Logopenic Variant Primary Progressive Aphasia Research Articles

Symptom-based staging for logopenic variant primary progressive aphasia.

Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

More than a piece of cake: Noun classifier processing in primary progressive aphasia.

Clinical understanding of primary progressive aphasia (PPA) has been primarily derived from Indo-European languages. Generalizing certain linguistic findings across languages is unfitting due to contrasting linguistic structures. While PPA patients showed noun classes impairments, Chinese languages lack noun classes. Instead, Chinese languages are classifier language, and how PPA patients manipulate classifiers is unknown. We included 74 native Chinese speakers (22 controls, 52 PPA). For classifier production task, participants were asked to produce the classifiers of high-frequency items. In a classifier recognition task, participants were asked to choose the correct classifier. Both semantic variant (sv) PPA and logopenic variant (lv) PPA scored significantly lower in classifier production task. In classifier recognition task, lvPPA patients outperformed svPPA patients. The classifier production scores were correlated to cortical volume over left temporal and visual association cortices. This study highlights noun classifiers as linguistic markers to discriminate PPA syndromes in Chinese speakers. Noun classifier processing varies in the different primary progressive aphasia (PPA) variants. Specifically, semantic variant PPA (svPPA) and logopenic variant PPA (lvPPA) patients showed significantly lower ability in producing specific classifiers. Compared to lvPPA, svPPA patients were less able to choose the accurate classifiers when presented with choices. In svPPA, classifier production score was positively correlated with gray matter volume over bilateral temporal and left visual association cortices in svPPA. Conversely, classifier production performance was correlated with volumetric changes over left ventral temporal and bilateral frontal regions in lvPPA. Comparable performance of mass and count classifier were noted in Chinese PPA patients, suggesting a common cognitive process between mass and count classifiers in Chinese languages.

Auditory naming is impaired in posterior cortical atrophy and early-onset Alzheimer's disease.

Visual naming ability reflects semantic memory retrieval and is a hallmark deficit of Alzheimer's disease (AD). Naming impairment is most prominently observed in the late-onset amnestic and logopenic variant Primary Progressive Aphasia (lvPPA) syndromes. However, little is known about how other patients across the atypical AD syndromic spectrum perform on tests of auditory naming, particularly those with primary visuospatial deficits (Posterior Cortical Atrophy; PCA) and early onset (EOAD) syndromes. Auditory naming tests may be of particular relevance to more accurately measuring anomia in PCA syndrome and in others with visual perceptual deficits. Forty-six patients with biomarker-confirmed AD (16 PCA, 12 lvPPA, 18 multi-domain EOAD), at the stage of mild cognitive impairment or mild dementia, were administered the Auditory Naming Test (ANT). Performance differences between groups were evaluated using one-way ANOVA and post-hoc t-tests. Correlation analyses were used to examine ANT performance in relation to measures of working memory and word retrieval to elucidate cognitive mechanisms underlying word retrieval deficits. Whole-cortex general linear models were generated to determine the relationship between ANT performance and cortical atrophy. Based on published cutoffs, out of a total possible score of 50 on the ANT, 56% of PCA patients (mean score = 45.3), 83% of EOAD patients (mean = 39.2), and 83% of lvPPA patients (mean = 29.8) were impaired. Total uncued ANT performance differed across groups, with lvPPA performing most poorly, followed by EOAD, and then PCA. ANT performance was still impaired in lvPPA and EOAD after cuing, while performance in PCA patients improved to the normal range with phonemic cues. ANT performance was also directly correlated with measures of verbal fluency and working memory, and was associated with cortical atrophy in a circumscribed semantic language network. Auditory confrontation naming is impaired across the syndromic spectrum of AD including in PCA and EOAD, and is likely related to auditory-verbal working memory and verbal fluency which represent the nexus of language and executive functions. The left-lateralized semantic language network was implicated in ANT performance. Auditory naming, in the absence of a visual perceptual demand, may be particularly sensitive to measuring naming deficits in PCA.

