Nonfluent Primary Progressive Aphasia Research Articles

Progression of Nonfluent Primary Progressive Aphasia and Primary Progressive Apraxia of Speech into Corticobasal Syndrome (S43.001)

Progression of Nonfluent Primary Progressive Aphasia and Primary Progressive Apraxia of Speech into Corticobasal Syndrome (S43.001)

Progression to corticobasal syndrome: a longitudinal study of patients with nonfluent primary progressive aphasia and primary progressive apraxia of speech.

Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on their progression remain unclear. We aimed to examine the clinical and neuroimaging evolution of nfvPPA and PPAOS into CBS. We conducted a retrospective longitudinal study in 140 nfvPPA or PPAOS patients and applied the consensus criteria for possible and probable CBS for every visit, evaluating limb rigidity, akinesia, limb dystonia, myoclonus, ideomotor apraxia, alien limb phenomenon, and nonverbal oral apraxia (NVOA). Given the association of NVOA with AOS, we also modified the CBS criteria by excluding NVOA and assigned every patient to either a progressors or non-progressors group. We evaluated the frequency of every CBS feature by year from disease onset, and assessed gray and white matter volume loss using SPM12. Asymmetric akinesia, NVOA, and limb apraxia were the most common CBS features that developed; while limb dystonia, myoclonus, and alien limb were rare. Eighty-two patients progressed to possible CBS; only four to probable CBS. nfvPPA and PPAOS had a similar proportion of progressors, although nfvPPA progressed to CBS earlier (p-value = 0.046), driven by an early appearance of limb apraxia (p-value = 0.0041). The non-progressors and progressors both showed premotor/motor cortex involvement at baseline, with spread into prefrontal cortex over time. An important proportion of patients with nfvPPA and PPAOS progress to possible CBS, while they rarely develop features of probable CBS even after long follow-up.

Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.

Clinical and cortical trajectories in non-fluent primary progressive aphasia and Alzheimer’s disease: A role for emotion processing

ObjectivesTo examine the clinical trajectories and neural correlates of cognitive and emotion processing changes in the non-fluent/agrammatic (nfvPPA) and the logopenic (lvPPA) variants of primary progressive aphasia (PPA). DesignObservational case-control longitudinal cohort study. SettingResearch clinic of frontotemporal dementia. ParticipantsThis study recruited 29 non-semantic PPA patients (15 nfvPPA and 14 lvPPA) and compared them with 15 Alzheimer’s disease (AD) patients and 14 healthy controls. MeasurementsParticipants completed an annual assessment (median = 2 years; range = 1–5 years) of general cognition, emotion processing and structural MRI. Linear mixed effects models investigated clinical and imaging trajectories between groups. ResultsOver time, lvPPA showed the greatest cognitive deterioration. In contrast, nfvPPA showed significant decline in emotion recognition, whereas AD showed preserved emotion recognition, even with disease progression. Importantly, lvPPA also developed emotion processing impairments, with disease progression. Both nfvPPA and lvPPA showed continuing cortical atrophy in hallmark language-processing regions associated with these syndromes, together with progressive involvement of the right hemisphere regions, mirroring left hemisphere atrophy patterns at presentation. Decline in emotion processing was associated with bilateral frontal atrophy in nfvPPA and right temporal atrophy in lvPPA. ConclusionsOur results show divergent clinical courses in nfvPPA and lvPPA, with rapid cognitive and neural deterioration in lvPPA and emotion processing decline in both groups and support the concurrent assessment of cognition and emotion processing in the clinic to inform diagnosis and monitoring in the non-semantic variants of PPA.

Measuring Sentence Information via Surprisal: Theoretical and Clinical Implications in Nonfluent Aphasia.

Nonfluent aphasia is characterized by simplified sentence structures and word-level abnormalities, including reduced use of verbs and function words. The predominant belief about the disease mechanism is that a core deficit in syntax processing causes both structural and word-level abnormalities. Here, we propose an alternative view based on information theory to explain the symptoms of nonfluent aphasia. We hypothesize that the word-level features of nonfluency constitute a distinct compensatory process to augment the information content of sentences to the level of healthy speakers. We refer to this process as lexical condensation. We use a computational approach based on language models to measure sentence information through surprisal, a metric calculated by the average probability of occurrence of words in a sentence, given their preceding context. We apply this method to the language of patients with nonfluent primary progressive aphasia (nfvPPA; n = 36) and healthy controls (n = 133) as they describe a picture. We found that nfvPPA patients produced sentences with the same sentence surprisal as healthy controls by using richer words in their structurally impoverished sentences. Furthermore, higher surprisal in nfvPPA sentences correlated with the canonical features of agrammatism: a lower function-to-all-word ratio, a lower verb-to-noun ratio, a higher heavy-to-all-verb ratio, and a higher ratio of verbs in -ing forms. Using surprisal enables testing an alternative account of nonfluent aphasia that regards its word-level features as adaptive, rather than defective, symptoms, a finding that would call for revisions in the therapeutic approach to nonfluent language production. ANN NEUROL 2023;94:647-657.

