the frequencies of AOS features among naPPA subgroups as a function of extrapyramidal disease. Features of AOS occur with varying frequency in the spontaneous speech of individuals with naPPA, independently of an underlying motor disorder.

An Update on Apraxia of Speech.

Apraxia of speech (AOS) is a motor speech disorder that has long been recognized to occur secondary to acute neurologic insults and, more recently, to neurodegenerative diseases as a harbinger for progressive supranuclear palsy and corticobasal syndrome. This article reviews recent findings regarding the clinic phenotypes of AOS, neuroimaging correlates, and the underlying disease processes. Two clinical subtypes of AOS map onto two underlying 4-repeat tauopathies. New imaging techniques have recently been applied to the study of progressive AOS. There is no data on the impact of behavioral intervention, although studies of nonfluent/agrammatic primary progressive aphasia that include patients with AOS suggest some benefit in speech intelligibility and maintenance. While recent findings suggest subtypes of AOS exist that are linked to molecular pathology and have important implications for disease progression, further research is needed to assess outcome of behavioral and other types of intervention.

Gaps in clinical research in frontotemporal dementia: A call for diversity and disparities-focused research.

Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.

Semantic variant Primary Progressive Aphasia: Additional semantic features in Chinese language users

AbstractBackgroundTo date, most literature on Primary Progressive Aphasia (PPA) has been based on English language users. Yet, there are more than 7,000 living languages worldwide with vast heterogeneities in their linguistic features. Contrary to English language, Chinese language is a classifier language in which it is grammatically mandatory to have classifiers present between numerals and nouns. In addition, Chinese characters typically have an abundance of homophones (i.e., words with same pronunciation but vary in orthography and meaning) and heteronyms (i.e., words with same orthography but vary in meaning and pronunciation). Chinese language users rely on semantic knowledge to identify the accurate classifiers, homophones, and heteronym pronunciations. Thus, we hypothesize that Chinese‐speaking semantic variant (sv) PPA patients have difficulties producing classifiers, homophones, and heteronyms.MethodTo assess classifier production, participants are presented with pictures of nouns. Participants are first tasked with producing noun‐specific classifiers spontaneously. If failed, they are presented with four classifiers to select. To evaluate homophone selection skills, participants are shown short sentences with one character/word removed. They are then tasked to complete the sentences by choosing one of the four homophones presented. For heteronym reading, participants are asked to read out loud Chinese compound words with heteronyms (e.g., “windmill” and “wind up”).ResultWe recruited 22 controls and 47 PPA individuals (12 svPPA, 10 nonfluent variant (nfv) PPA and 25 logopenic variant (lv) PPA). In classifier production test, svPPA and lvPPA patients produce fewer accurate classifiers (p&lt;0.0001, p = 0.001), with svPPA showing least improvement when presented with multiple choices (p = 0.003). In homophone selection test, svPPA and lvPPA scored lower than controls (p&lt;0.0001 and p = 0.007). For heteronym reading test, svPPA showed the lowest performance when tasked with reading heteronym characters (p = 0.001). Using voxel‐based morphometry, we noted that the ability to produce classifiers, read heteronyms and identify heteronyms are correlated with grey matter volumetric changes over the anterior portion of the left temporal lobe and fusiform gyri, brain regions associated with language semantic functions.ConclusionPPA symptomatology may vary across languages. Thus, studying PPA symptoms via a linguistically diverse approach potentially provides a more comprehensive understanding to the syndrome.

Tau‐PET imaging with 18F‐PI‐2620 reveals lateralized distribution of tau pathology in critical language regions in patients with early onset of Alzheimer’s Disease and patients with primary progressive aphasia