The neural substrates of transdiagnostic cognitive-linguistic heterogeneity in primary progressive aphasia

BackgroundClinical variants of primary progressive aphasia (PPA) are diagnosed based on characteristic patterns of language deficits, supported by corresponding neural changes on brain imaging. However, there is (i) considerable phenotypic variability within and between each diagnostic category with partially overlapping profiles of language performance between variants and (ii) accompanying non-linguistic cognitive impairments that may be independent of aphasia magnitude and disease severity. The neurobiological basis of this cognitive-linguistic heterogeneity remains unclear. Understanding the relationship between these variables would improve PPA clinical/research characterisation and strengthen clinical trial and symptomatic treatment design. We address these knowledge gaps using a data-driven transdiagnostic approach to chart cognitive-linguistic differences and their associations with grey/white matter degeneration across multiple PPA variants.MethodsForty-seven patients (13 semantic, 15 non-fluent, and 19 logopenic variant PPA) underwent assessment of general cognition, errors on language performance, and structural and diffusion magnetic resonance imaging to index whole-brain grey and white matter changes. Behavioural data were entered into varimax-rotated principal component analyses to derive orthogonal dimensions explaining the majority of cognitive variance. To uncover neural correlates of cognitive heterogeneity, derived components were used as covariates in neuroimaging analyses of grey matter (voxel-based morphometry) and white matter (network-based statistics of structural connectomes).ResultsFour behavioural components emerged: general cognition, semantic memory, working memory, and motor speech/phonology. Performance patterns on the latter three principal components were in keeping with each variant’s characteristic profile, but with a spectrum rather than categorical distribution across the cohort. General cognitive changes were most marked in logopenic variant PPA. Regardless of clinical diagnosis, general cognitive impairment was associated with inferior/posterior parietal grey/white matter involvement, semantic memory deficits with bilateral anterior temporal grey/white matter changes, working memory impairment with temporoparietal and frontostriatal grey/white matter involvement, and motor speech/phonology deficits with inferior/middle frontal grey matter alterations.ConclusionsCognitive-linguistic heterogeneity in PPA closely relates to individual-level variations on multiple behavioural dimensions and grey/white matter degeneration of regions within and beyond the language network. We further show that employment of transdiagnostic approaches may help to understand clinical symptom boundaries and reveal clinical and neural profiles that are shared across categorically defined variants of PPA.

Hearing symptom profiles in Alzheimer’s disease and frontotemporal dementia

AbstractBackgroundHearing loss has emerged as a marker of cognitive decline and potential treatment target in dementia, however the symptom profiles that characterise hearing impairment in different dementia syndromes are poorly characterised. Beyond sound detection, these diseases impair aspects of auditory perception that are crucial for communication in daily life. Here we addressed changes in everyday hearing function in Alzheimer’s disease and frontotemporal dementia syndromes, using standardised auditory symptom questionnaires completed by patients’ caregivers.MethodPrimary caregivers for patients with Alzheimer’s disease (n = 20), logopenic variant primary progressive aphasia (n = 8), nonfluent variant primary progressive aphasia (n = 13), semantic variant primary progressive aphasia (n = 13) and behavioural variant frontotemporal dementia (n = 18) completed the Hearing Impairment Impact – Significant Other Profile, adapted Amsterdam Inventory for Auditory Disability and Khalfa Hyperacusis questionnaires. The Amsterdam Inventory for Auditory Disability was also completed by 15 healthy age‐matched individuals. No participant had a past history of significant otological disease.ResultScores on the Hearing Impairment Impact – Significant Other Profile and Khalfa Hyperacusis Questionnaire respectively demonstrated greater carer burden and increased sensitivity to sound in the behavioural variant frontotemporal dementia group compared with the Alzheimer’s disease group. On the Amsterdam Inventory for Auditory Disability, multi‐domain hearing difficulties were endorsed for the behavioural variant frontotemporal dementia and primary progressive aphasia groups relative to healthy controls, and total scores in the logopenic and semantic variant primary progressive aphasia groups were significantly worse than both the healthy control and Alzheimer’s disease groups. Syndromic groups showed differentiable hearing profiles across hearing domains.ConclusionMajor dementia syndromes have distinct profiles of everyday hearing difficulty, and patients with frontotemporal dementia and progressive aphasia syndromes may have particularly marked (albeit often unrecognised) changes in their hearing. These findings should motivate the development of bespoke auditory tests to assess central hearing function and personalised hearing management strategies in these diseases.

