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Objectives Previous reports established the feasibility of a telehealth model for delivering speech–language therapy via Internet videoconferencing, which connects individuals with primary progressive aphasia (PPA) to an expert speech and language pathologist for treatment. This study reports feasibility of the same telehealth intervention in a larger set of progressive aphasia participants and explores factors potentially influencing functional intervention outcomes. Methods Participants with PPA or progressive aphasia in the context of a neurodegenerative dementia syndrome and their communication partners were enrolled into an 8-session intervention, with 3 evaluations (baseline, 2 months, and 6 months postenrollment). Half of the participants were randomized into a "check-in" group and received 3-monthly half-hour sessions postintervention. Mixed linear models with post hoc testing and percent change in area under the curve were used to examine communication confidence over time, as well as the influence of check-in sessions and the role of communication partner engagement on communication confidence. Results Communication confidence improved at the 2-month evaluation and showed no significant decline at the 6-month evaluation. Item-level analysis revealed gains in communication confidence across multiple communication contexts. Gains and maintenance of communication confidence were only present for the engaged communication partner group and were not bolstered by randomization to the check-in group. Discussion Internet-based, person-centered interventions demonstrate promise as a model for delivering speech–language therapy to individuals living with PPA. Maintenance is possible for at least 6 months postenrollment and is better for those with engaged communication partners, which supports the use of dyadic interventions. [ABSTRACT FROM AUTHOR]

The term primary progressive aphasia (PPA) describes a group of neurodegenerative disorders with predominant speech and language dysfunction as their main feature. There are three main variants -- the semantic variant, the nonfluent or agrammatic variant and the logopenic variant -- each with specific linguistic deficits and different neuroanatomical involvement. There are currently no curative treatments or symptomatic pharmacological therapies. However, speech and language therapists have developed several impairmentbased interventions and compensatory strategies for use in the clinic. Unfortunately, multiple barriers still need to be overcome to improve access to care for people with PPA, including increasing awareness among referring clinicians, improving training of speech and language therapists and developing evidence- based guidelines for therapeutic interventions. This review highlights this inequity and the reasons why neurologists should refer people with PPA to speech and language therapists. [ABSTRACT FROM AUTHOR]

On average, memory capacity is significantly higher in populations of 50–60 year olds than in populations of 80 year olds. We define SuperAgers as individuals 80 or older whose episodic memory capacity is at least as good as that of cognitively average individuals in their 50s and 60s. SuperAgers therefore have memory capacity that is superior for age. Previous work showed that SuperAgers have greater cortical volumes and greater resistance to age‐related cortical atrophy than "cognitively average" individuals of the same age. Here we report on the cognitive, personality, and neuropathologic characteristics of the first 10 autopsy cases in the Northwestern SuperAging Program. During the follow‐up period, seven SuperAgers maintained episodic memory performance within or above the average range for 50–65 year‐old norms and all 10 SuperAgers maintained episodic memory scores within normal limits for their own age. Extraversion scores tended to be high on the NEO‐PI‐R measure of personality. The 10 autopsy specimens showed variable findings within the spectrum of Alzheimer pathology. The hippocampus and entorhinal cortex contained neurofibrillary degeneration mostly in the Braak II–III stages. However, even these limbic areas contained many healthy appearing neurons and the neocortex was generally free of neurofibrillary degeneration. In contrast, neocortical areas in at least five of the cases contained moderate to high densities of neuritic plaques. These findings need to be placed in context by comparing them to the neuropathology of cognitively average individuals of the same age. Future research on SuperAgers is likely to offer insights into factors that either prevent the emergence of involutional changes in the brain or that makes cognitive function more resistant to their consequences. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia (PPA) is a clinical neurodegenerative dementia syndrome characterized by deficits in spoken and written word retrieval, word usage, and/or word comprehension. Currently, there are no effective treatments to reverse or halt the underlying disease process; however, speech-language therapy may be helpful. The Communication Bridge Care Model was developed to address the unique communication and quality of life needs of individuals living with PPA. The core elements include person-centered care with dyadic instruction for disease education, and counseling, along with tailored levels of impairment- and compensatory-based communication strategy training. Our multicomponent approach incorporates guidance from the Life Participation Approach for Aphasia, including client-directed assessment and interventions that aim to maximize functional communication and participation in desired life activities. The direct and indirect use of technology is integrated into our tailored model of care to facilitate achievement of the client's functional goals. Here, we describe how to practically apply the Communication Bridge Care Model across treatment settings, including case examples from the Communication Bridge research study. This approach to care provides an opportunity to maximize communication effectiveness and quality of life for individuals living with PPA throughout the course of disease. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network. [ABSTRACT FROM AUTHOR]