A cognitive marker for Alzheimer disease pathology in primary progressive aphasia? A validation study in the clinical setting

We validated in the clinical setting a putative clinical marker for a biological diagnosis of primary progressive aphasia (PPA) due to amyloid previously identified in an autopsy cohort and including impaired (score ≤4) digit span (DS) as index of phonological loop dysfunction and broadened criteria for logopenic PPA. In 29 PPA patients with an amyloid-positive (A+) biomarker and 28 PPA patients with an amyloid-negative (A−) biomarker, Receiver Operating Characteristics (ROC) curve analysis showed moderate specificity (71%) but insufficient sensitivity (41%) for the proposed marker. Specificity was particularly poor (58%) for the discrimination between A+ PPA and the A− subgroup with nonfluent PPA. DS may be compromised in both logopenic and nonfluent PPA, whose loci of neurodegeneration lie at the 2 ends of the left fronto-parieto-temporal system that underpins phonology. An Statistical Parametric Mapping (SPM) correlation analysis between DS score and metabolism on brain 18-fluoro-deoxy-glucose positron emission tomography also showed a major contribution of the left frontal cortex to impaired span.

Multimodality in PPA

Purpose: In primary progressive aphasia (PPA), multimodal means may gradually become more important in conversations. In this study, the aim was to investigate the functions of hand movements of a man with PPA. Method: Peter and Karen participated in this study. Peter was diagnosed with nonfluent PPA two years prior to data collection. Casual conversation and cognitive and linguistic testing were audio- and video-recorded. Analyses were informed by multimodal interaction analytical approaches. Results: The results showed that Peter’s opportunities to engage in conversations were enabled within a co-operative framework, where Peter would contribute within a predetermined slot using a variety of multimodal resources to, for example, organize turn-taking or repair difficulties relating to verbal output. Discussion and conclusions: Studying multimodal resources across tasks may reveal important features of the ways in which persons with communicative impairment adjust to different contexts. In clinical settings, multimodal resources need to be viewed as multi-layered actions rather than as isolated contributions.

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.

Cerebrospinal Fluid Neurofilament Light as a Marker of Neuro-axonal Injury in Normal Pressure Hydrocephalus (P10-6.001)

<h3>Objective:</h3> To compare Cerebrospinal fluid (CSF) Neurofilament-light chain (NfL) and NfL/amyloid beta₄₂ (Abeta42) ratio levels in normal pressure hydrocephalus (NPH) patients with healthy controls (HC), Alzheimer’s disease (AD), and Frontotemporal lobar degeneration (FTLD). <h3>Background:</h3> Levels of CSF NfL have been shown to be a marker of neuro-axonal injury and are elevated in neurodegenerative disease. One putative etiology of NPH involves axonal injury; however, low CSF Abeta42 has been reported in NPH. To control for the higher volume of CSF in NPH, the NfL/Abeta42 ratio was used. <h3>Design/Methods:</h3> 120 patients with CSF analysis: (a) 46 NPH: ventriculomegaly on MRI or CT, negative AD biomarkers, clinical symptoms of NPH, improvement in gait after tap test; (b) 39 FTLD: 5 behavioural-variant frontotemporal dementia, 14 corticobasal syndrome, 4 frontotemporal dementia with motor neuron disease, 12 progressive supranuclear palsy, 2 semantic-variant primary progressive aphasia (PPA), and 2 non-fluent PPA; (c) 29 AD; and (d) 6 HC. Levels of CSF NfL were measured using single molecule array (Simoa) technology while Abeta42 was measured using a sandwich ELISA method (Innotest). All statistical analyses were corrected for multiple comparisons and age. <h3>Results:</h3> Log transformed NfL levels in the NPH group were significantly higher than HC (p &lt; 0.05), but lower than FTLD and AD group (p &lt;0 .001). Log transformed CSF NfL/Abeta42 ratio was significantly higher in the NPH group compared to HC (p&lt;0.05); but no significant difference with FTLD and AD groups. <h3>Conclusions:</h3> Intermediate CSF NfL levels in NPH patients suggest that there is some neuro-axonal injury present - although less than in FTLD and AD. Further investigations are warranted to determine whether the NfL normalizes after shunting or the neuroaxonal injury is irreversible. NfL in NPH may help elucidate the pathophysiology of the disease. <b>Disclosure:</b> Ms. Davenport has nothing to disclose. Dr. Taghdiri has nothing to disclose. Anna Vasilevskaya has nothing to disclose. Ms. Anastassiadis has received research support from Fonds de Recherche du Québec - Santé (FRQS). Dr. Thapa has nothing to disclose. Dr. Dimal has nothing to disclose. Namita Multani, 14039 has nothing to disclose. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbott. Dr. Fasano has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medtronic. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Boston Scientific. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbott. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medtronic. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sunovion. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ceregate. The institution of Dr. Fasano has received research support from Boston Scientific. The institution of Dr. Fasano has received research support from Medtronic. The institution of Dr. Fasano has received research support from Abbvie. Dr. Fasano has received publishing royalties from a publication relating to health care. Dr. Tang-Wai has nothing to disclose. Dr. Tartaglia has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Tartaglia has received research support from NIH. The institution of Dr. Tartaglia has received research support from University of Toronto.