Tau epicenter identification and connectivity in clinically heterogeneous Alzheimer’s disease variants

AbstractBackgroundWhile the spread of tau throughout the brain is well‐characterized in amnestic Alzheimer’s disease (AD), tau staging remains less clear for those suffering from clinically heterogeneous variants including logopenic variant primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA). We created a method to identify local maxima of tau SUVR (“epicenters”) in participants with early‐stage clinically heterogeneous AD with the goal of classifying participant subtypes based on the functional connectivity of these epicenters.MethodWe obtained 18F‐MK‐6240 tau PET scans from 10 participants with diagnoses of early‐stage clinically heterogeneous AD (5 lvPPA, 5 PCA, Clinical Dementia Rating 0.5‐1.0). We identified three local maxima of tau SUVR with a minimum specified distance of 20mm between them for each participant (Fig. 1). We then derived each epicenter’s functional connectivity in 1000 healthy controls using Neurosynth and sorted participants into subtypes based on the overlap of these functional connectivity maps.ResultParticipants with lvPPA showed highest tau burden in the posterior temporoparietal and temporoocciptal regions, left side predominant, and participants with PCA displayed highest tau burden in the bilateral parietooccipital cortex, frontal eye fields, and fusiform gyrus. We identified nine distinct subtypes of functional connectivity and most participants’ epicenters participated in more than one subtype. All subtypes highlight functional connectivity networks that have been associated with language and, or visuospatial processing. The most common subtype (seen in 7 of the 10 participants and 11 of the 30 epicenters) features connectivity within the bilateral occipital lobule, fusiform gyrus, and superior parietal lobule (Fig. 2).ConclusionWe used a novel method to identify tau “epicenters” in the brains of participants with early‐stage clinically heterogeneous AD. Using these epicenters, we derived functional connectivity maps, which we then grouped into nine subtypes across participants. We will shortly begin collecting longitudinal tau PET in these clinically heterogeneous individuals with AD, allowing us to assess the extent to which tau spreads along the functional connectivity maps predicted by each participant’s epicenters and whether individually tailored epicenters outperform subtype classification. This work could serve as the basis for patient‐specific biomarkers of expected disease spread in clinically heterogeneous AD.

Single‐nuclei transcriptomic identifies type‐specific neuronal cell vulnerability and non‐neuronal molecular changes in Amnestic and Logopenic Variant Primary Progressive Aphasia Alzheimer’s disease

AbstractBackgroundIndividuals with neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Therefore, we investigated factors underlying selective vulnerability using brain samples from individuals with pure AD with different clinical manifestations.MethodsnRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 24 individuals either meeting pathological criteria for AD (A3B3C3; 12 amnestic and eight lvPPA) and healthy controls (A≤1B≤1C≤1; n = 4) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with Wald statistical test, and p‐values < .05 were considered significant.ResultAfter quality control, we recovered 98,180 nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 27 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients. Furthermore, two astrocytes subpopulations (one in both areas and one in STG) and three STG microglia subpopulations showed proportional composition changes comparing AD patients and HC.ConclusionOur preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.

Dyslexia phenotypes in Chinese‐speaking individuals with Primary Progressive Aphasia

AbstractBackgroundThere are more than 7,000 living languages worldwide with wide heterogeneities in their linguistic features. Varying dementia symptomatology has been noted across speakers of different languages. Chinese languages adopt logographic scripts that contrast greatly from Indo‐European languages with alphabetic writing systems. For instance, Chinese characters have weak grapheme‐phoneme correspondence, with only 19‐ 39% pronounced per their phonetic components. Chinese characters also have 20 different spatial configurations with varying visuospatial complexity and abundant heteronyms. Past literature has focused on the reading presentations of primary progressive aphasia (PPA) patients that adopt Indo‐European languages. This study outlined the reading presentations of Chinese‐speaking PPA patients.MethodThe CLAP (Chinese Language Assessment for PPA) battery is designed to characterize the neurolinguistics features of Chinese‐speaking PPA individuals. In CLAP character reading test, participants are tasked to read aloud 50 Chinese characters that vary in lexicality (pictographic, regular compound, and irregular compound characters), character frequency and concreteness. Voxel‐based morphometry(VBM) was performed to examine the neural basis of reading performance. Participants are also tasked with reading pairs of compound words with heteronyms (e.g., “bow tie” vs “bow down).ResultsA total of 15 Mandarin‐speaking controls and 38 PPA individuals [6 nonfluent variant (nfv) PPA, 9 semantic variant (sv) PPA and 23 logopenic variant (lv) PPA] completed CLAP reading task. In character reading test, svPPA scored significantly lower than controls and nfvPPA (pictographic: p = 0.026; regular compound: p = 0.007; irregular compound characters: p<0.001). Regardless of lexicality, the reading score significantly correlated with volumetric changes over left temporal pole. While over‐regularization errors/surface dyslexia was the most common reading error across control and PPA groups, it was not specific to svPPA (p = 0.109). Conversely, on heteronym word reading test, svPPA and lvPPA scored significantly lower in accuracy, with over‐regularization errors more frequently noted in svPPA group.ConclusionContrary to English svPPA patients that struggled specifically with irregular word reading and showed frequent surface dyslexia, Chinese PPA patients showed no variant‐specific differences across lexicality, and svPPA‐specific over‐regularization phenomenon were found at the lexical (i.e., heteronym‐reading) and not sub‐lexical reading. Diagnostic criteria for PPA syndrome vary with languages and should ideally be tailored linguistically.