The determinants of selective vulnerability in neurodegenerative diseases remain elusive. The asymmetric loss of neurons in primary progressive aphasia offers a unique setting for addressing this question. Although no factor can yet account for the selective vulnerability of the left hemisphere language network to degenerative diseases, a few themes are emerging as potential targets of further investigation. [ABSTRACT FROM AUTHOR]

Abstract: The determinants of selective vulnerability in neurodegenerative diseases remain elusive. The asymmetric loss of neurons in primary progressive aphasia offers a unique setting for addressing this question. Although no factor can yet account for the selective vulnerability of the left hemisphere language network to degenerative diseases, a few themes are emerging as potential targets of further investigation. [Copyright &y& Elsevier]

Primary progressive aphasia (PPA) and behavioural-variant frontotemporal dementia (bvFTD) are clinical syndromes under the umbrella term 'frontotemporal dementia' (FTD) and are caused by a neurodegenerative disease with an onset most typically in the productive years of adulthood. The cognitive and behavioural impairments associated with FTD interfere with successful engagement in typical life roles, such as parenting, working, and maintenance of interpersonal relationships. There are currently no treatments to stop or slow the degenerative process and there are only very limited medication options for the management of the cognitive-behavioural symptoms. However, alternative, non-pharmacological interventions may offer significant benefit to the quality of life of the diagnosed individual. The goal of this paper is to provide an overview of the approaches available through neurorehabilitation and community-based services that facilitate successful engagement in life activities and promote optimal quality of life for the individuals and families living with FTD. It is hoped that as medical providers become more familiar with behavioural interventions, referrals for services will increase thereby allowing individuals with FTD and their caregivers to learn ways to adapt, adjust, and participate in life to the fullest despite the impairments from this progressive disease. [ABSTRACT FROM AUTHOR]

It is notoriously difficult to name odours. Without the benefit of non-olfactory information, even common household smells elude our ability to name them. The neuroscientific basis for this olfactory language ‘deficit’ is poorly understood, and even basic models to explain how odour inputs gain access to transmodal representations required for naming have not been put forward. This study used patients with primary progressive aphasia, a clinical dementia syndrome characterized by primary deficits in language, to investigate the interactions between olfactory inputs and lexical access by assessing behavioural performance of olfactory knowledge and its relationship to brain atrophy. We specifically hypothesized that the temporal pole would play a key role in linking odour object representations to transmodal networks, given its anatomical proximity to olfactory and visual object processing areas. Behaviourally, patients with primary progressive aphasia with non-semantic subtypes were severely impaired on an odour naming task, in comparison with an age-matched control group. However, with the availability of picture cues or word cues, odour matching performance approached control levels, demonstrating an inability to retrieve but not to recognize the name and nature of the odorant. The magnitude of cortical thinning in the temporal pole was found to correlate with reductions in odour familiarity and odour matching to visual cues, whereas the inferior frontal gyrus correlated with both odour naming and matching. Volumetric changes in the mediodorsal thalamus correlated with the proportion of categorical mismatch errors, indicating a possible role of this region in error-signal monitoring to optimize recognition of associations linked to the odour. A complementary analysis of patients with the semantic subtype of primary progressive aphasia, which is associated with marked temporopolar atrophy, revealed much more pronounced impairments of odour naming and matching. In identifying the critical role of the temporal pole and inferior frontal gyrus in transmodal linking and verbalization of olfactory objects, our findings provide a new neurobiological foundation for understanding why even common odours are hard to name. [ABSTRACT FROM AUTHOR]

Objectives: To investigate cognitive components and mechanisms of learning and memory in primary progressive aphasia (PPA) using a simple clinical measure, the Three Words Three Shapes Test (3W3S). Background: PPA patients can complain of memory loss and may perform poorly in standard tests of memory. The extent to which these signs and symptoms reflect dysfunction of the left hemisphere language versus limbic memory network remains unknown. Methods: 3W3S data from 26 patients with a clinical diagnosis of PPA were compared with previously published data from patients with typical dementia of the Alzheimer type (DAT) and cognitively healthy elders. Results: PPA patients showed two bottlenecks in new learning. First, they were impaired in the effortless (but not effortful) on-line encoding of verbal (but not non-verbal) items. Second, they were impaired in the retrieval (but not retention) of verbal (but not non-verbal) items. In contrast, DAT patients had impairments also in effortful on-line encoding and retention of verbal and nonverbal items. Conclusions: PPA selectively interferes with spontaneous on-line encoding and subsequent retrieval of verbal information. This combination may underlie poor memory test performance and is likely to reflect the dysfunction of the left hemisphere language rather than medial temporal memory network. [ABSTRACT FROM AUTHOR]