Changes in motor activity level in individuals with frontotemporal dementia.

Changes in motor activity are common in individuals with Frontotemporal dementia (FTD). Yet, it remains unclear why some individuals become motorically hyperactive, while others hypoactive even in early stages of the disease. This study aimed to examine the relationship between motor activity level and (1) FTD clinical subtype, and (2) cortical thickness and subcortical volumes. Eighty-two charts were retrospectively reviewed from patients meeting consensus criteria for one of the three main clinical subtypes of FTD: probable bvFTD, semantic variant Primary Progressive Aphasia (PPA), or non-fluent variant PPA. Participants were assigned to one of three groups: (1) hyperactive, (2) hypoactive, or (3) no record of change. Hyperactivity was prevalent among bvFTD (58.5%) and semantic PPA (68.8%) subtypes while hypoactivity was less common in both subtypes (29.3% and 18.8%, respectively). The majority of patients with non-fluent PPA showed no record of change in motor activity (66.7%). The analysis of cortical thickness and subcortical volumes did not identify significant associations with motor activity levels. In conclusion, increased motor activity is highly prevalent among individuals with FTD, especially bvFTD and svPPA subtypes. These findings may inform prognosis and prediction of changes in motor activity, and allow planning for appropriate environmental and behavioural interventions. Future studies with prospective, standardized longitudinal collection of information regarding the type and level of change in motor activity, including wearable measures of actigraphy, may help to further delineate the onset and progression of abnormal motor behaviours and determine neuroanatomic associations in FTD.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome

Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Hesitations in Primary Progressive Aphasia

Hesitations are often used by speakers in spontaneous speech not only to organise and prepare their speech but also to address any obstacles that may arise during delivery. Given the relationship between hesitation phenomena and motor and/or cognitive–linguistic control deficits, characterising the form of hesitation could be potentially useful in diagnosing specific speech and language disorders, such as primary progressive aphasia (PPA). This work aims to analyse the features of hesitations in patients with PPA compared to healthy speakers, with hesitations understood here as those related to speech planning, that is, silent or empty pauses, filled pauses, and lengthened syllables. Forty-three adults took part in this experiment, of whom thirty-two suffered from some form of PPA: thirteen from logopenic PPA (lvPPA), ten from nonfluent PPA (nfvPPA), and nine from semantic PPA (svPPA). The remaining 11 were healthy speakers who served as a control group. An analysis of audio data recorded when participants produced spontaneous speech for a picture description task showed that the frequency of silent pauses, especially those classified as long (&gt;1000 ms) was particularly useful to distinguish PPA participants from healthy controls and also to differentiate among PPA types. This was also true, albeit to a lesser extent, of the frequency of filled pauses and lengthened syllables.