EEG correlates in the three variants of Primary Progressive Aphasia

AbstractBackgroundThe analysis of EEG cortical sources is promising for the investigation of neurodegenerative disorders. The aim of this study is to explore its value in the characterization of the three clinical presentations of primary progressive aphasia (PPA).MethodA resting‐state 19‐channel EEG was obtained in 48 patients diagnosed with PPA (21 nonfluent/agrammatic variant PPA [nfv‐PPA], 18 logopenic variant PPA [lv‐PPA], 9 semantic variant PPA [sv‐PPA]) and in 21 matched healthy controls. Using eLORETA, EEG current source density (CSD) values were estimated at voxel‐level and compared among groups of patients and controls.ResultPatients showed a low‐to‐moderate cognitive impairment. Lv‐PPA cases showed a higher delta density over the left frontal and temporal regions when compared to sv‐PPA subjects, and in left precuneus and posterior cingulate when compared to nfv‐PPA patients. They also displayed a higher delta density in left frontal, parietal and temporal regions than healthy subjects, and lower alpha1 density in left occipital regions compared with other patient groups. Lv‐PPA patients also showed reduced alpha2, beta1 and beta2 density over the left occipital regions when compared to healthy subjects. No significant differences were found in terms of CSD among sv‐PPA, nfv‐PPA and healthy subjects.ConclusionConsistently with our previous studies, findings in PPA patients suggest that Alzheimer’s disease (AD), but not fronto‐temporal degeneration (FTD), might induce a characteristic disruption of the cortical electrical activity, detectable by EEG. EEG might thus help in the differential diagnosis between AD‐related and FTD‐related PPA variants.

Social cognition and behavioral changes in patients with posterior cortical atrophy.

Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual and visuospatial dysfunction. The consensus criteria state that patients should present "relatively spared behavior and personality" in early stages. However, limited research has focused on these symptoms in PCA. This study compared 157 patients with PCA in early stages of the disease with 352 healthy controls (HC), 202 typical AD (tAD), and 177 logopenic variant primary progressive aphasia (lvPPA) patients from the National Alzheimer's Coordinating Center (NACC) dataset. They were compared using clinician ratings of behavioral symptoms, informant- and clinician-filled questionnaires and patient-facing tests of behavior and social cognition. Results showed that PCA individuals exhibited many behavioral symptoms, the more frequently reported being anxiety, depression, apathy, and irritability. During cognitive testing, clinicians observed disorganized and reactive behaviors, but no insensitive behaviors. Informant reports indicated that PCA patients exhibited higher levels of inhibition and anxiety in response to stimuli associated with non-reward, novelty, and punishment. Social norms knowledge and empathy were overall preserved, although slight decreases in perspective-taking and socioemotional sensitivity were observed on informant-rated questionnaires. Except for more elevated neuropsychiatric symptoms in tAD, the three AD variants had similar profiles. Our findings provide insights into the social cognition and behavioral profiles of PCA, highlighting patterns of preservations and mild impairments, even in the early stages of the disease. These results contribute to a more complete understanding of non-visual symptoms in PCA and have implications for diagnostic and intervention strategies.

Medial Temporal Lobe Tau Aggregation Relates to Divergent Cognitive and Emotional Empathy Abilities in Alzheimer's Disease.