AbstractBackgroundLanguage disorders are frequent in patients in advanced and early stages of dementia (Goth &amp; Strøm, 2018) together with the deterioration of other cognitive domains (e.g., memory) (Taler &amp; Phillips, 2008). The first complaint in people with dementia often is language impairment, even preceding other cognitive declines (Ferris &amp; Farlow, 2013). Logopenic variant primary progressive aphasia (lvPPA) and non‐fluent/agrammatic variant PPA (nf/avPPA) are rare neurodegenerative disorders being language impairment the main feature (Gono‐Tempini, 2011). Both β‐amyloid (Aβ) and tau appear to occur in Alzheimer disease (AD). Moreover, Aβ and tau aggregates also represent the underlying pathology in lvPPA (Montembeault et al. 2018) while nf/avPPA resembles a pure tau‐pathology. The purpose of this study is to explore the distribution of tau‐pathology in critical language regions in patients with early‐onset AD (EOAD) and patients diagnosed with primary progressive aphasia (PPA).MethodEight participants (55‐77y): 4 with EOAD, 3 with lvPPA (these first seven patients additionally had a positive 18F‐Florbetaben Amyloid PET), 1 with nf/avPPA, and 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans with 18F‐PI‐2620 to examine the distribution of tau‐pathology in the following cortical language regions: inferior frontal gyrus (IFG), superior temporal gyrus (STG), supramarginal and angular gyrus (PL). Group differences in language regions were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.ResultCompared to HC, 3/4 patients with EOAD showed elevated levels of 18F‐PI‐2620 binding, mainly in the right IFG and IPL and left STG, while 3/4 patients with PPA (2 lvPPA and 1 nf/avPPA) showed left lateralized elevated uptake of 18F‐PI‐2620 in all language regions. All PPA patients showed increased binding of 18F‐PI‐2620 predominantly in the left parietal regions.ConclusionOur preliminary results reveal a lateralized distribution pattern of 18F‐PI‐2620 in language regions in patients with EOAD and particularly in those with PPA. These findings suggest that 18F‐PI‐2620 PET imaging is a promising tool to visualize tau aggregations in patients with EOAD and PPA. However, further studies are needed to confirm these preliminary results.

Distinct regional and hemispheric tau distributions in Primary Progressive Aphasia with neuropathologic Progressive Supranuclear Palsy: A stereological study

AbstractBackgroundPrimary Progressive Aphasia (PPA) is a dementia syndrome characterized by isolated and progressive impairment of language and focal atrophy of left‐hemispheric cortical regions. PPA presents with various underlying FTLD‐tauopathies such as Pick’s disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). This study investigated clinicopathologic concordance between the aphasic phenotype of PPA and regional distributions of PSP markers quantified in language‐related cortical areas and the dentate gyrus (DG) of the hippocampus—an area of interest due to intact memory exhibited in PPA. Another goal was to compare regional distributions of tau‐positive markers in PSP compared to CBD and PiD to identify differential susceptibility patterns across FTLD‐tauopathies.MethodParaffin‐embedded sections were stained immunohistochemically with AT‐8 to visualize neuronal tau inclusions and astrocytes containing phosphorylated tau in 8 right‐handed cases with PPA and autopsy‐confirmed PSP. Modified unbiased stereology was performed in bilateral middle frontal gyrus (MFG) and inferior parietal lobule (IPL), and left DG. A secondary analysis compared distributions of tau markers in cases with PiD (N = 6; tau‐positive inclusions) and CBD (N = 4; tau‐positive inclusions + astrocytic plaques). One‐way ANOVAs and students’ t‐tests were used to analyze distributions.ResultWithin the PSP group, there was significant left‐sided asymmetric predominance of tau‐positive neuronal inclusions and astrocytic tau in cortical areas; left MFG showed over double the total marker density vs right (3,490 vs 1,549 counts/mm3, respectively; p&lt;0.05). In PSP, there was significantly less tau‐positive inclusions and astrocytes in the DG relative to cortical regions, where the ratio of left‐sided dentate‐to‐cortical inclusions was ∼1:2. This was remarkably lower than dentate‐to‐cortical ratios of ∼2:1 in CBD and ∼3:1 in PiD (p&lt;0.01). Finally, PSP cases showed significantly greater astrocytic tau in cortical regions compared to CBD, by ∼100 fold in the left hemisphere (p&lt;0.01).ConclusionFindings from this stereological study of PPA with FTLD‐PSP show leftward cortical predominance of pathology concordant with the salience of the aphasic phenotype. Dentate predominance of pathology in PPA due to FTLD‐tau remains a mystery. The relative distribution of dentate‐to‐cortical tau pathology is different across FTLD‐tau species, offering insights into the selective vulnerability of distinct neuronal populations in neurodegenerative dementias.