Word picture verification performance reveals auditory comprehension deficits in primary progressive aphasia

Word/picture verification has been found to be a sensitive measure of lexical-semantic abilities in post-stroke aphasia and reveals information about disruptions in semantic and phonological processing. Exploration of the nature of auditory comprehension deficits using word/picture verification has not been replicated in primary progressive aphasia (PPA). We tested 108 individuals with PPA [logopenic variant PPA (lvPPA), n = 50; nonfluent agrammatic PPA (nfaPPA), n = 36; semantic variant PPA (svPPA), n = 22] on a spoken word/picture verification task and a spoken word/picture matching task. The spoken word/picture matching task identified 22 (20%) of individuals as impaired, whereas the spoken word/picture verification task identified 51 (47%) of individuals as impaired (two-tailed p < 0.001). Errors on spoken word/picture verification were due to semantic rather than phonologic foils in lvPPA (nouns, p < 0.001; verbs, p < 0.001), svPPA (nouns, p < 0.001; verbs, p < 0.001), and for nouns (p = 0.001) but not verbs in nfaPPA. Spoken word/picture verification was a more sensitive measure of single-word auditory comprehension deficits in PPA than word/picture matching. The error pattern, consistent with the distributed model of semantic knowledge, suggests that degradation of semantic representations for both nouns and verbs can occur in lvPPA, which may help to distinguish lvPPA versus nfaPPA and guide treatment for anomia. • We investigated picture verification and picture matching to assess auditory comprehension impairment in primary progressive aphasia (PPA). • Picture verification was a more sensitive measure of single-word auditory comprehension deficits in PPA than picture matching. • Errors on spoken word/picture verification were due to semantic rather than phonologic foils for nouns and verbs in logopenic variant and semantic variant PPA.

Sentence repetition span in primary progressive aphasia and Alzheimer's disease: Insights from preliminary results

Primary Progressive Aphasia (PPA) is a neurocognitive disorder ascribed to cortical atrophy impacting language abilities. It is widely classified into three main variants, logopenic PPA (lvPPA), the semantic variant of PPA (svPPA), and the non-fluent PPA (nfvPPA), showing different impairment patterns across variants. However, in the early phases of PPA, it is not always easy to dissociate different PPA variants and distinguish PPA from other neurodegenerative disorders. One characteristic language symptom that seems to be a distinguishing factor of PPA, especially the logopenic variant, is impaired sentence repetition. Nonetheless, studies examining sentence repetition in PPA, and Alzheimer's disease (AD) more broadly, have resulted in mixed findings. To better understand the working memory-intensive nature of sentence repetition deficits, we designed a sentence repetition span task. We seek to understand (i) whether three diagnostic groups (lvPPA, svPPA, and AD) encounter greater sentence repetition difficulties than the controls, and (ii) whether using a span task design, in which the number of content words increases as the span length increases, would help dissociate PPA variants from AD type dementia. In this study, we administered a sentence repetition span task to four groups of French-speaking individuals with lvPPA (n = 14), svPPA (n = 5), and with AD (n = 13), and their age-matched healthy controls (n = 61). The results showed that all three diagnostic groups (lvPPA, svPPA, and AD) performed equally poorly compared to the controls on the repetition span task virtually in all measures (i.e., sentence span, the number of content words, and the number of omission and substitution errors). One intriguing finding was that the lvPPA group produced an exalted number of phonological errors during repeating sentences, while this type of error was somewhat moderate in the svPPA group and only minimal in the AD group. We conclude that the sentence repetition difficulty in PPA and AD should be modulated by working memory capacity, as our participants undoubtedly demonstrated greater difficulty as the span length increased. However, we note that working memory-intensive sentence repetition deficits based on the number of content words might not reveal critical diagnostic differences between the neurodegenerative groups.

Clinical Spectrum of Tauopathies.

Tauopathies are both clinical and pathological heterogeneous disorders characterized by neuronal and/or glial accumulation of misfolded tau protein. It is now well understood that every pathologic tauopathy may present with various clinical phenotypes based on the primary site of involvement and the spread and distribution of the pathology in the nervous system making clinicopathological correlation more and more challenging. The clinical spectrum of tauopathies includes syndromes with a strong association with an underlying primary tauopathy, including Richardson syndrome (RS), corticobasal syndrome (CBS), non-fluent agrammatic primary progressive aphasia (nfaPPA)/apraxia of speech, pure akinesia with gait freezing (PAGF), and behavioral variant frontotemporal dementia (bvFTD), or weak association with an underlying primary tauopathy, including Parkinsonian syndrome, late-onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), and amnestic syndrome. Here, we discuss clinical syndromes associated with various primary tauopathies and their distinguishing clinical features and new biomarkers becoming available to improve in vivo diagnosis. Although the typical phenotypic clinical presentations lead us to suspect specific underlying pathologies, it is still challenging to differentiate pathology accurately based on clinical findings due to large phenotypic overlaps. Larger pathology-confirmed studies to validate the use of different biomarkers and prospective longitudinal cohorts evaluating detailed clinical, biofluid, and imaging protocols in subjects presenting with heterogenous phenotypes reflecting a variety of suspected underlying pathologies are fundamental for a better understanding of the clinicopathological correlations.