In Alzheimer's disease (AD), the gradual accumulation of amyloid-β (Aβ) and tau proteins may underlie alterations in empathy. To assess whether tau aggregation in the medial temporal lobes related to differences in cognitive empathy (the ability to take others' perspectives) and emotional empathy (the ability to experience others' feelings) in AD. Older adults (n = 105) completed molecular Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer's type, logopenic variant primary progressive aphasia, or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aβ negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (Perspective-Taking subscale) and emotional empathy (Empathic Concern subscale) in the Aβ positive and negative participants. The Aβ positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy. Aβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy. Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern.

Auditory phonological identification impairment in primary progressive aphasia

ObjectiveTo examine the audiological characteristics and neuroanatomical regions associated with auditory phonological identification impairment in primary progressive aphasia (PPA). MethodsTwenty-seven patients with PPA [13 non-fluent/agrammatic variant PPA (nfvPPA), three logopenic variant PPA (lvPPA), seven semantic variant PPA (svPPA), and four mixed type PPA] were included in the study. Neuropsychological, language, audiological, and neuroradiological examinations were also performed. Auditory function examinations consisted of a pure-tone threshold test, a phonological identification task, and temporal auditory acuity tests, such as click counting or fusion. As an evaluation value of phonological identification ability, we calculated the discrepancy scores, which were the smaller discrepancy (left or right ear) in phonological identification ability scores between measured and expected values from the pure-tone threshold. In the neuroradiological examination, we evaluated the regional cerebral blood flow using 123I-iodoamphetamine single-photon emission computed tomography. ResultsEight of the 27 patients were allocated to the impaired phonological identification group, and four were considered to have significant impairment on further analysis. Two of these patients, one with lvPPA and one with mixed type of lvPPA and nfvPPA, showed apparent phonological identification deficits that could be observed in daily life. The discrepancy scores were not significantly related to the results of neuropsychological, language, or any other auditory examinations, except for the click counting score in the left ear. Voxel-based correlation analyses revealed that regional cerebral blood flow in the bilateral superior temporal gyrus and bilateral primary auditory cortex was significantly and positively correlated with phonological identification ability. ConclusionsOur results suggest that progressive dysfunction of the bilateral superior temporal gyrus and bilateral primary auditory cortex due to neurodegenerative diseases leads to phonological identification impairment in PPA 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 & Strøm, 2018) together with the deterioration of other cognitive domains (e.g., memory) (Taler & Phillips, 2008). The first complaint in people with dementia often is language impairment, even preceding other cognitive declines (Ferris & 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.

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<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<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.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Aphasic Binary Reversals as a Novel Biomarker Across Dementia Syndromes (P6-6.010)