The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of agematched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ε4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by progressive decline in language function but relative sparing of other cognitive domains. There are three recognized PPA variants: agrammatic, semantic, and logopenic. Although each PPA subtype is characterized by the nature of the principal deficit, individual patients frequently display subtle impairments in additional language domains. The present study investigated the distribution of atrophy related to performance in specific language domains (i.e., grammatical processing, semantic processing, fluency, and sentence repetition) across PPA variants to better understand the anatomical substrates of language. Results showed regionally specific relationships, primarily in the left hemisphere, between atrophy and impairments in language performance. Most notable was the neuroanatomical distinction between fluency and grammatical processing. Poor fluency was associated with regions dorsal to the traditional boundaries of Broca's area in the inferior frontal sulcus and the posterior middle frontal gyrus, whereas grammatical processing was associated with more widespread atrophy, including the inferior frontal gyrus and supramarginal gyrus. Repetition performance was correlated with atrophy in the posterior superior temporal gyrus. The correlation of atrophy with semantic processing impairment was localized to the anterior temporal poles. Atrophy patterns were more closely correlated with domain-specific performance than with subtype. These results show that PPA reflects a selective disruption of the language network as a whole, with no rigid boundaries between subtypes. Further, these atrophy patterns reveal anatomical correlates of language that could not have been surmised in patients with aphasia resulting from cerebrovascular lesions. [ABSTRACT FROM AUTHOR]

The semantic variant of primary progressive aphasia (PPA) is characterized by the combination of word comprehension deficits, fluent aphasia and a particularly severe anomia. In this study, two novel tasks were used to explore the factors contributing to the anomia. The single most common factor was a blurring of distinctions among members of a semantic category, leading to errors of overgeneralization in word–object matching tasks as well as in word definitions and object descriptions. This factor was more pronounced for natural kinds than artifacts. In patients with the more severe anomias, conceptual maps were more extensively disrupted so that inter-category distinctions were as impaired as intra-category distinctions. Many objects that could not be named aloud could be matched to the correct word in patients with mild but not severe anomia, reflecting a gradual intensification of the semantic factor as the naming disorder becomes more severe. Accurate object descriptions were more frequent than accurate word definitions and all patients experienced prominent word comprehension deficits that interfered with everyday activities but no consequential impairment of object usage or face recognition. Magnetic resonance imaging revealed three characteristics: greater atrophy of the left hemisphere; atrophy of anterior components of the perisylvian language network in the superior and middle temporal gyri; and atrophy of anterior components of the face and object recognition network in the inferior and medial temporal lobes. The left sided asymmetry and perisylvian extension of the atrophy explains the more profound impairment of word than object usage and provides the anatomical basis for distinguishing the semantic variant of primary progressive aphasia from the partially overlapping group of patients that fulfil the widely accepted diagnostic criteria for semantic dementia. [ABSTRACT FROM PUBLISHER]

Abstract: Recognition memory was tested in patients with primary progressive aphasia (PPA), a language based dementia with relative preservation of memory for at least the first 2 years. The goal of the study was two-fold: (1) to compare true and false recognition rates for words versus pictures in patients with PPA and cognitively intact controls and (2) to determine if the semantic relatedness of distracters-to-targets influences recognition memory performance. Overall, performance of PPA patients was worse for words than pictures. PPA patients and healthy elderly controls showed similar recognition rates for studied items. However, the patients had significantly more false alarms than controls, particularly to semantically related items. This suggests that the aphasia in PPA patients contributes to their difficulty in selecting among items within a semantic class. [Copyright &y& Elsevier]

Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies. [ABSTRACT FROM AUTHOR]