Differences in aphasia syndromes between progressive supranuclear palsy-Richardson's syndrome, behavioral variant frontotemporal dementia and Alzheimer's dementia.

Language impairments, hallmarks of speech/language variant progressive supranuclear palsy, also occur in Richardson's syndrome (PSP-RS). Impaired communication may interfere with daily activities. Therefore, assessment of language functions is crucial. It is uncertain whether the Aachen Aphasia Test (AAT) is practicable in PSP-RS, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's dementia (AD) and language deficits differ in these disorders. 28 PSP-RS, 24 AD, and 24 bvFTD patients were investigated using the AAT and the CERAD-Plus battery. 16-25% of all patients failed in AAT subtests for various reasons. The AAT syndrome algorithm diagnosed amnestic aphasia in 5 (23%) PSP-RS, 7 (36%) bvFTD and 6 (30%) AD patients, Broca aphasia in 1 PSP-RS and 1 bvFTD patient, Wernicke aphasia in 1 bvFTD and 3 (15%) AD patients. However, aphasic symptoms resembled non-fluent primary progressive aphasia in 14 PSP-RS patients. In up to 46% of PSP-RS patients, 61% of bvFTD and 64% of AD patients significant impairments were found in the AAT subtests spontaneous speech, written language, naming, language repetition, language comprehension and the Token subtest. The CERAD-Plus subtest semantic fluency revealed significant impairment in 81% of PSP-RS, 61% of bvFTD, 44% of AD patients, the phonemic fluency subtest in 31, 40 and 31%, respectively. In contrast to bvFTD and AD, severity of language impairment did not correlate with cognitive decline in PSP-RS. In summary, the patterns of aphasia differ between the diagnoses. Local frontal language networks might be impaired in PSP-RS, whereas in AD and bvFTD, more widespread neuropathology might underly language impairment.

Longitudinal changes in connected speech over a one-year span in the nonfluent/agrammatic variant of Primary Progressive Aphasia

ABSTRACT Background Connected speech assessment is essential to characterize the language features in primary progressive aphasia (PPA). This is especially true for the non-fluent/agrammatic variant (nfvPPA) in which one of the core features is agrammatism. Identification of agrammatism typically involves the analysis of sentence production, as in connected speech, in order to detect syntactic deficits. However, little is known about the longitudinal changes occurring in connected speech of individuals with non-fluent PPA. Aim The aim of this study was to assess changes in connected speech over a one-year span in participants with nfvPPA using semi-structured interviews. Methods and procedures We conducted a prospective group study including participants with nfvPPA (n=9) and age- and education-matched healthy controls (n=9). For each individual, connected speech was obtained using topic-directed interviews at two testing rounds, each approximately one year apart. Production on each task was recorded, transcribed and analyzed according to the Quantitative Production Analysis (QPA) protocol, a tool developed by Berndt and colleagues (2000) for the analysis of sentence production in aphasia. For each group, the probability of deterioration between the two testing rounds was estimated using Bayesian analysis. Results and outcomes For individuals with nfvPPA, statistical evidence of deterioration from the first testing round to the second was found for five variables, namely the proportion of pronouns, the proportion of verbs, the proportion of closed class words, the inflection index and the proportion of well-formed sentences. Conclusions Results from the present study suggest that variables relating to word-finding and morphology are more vulnerable to time and therefore may be relevant potential targets for intervention.

Sentence Comprehension in Primary Progressive Aphasia: A Study of the Application of the Brazilian Version of the Test for the Reception of Grammar (TROG2-Br).