<h3>Objective:</h3> To investigate the prevalence, demographics, cognitive profiles, and neuropathology of yes/no confusion, a.k.a. aphasic binary reversals (ABR), in primary progressive aphasia (PPA) and frontotemporal lobar degeneration (FTLD) spectrum disorders. <h3>Background:</h3> ABR occurs when patients frequently answer binary choice questions (e.g., yes/no) incorrectly. High rates have been observed in nonfluent PPA (nfvPPA), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP), diseases often considered as part of a spectrum. To date, no study has thoroughly explored ABR specificity within the broader PPA/FTLD spectrum disorders or deeply examined the cognitive mechanisms behind this phenomenon. <h3>Design/Methods:</h3> Clinical histories across nfvPPA (n=152), CBS (n=106), PSP (n=111), behavioral variant FTD (bvFTD; n=329), logopenic variant PPA (lvPPA; n=213), and semantic variant PPA (svPPA; n=143) were screened for the presence of ABR. Demographics, cognitive measures, and neuropathology were compared between groups with and without ABR. <h3>Results:</h3> ABR prevalence was highest in nfvPPA (43.42%) followed by PSP (16.21%), CBS (13.21%), bvFTD (3.34%), lvPPA (2.81%), and svPPA (0.0%). ABR was highly predictive of nfvPPA diagnosis (OR=25.03 [95% CI: 16.3–38.42]) and the combined nfvPPA/CBS/PSP spectrum (OR=30.06 [95% CI: 17.67–51.12]). Analyses restricted to the nfvPPA/CBS/PSP group revealed no differences in demographics or CDR between those with and without ABR. On cognitive testing, Verbal Agility, Repetition, Digits Forward, Digits Backward, Modified Trails, Semantic Fluency, Phonemic Fluency, Stroop Color Naming and Interference were significantly worse (all <i>p</i>&lt;0.05) in nfvPPA/CBS/PSP with ABR vs. without. On autopsy, 93% (n=38/41) with ABR possessed a sole tauopathy (PSP/CBD/Pick’s/GGT/AGD/unclassifiable tau) vs. 78% (n=85/109) without (Fisher’s Exact, <i>p</i>=0.05; restricting to nfvPPA/CBS cases, 90% [n=27/30] vs. 67% [n=41/61] had sole tauopathy, <i>p</i>=0.02). <h3>Conclusions:</h3> ABR is highly specific to nfvPPA/CBS/PSP spectrum disorders and is associated with worse language and executive function testing and sole tauopathy. Together, the presence of ABR may be capturing pathophysiological differences within these disorders and thus might reflect a novel disease biomarker. <b>Disclosure:</b> Rian Bogley has nothing to disclose. Maxime Montembeault has nothing to disclose. Isabel Allen has nothing to disclose. Dr. Spina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acsel Health. Dr. Spina has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Precision Xtract. Dr. Spina has received research support from Tau Consortium. Dr. Spina has received research support from Chan Zuckerberg Initiative, LLC. Dr. Spina has received research support from Bluefield Project to Cure FTD. Lea Grinberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Curasen Inc. The institution of Lea Grinberg has received research support from NIH. The institution of Lea Grinberg has received research support from Eli Lilly. The institution of Lea Grinberg has received research support from BrightFouus. The institution of Lea Grinberg has received research support from Rainwater Charity Foundation. Prof. Huang has nothing to disclose. The institution of Dr. Kramer has received research support from tau consortium. Dr. Kramer has received publishing royalties from a publication relating to health care. Dr. Possin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ClearView Healthcare Partners. The institution of Dr. Possin has received research support from Quest Diagnostics. The institution of Dr. Possin has received research support from NIH. The institution of Dr. Possin has received research support from The Global Brain Health Institute. The institution of Dr. Possin has received research support from The Rainwater Foundation. The institution of Dr. Rankin has received research support from Marcus Foundation. Dr. Rosen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Pharmaceuticals. Dr. Rosen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. The institution of Dr. Rosen has received research support from NIH. The institution of Dr. Rosen has received research support from State of CA. Dr. Rosen has a non-compensated relationship as a Consultant with Alector that is relevant to AAN interests or activities. An immediate family member of Dr. Boxer has received personal compensation for serving as an employee of Kaiser Permanente. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Third Rock. Dr. Boxer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Transposon. Dr. Boxer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Oligomerix. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GSK. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Humana. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Wave. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boehringer Ingelheim. Dr. Boxer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Oscotec. Dr. Boxer has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arvinas. Dr. Boxer has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arkuda. Dr. Boxer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AZTherapeutics. Dr. Boxer has stock in Alector. Dr. Boxer has stock in Arkuda. Dr. Boxer has stock in Arvinas. An immediate family member of Dr. Boxer has stock in AZtherapies. Dr. Boxer has stock in TrueBinding. The institution of Dr. Boxer has received research support from Biogen. The institution of Dr. Boxer has received research support from Eisai. The institution of Dr. Boxer has received research support from Regeneron. The institution of Dr. Boxer has received research support from NIH. The institution of Dr. Boxer has received research support from Bluefield Project. Dr. Boxer has received research support from Rainwater Charitable Foundation. The institution of Dr. Boxer has received research support from Association for Frontotemporal Degeneration. Dr. Rabinovici has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Eisai. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GE Healthcare. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Johnson &amp; Joihnson. Dr. Rabinovici has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. The institution of Dr. Rabinovici has received research support from NIH. The institution of Dr. Rabinovici has received research support from American College of Radiology. The institution of Dr. Rabinovici has received research support from Alzheimer’s Association. The institution of Dr. Rabinovici has received research support from Rainwater Charitable Foundation. The institution of Dr. Rabinovici has received research support from Genentech. Dr. Rabinovici has received personal compensation in the range of $5,000-$9,999 for serving as a Topic Chair, Course Director and teacher with AAN. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Grant reviewer with NIH. Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG Council. Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Global Consulting. Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Corcept Therapeutics. Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BridgeBio. Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Private attorney. The institution of Dr. Seeley has received research support from NIH. The institution of Dr. Seeley has received research support from Rainwater Charitable Foundation. The institution of Dr. Seeley has received research support from Bluefield Project to Cure FTD. The institution of Dr. Seeley has received research support from Chan-Zuckerberg Initiative. Dr. Sturm has nothing to disclose. The institution of Dr. Perry has received research support from NIH/NIA. Dr. Miller has nothing to disclose. The institution of Dr. Gorno Tempini has received research support from NIH. Dr. Miller has nothing to disclose.