Introduction: Identifying responsive outcome measures for assessing functional change related to cognition, communication, and quality of life for individuals with neurodegenerative disease is important for intervention design and clinical care. Goal Attainment Scaling (GAS) has been used as an outcome measure to formally develop and systematically measure incremental progress toward functional, patient-centered goals in clinical settings. Evidence suggests that GAS is reliable and feasible for use in older adult populations and in adult populations with cognitive impairment, but no review has assessed the suitability of GAS in older adults with neurodegenerative disease experiencing dementia or cognitive impairment, based on responsiveness. This study conducted a systematic review to evaluate the suitability of GAS as an outcome measure for older adult populations with neurodegenerative disease experiencing dementia or cognitive impairment, based on responsiveness. Methods: The review was registered with PROSPERO and performed by searching ten electronic scientific databases (PubMed, Medline OVID, CINAHL, Cochrane, Embase, Web of Science, PsycINFO, Scopus, OTSeeker, REHABDATA) and four registries (Clinicaltrials.gov, Grey Literature Report, Mednar, OpenGrey). A summary measure of responsiveness (post-intervention minus pre-intervention mean GAS T-score) was compared across eligible studies using a random-effects meta-analysis. Risk of bias in included studies was assessed using the NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group. Results: 882 eligible articles were identified and screened by two independent reviewers. Ten studies met inclusion criteria for the final analysis. Of the ten included reports, 3 focus on all-cause dementia, 3 on multiple sclerosis, 1 on Parkinson's disease, 1 on mild cognitive impairment, 1 on Alzheimer's disease, and 1 on primary progressive aphasia. Responsiveness analyses showed pre- and post-intervention GAS goals were significantly different from zero (Z = 7.48, p < 0.001), with post-intervention GAS scores being higher than pre-intervention GAS scores. Three included studies showed a high risk of bias, 3 showed a moderate risk of bias, and 4 showed a low risk of bias. Overall risk of bias of included studies was rated as moderate. Conclusion: GAS showed an improvement in goal attainment across different dementia patient populations and intervention types. The overall moderate risk of bias suggests that while bias is present across included studies (e.g., small sample size, unblinded assessors), the observed effect likely represents the true effect. This suggests that GAS is responsive to functional change and may be suitable for use in older adult populations with neurodegenerative disease experiencing dementia or cognitive impairment. [ABSTRACT FROM AUTHOR]

The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA‐binding protein type C (TDP‐C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP‐C patients has highlighted the importance of this region for complex cognitive and behavioral functions. This review includes observations on 28 TDP‐C patients, 18 with semantic primary progressive aphasia and 10 with other syndromes. Longitudinal imaging allowed the delineation of progression trajectories. At post‐mortem examination, the pathognomonic feature of TDP‐C consisted of long, thick neurites found predominantly in superficial cortical layers. These neurites may represent dystrophic apical dendrites of layer III and V pyramidal neurons that are known to play pivotal roles in complex cortical computations. Other types of frontotemporal lobar degeneration TDP, such as TDP‐A and TDP‐B, are not associated with long dystrophic neurites in the cerebral cortex, and do not show similar predilection patterns for ATL. Research is beginning to identify molecular, structural, and immunological differences between pathological TDP‐43 in TDP‐C versus TDP‐A and B. Parallel investigations based on proteomics, somatic mutations, and genome‐wide association studies are detecting molecular features that could conceivably mediate the selective vulnerability of ATL to TDP‐C. Future work will focus on characterizing the distinctive features of the abnormal TDP‐C neurites, the mechanisms of neurotoxicity, initial cellular targets within the ATL, trajectory of spread, and the nature of ATL‐specific markers that modulate vulnerability to TDP‐C. ANN NEUROL 2023;94:1–12 [ABSTRACT FROM AUTHOR]

Objective: Older adults with exceptional memory function, designated "SuperAgers," include individuals over age 80, with episodic memory at least as good as individuals ages 50s–60s. The Northwestern University SuperAging cohort is defined by performance on an established test of verbal memory. The purpose of this study was to determine if superior verbal memory extends to nonverbal memory in SuperAgers by examining differences in the National Institutes of Health Toolbox® (NIHTB) between older adults with exceptional memory and those with average-for-age cognition. Method: SuperAgers (n  = 46) and cognitively average-for-age older adults (n  = 31) completed a comprehensive neuropsychological battery and the NIHTB Cognition module. Multiple linear regressions were used to examine differences on subtests between groups. Results: There was a significant effect of group on the Picture Sequence Memory score, (p = .007), such that SuperAgers had higher scores than cognitively average-for-age older adults. There were no other group effects across other non-episodic memory NIHTB Cognition measures. Conclusions: Findings from this study demonstrated stronger performance on the memory measure of the NIHTB in SuperAgers compared to cognitively average-for-age older adults demonstrating superior memory in not only verbal but also nonverbal episodic memory in this group. Additionally, this study adds to the literature validating the NIHTB in older adults, particularly in a novel population of adults over age 80 with exceptional memory. [ABSTRACT FROM AUTHOR]