Sentence-comprehension deficits have been described in patients with primary progressive aphasia (PPA). However, most instruments to address this domain in more detail and in a clinical context have not been adapted and translated into several languages, posing limitations to clinical practice and cross-language research.ObjectivesThe study aimed to (1) test the applicability of the Brazilian version of the Test for Reception of Grammar (TROG2-Br) to detect morphosyntactic deficits in patients with PPA; (2) investigate the association between performance in the test and sociodemographic and clinical variables (age, years of formal education, and disease duration); (3) characterize the performance of individuals presenting with the three more common variants of PPA (non-fluent, semantic, and logopenic) and mixed PPA (PPA-Mx) and analyze whether TROG-2 may assist in the distinction of these clinical profiles.MethodsA total of 74 cognitively healthy participants and 34 individuals diagnosed with PPA were assessed with TROG2-Br. Overall scores (correct items, passed blocks), types, and categories of errors were analyzed.ResultsIn controls, block scores were significantly correlated with years of formal education (Spearman's r = 0.33, p = 004) but not with age. In PPA, age, education, and disease duration were not significantly associated with performance in the test. Controls presented a significantly higher performance on TROG2-Br compared to PPA individuals and their errors pattern pointed to mild general cognitive processing difficulties (attention, working memory). PPA error types pointed to processing and morphosyntactic deficits in nonfluent or agrammatic PPA, (PPA-NF/A), logopenic PPA (PPA-L), and PPA-Mx. The semantic PPA (PPA-S) subgroup was qualitatively more similar to controls (processing difficulties and lower percentage of morphosyntactic errors). TROG2-Br presented good internal consistency and concurrent validity.DiscussionOur results corroborate findings with TROG-2 in other populations. The performance of typical older adults with heterogeneous levels of education is discussed along with recommendations for clinical use of the test and future directions of research.

Inter-hemispheric synchronicity and symmetry: The functional connectivity consequences of stroke and neurodegenerative disease

Stroke and neurodegenerative diseases differ along several dimensions, including their temporal trajectories -abrupt onset versus slow disease progression. Despite these differences, they can give rise to very similar cognitive impairments, such as specific forms of aphasia. What has been scarcely investigated, however, is the extent to which the underlying functional neuroplastic consequences are similar or different for these diseases. Here, for the first time, we directly compare changes in the brain’s functional network connectivity, measured with resting-state fMRI, in stroke and progressive neurological disease. Specifically, we examined two groups of individuals with chronic post-stroke aphasia or non-fluent primary progressive aphasia, matched for their behavioral profiles and distribution of left-hemisphere damage. Using previous proposals regarding the neural functional connectivity (FC) phenotype of stroke as a starting point, we compared the two diseases in terms of homotopic FC, intra-hemispheric FC changes and also the symmetry of the FC patterns between the two hemispheres. We found, first, that progressive disease showed significantly higher levels of homotopic connectivity than neurotypical controls and, further, that stroke showed the reverse pattern. For both groups these effects were found to be behaviorally relevant. In addition, within the directly impacted left hemisphere, FC changes for the two diseases were significantly correlated. In contrast, in the right hemisphere, the FC changes differed markedly between the two groups, with the progressive disease group exhibiting rather symmetrical FC changes across the hemispheres whereas the post-stroke group showed asymmetrical FC changes across the hemispheres. These findings constitute novel evidence that the functional connectivity consequences of stroke and neurodegenerative disease can be very different despite similar behavioral outcomes and damage foci. Specifically, stroke may lead to greater independence of hemispheric responses, while neurodegenerative disease may produce more symmetrical changes across the hemispheres and more synchronized activity between the two hemispheres.

Longitudinal decline in spoken word recognition and object knowledge in primary progressive aphasia.

The premise of this study is that spoken word recognition and object knowledge are impaired in semantic variant primary progressive aphasia (PPA) (svPPA) and are spared in logopenic variant (lvPPA) and nonfluent agrammatic primary progressive aphasia (nfaPPA) at disease onset. Over time, however, there may be heterogeneity in these abilities in lvPPA and nfaPPA. We hypothesized that individuals with svPPA would demonstrate poorer performance on baseline spoken word recognition and object knowledge than those with lvPPA and nfaPPA) as documented in the literature, but that rates of decline over time on spoken word recognition and object knowledge would be similar in all 3 PPA variants because these become less distinguishable with disease progression.The aim of this study was to investigate longitudinal patterns of decline in spoken word recognition and object knowledge across PPA variants.Ninety-five individuals with PPA completed the Semantic Word Picture Matching and Semantic Associates tests at baseline to establish expected performance in these areas. Thirty-five individuals completed follow-up testing.The distributions of trichotomized mean rates of decline in object knowledge were similar for lvPPA and svPPA (P = .05). There were weak negative correlations between symptom duration and baseline scores on Semantic Word Picture Matching (r[37] = −0.399, P = .01), and baseline scores on Semantic Associates (r[37] = −0.394, P = .01) in lvPPA.Degradation of spoken word recognition and object knowledge occurs over time in lvPPA. Further investigation of the receptive language deficits in PPA is warranted to characterize language changes that lessen the distinctions between PPA variants with disease progression.