EEG correlates in the three variants of Primary Progressive Aphasia (P13-6.002)

<h3>Objective:</h3> The aim of this study is to explore the value of EEG analysis in the characterization of the three clinical presentations of primary progressive aphasia (PPA). <h3>Background:</h3> The analysis of EEG cortical sources is promising for the investigation of neurodegenerative disorders. <h3>Design/Methods:</h3> A resting-state 19-channel EEG was obtained in 48 patients diagnosed with PPA (21 nonfluent/agrammatic variant PPA [nfv-PPA], 18 logopenic variant PPA [lv-PPA], 9 semantic variant PPA [sv-PPA]) and in 21 matched healthy controls. Applying seed-based analysis on 3T fMRI data of an independent group of young healthy controls (n.40), we built the maps of three networks belonging to the left perisylvian language network (nodes: middle temporal gyrus–MTG, inferior frontal gyrus–IFG, anterior temporal lobe–ATL) and the maps of default-mode network (DMN) and salience network (SN). Using eLORETA, EEG current source density (CSD) and linear-lagged connectivity (LLC) values were estimated and compared. CSD and LLC analysis were performed at whole-brain level and at network level, respectively. <h3>Results:</h3> Patients showed a low-to-moderate cognitive impairment. At CSD analysis lv-PPA patients showed a higher delta density than nfvPPA, svPPA and healthy subjects. They also showed a higher theta density relative to controls. Level of statistical significance showed a pronounced descending posterior-to-anterior and left-to-right gradient over the brain cortex at theta band. Also nfvPPA patients deviated from healthy subjects in terms of widespread higher theta density. LLC analysis pointed out a significantly higher connectivity at delta and theta frequency bands characterizing all three groups of patients relative to controls in language networks. Connectivity disruption was also evident in non-language networks. <h3>Conclusions:</h3> Findings in PPA patients suggest that Alzheimer’s disease (AD), but not fronto-temporal degeneration (FTD), might induce a characteristic disruption of the cortical electrical activity in lvPPA patients, detectable by EEG. EEG might thus help in the differential diagnosis between AD-related and FTD-related PPA variants. <b>Disclosure:</b> Giordano Cecchetti has nothing to disclose. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Silvia Basaia has nothing to disclose. Dr. Spinelli has nothing to disclose. Ms. Cividini has nothing to disclose. Marco Cursi has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Leocadi has nothing to disclose. Roberto Santangelo, 4503 has nothing to disclose. Dr. Caso has nothing to disclose. Dr. Fanelli has nothing to disclose. Dr. Minicucci has nothing to disclose. Giuseppe Magnani has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Tau accumulates differently in four subtypes of Alzheimer's disease

AbstractBackgroundHeterogeneity in Alzheimer's disease (AD) has been reported on the basis of clinical, neuropathological, and neuroimaging data. However, most of the indices, including cerebral atrophy evaluated using magnetic resonance imaging and amyloid β (Aβ) accumulation detected using positron emission tomography (PET), lack sensitivity, and specificity for categorization.AimHerein, we used a novel PET ligand for tau to estimate the differential distribution of tau in the subtypes of AD.MethodsPatients with posterior cortical atrophy (PCA; n = 3), frontal variant of AD (FAD; n = 1), logopenic variant primary progressive aphasia (LPPA; n = 2), typical AD (TAD; n = 6), and healthy controls (HC; n = 12) were studied. Aβ and tau accumulation were evaluated using [11C]PiB and [11C]PBB3, respectively.ResultsAmyloid β accumulation was confirmed in all PCA, FAD, LPPA, and TAD cases. Tau accumulation was dominantly high in the occipital lobes in the PCA, strikingly high in the frontal lobes in the FAD, and moderately high in the angular gyrus of the dominant hemisphere in the LPPA. Tau accumulation in TAD cases was significantly higher than age‐dependent tau accumulation in HC in these subtype‐specific regions as well as in AD signature regions. Glucose utilization was reversely correlated with PBB3 accumulation in the subtype‐specific regions.ConclusionsTau accumulates differently in the four subtypes of AD, suggesting that tau pathology may be closely associated with unique clinical features.

The ScreeLing: Detecting Semantic, Phonological, and Syntactic Deficits in the Clinical Subtypes of Frontotemporal and Alzheimer's Dementia.

The ScreeLing is a screening instrument developed to assess post-stroke aphasia, via the linguistic levels Syntax, Phonology, and Semantics. It could also be a useful test for the clinical subtypes of frontotemporal dementia (FTD) and Alzheimer's dementia (AD), as specific and often selective disorders are expected. Its ability to differentiate between the clinical subtypes of FTD and AD is, however, still unknown. We investigated differences in ScreeLing total and subscores, linguistic-level disorders' relationship with disease severity, and classification abilities, in patients with behavioral variant FTD (bvFTD; n = 46), patients with primary progressive aphasia (PPA; n = 105) (semantic variant primary progressive aphasia [svPPA], non-fluent variant primary progressive aphasia [nfvPPA], and logopenic variant primary progressive aphasia [lvPPA], AD [n = 20] and controls [n = 35]). We examined group differences in ScreeLing total and subscores, and one-, two- or three-level linguistic disorders using one-way analyses of covariance (ANCOVAs) or Quade's rank ANCOVA. We used frequency analyses to obtain the occurrence of the linguistic-level disorders. We determined sensitivity and specificity by the area under the curve by receiver-operating characteristics analyses to investigate classification abilities. The total score was lower in patients (bvFTD: 63.8 ± 8.5, svPPA: 58.8 ± 11.3, nfvPPA: 63.5 ± 8.4, lvPPA: 61.7 ± 6.6, AD: 63.8 ± 5.5) than controls (71.3 ± 1.0) (p < .001). Syntax subscores were lower in svPPA (19.4 ± 4.6; p < .001) and lvPPA (20.3 ± 3.2; p = .002) than controls (23.8 ± 0.4). Phonology subscores were lower in lvPPA (19.8 ± 2.6) than bvFTD (21.7 ± 2.8) (p = .010). Semantics subscores were lowest in svPPA (17.8 ± 5.0; p < .002). A selective phonological disorder was most prevalent in lvPPA (34.9%). The higher the disease severity, the more linguistic-level disorders. The optimal cutoff for the total score was 70, and 23 for all three subscores. Good classification abilities were found for the Semantics (svPPA vs. bvFTD), Phonology (lvPPA vs. svPPA), and Syntax (nfvPPA vs. lvPPA) subscores. This easy to administer test gives information about language processing with the potential to improve differential diagnosis in memory clinics and in the future potentially also clinical trial planning.

Static first-minute-frame (FMF) PET imaging after 18F-labeled amyloid tracer injection is correlated to [18F]FDG PET in patients with primary progressive aphasia

ObjectiveTo study the correlation between a static PET image of the first-minute-frame (FMF) acquired with 18F-labeled amyloid-binding radiotracers and brain [18F]FDG PET in patients with primary progressive aphasia (PPA). Material and methodsThe study cohort includes 17 patients diagnosed with PPA with the following distribution: 9 nonfluent variant PPA, 4 logopenic variant PPA, 1 semantic variant PPA, 3 unclassifiable PPA. Regional SUVRs are extracted from FMFs and their corresponding [18F]FDG PET images and Pearson’s correlation coefficients are calculated. ResultsSUVRs of both images show similar patterns of regional cerebral alterations. Intrapatient correlation analyses result in a mean coefficient of r=0.94±0.06. Regional interpatient correlation coefficients of the study cohort are greater than 0.81. Radiotracer-specific and variant-specific subcohorts show no difference in the similarity between the images. ConclusionsThe static FMF could be a valid alternative to dynamic early-phase amyloid PET proposed in the literature, and a neurodegeneration biomarker for the diagnosis and classification of PPA in amyloid PET studies.