The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles—3R Pick's disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p < 0.001), followed by CBD, AD, then PSP. PPA-AD cases showed more inclusions in hilar cells compared to granule cells, while the opposite was true in PiD and CBD. Inclusion-to-neuron ratios revealed, on average, 33% of all DG neurons in PiD cases contained a tau inclusion, compared to ~ 7% in CBD, 2% in AD, and 0.4% in PSP. There was no significant difference between DAT-AD and PPA-AD pathologic tau burden, suggesting that differences in DG burden are not specific to clinical phenotype. We conclude that the DG is differentially vulnerable to pathologic tau accumulation, raising intriguing questions about the structural integrity and functional significance of hippocampal circuits in neurodegenerative dementias. [ABSTRACT FROM AUTHOR]

Purpose: Primary progressive aphasia (PPA) is a clinical neurodegenerative dementia syndrome characterized by early, selective, and progressive language impairment. PPA onset is gradual, providing time to potentially identify additional or alternative expressive communication modes; however, reports of communication mode use and effectiveness by persons with PPA have not been described. This study characterized the use, frequency, and perceived effectiveness of communication modes reported by individuals with PPA. Method: Forty-one participants with mild-to-moderate PPA completed a structured interview detailing the type, frequency, and perceived effectiveness of 12 potential communication modes, categorized by technology required (no-tech, low-tech, and high-tech). The ratio of modes used was compared across technology categories with a repeated-measures generalized linear model assuming a binomial distribution with an overall Wald chi-square statistic, followed by pairwise post hoc t-test comparisons. Results: Of the 12 communication modes assessed, participants reported using a median of eight (range: 5-10). All participants affirmed using speech, facial expressions, and talking on the phone. Frequency and perceived effectiveness ratings for these three modes were endorsed at the "some/most of the time" level for more than 80% of the participants. No-tech mode use was significantly higher than reported high-tech and low-tech modes (p = .004 and p < .0001, respectively). Even so, while some high-tech modes (apps) and some low-tech modes (nonelectronic augmentative and alternative communication) had fewer users, effectiveness ratings were moderate to high for all but one user. Conclusions: Persons with mild-to-moderate language impairment due to PPA report using a range of communication modes with moderate-to-high frequency and perceived effectiveness. These outcomes provide practical information when considering mode refinement or expansion during intervention to maximize communication participation. Barriers to modality use may include low awareness or access, which could be queried by future studies and supported by speech and language interventions. Supplemental Material: https://doi.org/10.23641/asha.21614262 [ABSTRACT FROM AUTHOR]

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20-30 years their junior. This study investigated whether neuronal integrity in the entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively healthy younger individuals, cognitively average peers ("Normal Elderly"), and individuals with amnestic mild cognitive impairment. Postmortem sections of the ERC were stained with cresyl violet to visualize neurons and immunostained with mouse monoclonal antibody PHF-1 to visualize neurofibrillary tangles. The crosssectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was used to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixedeffect models were used to determine differences across groups. Quantitative measurements found that the soma size of layer II ERC neurons in postmortem brain specimens were significantly larger in SuperAgers compared with all groups (p,0.05)--including younger individuals 20-30 years their junior (p<0.005). SuperAgers had significantly fewer stereologically quantified Alzheimer's disease-related neurofibrillary tangles in layer II ERC than Normal Elderly (p<0.05). This difference in tangle burden in layer II between SuperAgers and Normal Elderly suggests that tangle-bearing neurons may be prone to shrinkage during aging. The finding that SuperAgers show ERC layer II neurons that are substantially larger even compared with individuals 20-30 years younger is remarkable, suggesting that layer II ERC integrity is a biological substrate of exceptional memory in old age. [ABSTRACT FROM AUTHOR]

Quantification of in vivo amyloid and tau PET imaging relationships with postmortem measurements are critical for validating the sensitivity and specificity imaging biomarkers across clinical phenotypes with Alzheimer disease neuropathologic change (ADNC). This study examined the quantitative relationship between regional binding of in vivo 18F-florbetapir amyloid PET and 18F-flortaucipir tau PET with postmortem stereological counts of amyloid plaques and neurofibrillary tangles (NFT) in a case of primary progressive aphasia (PPA) with ADNC, where neurodegeneration asymmetrically targets the left hemisphere. Beginning 2 years prior to death, a 63-year-old right-handed man presenting with agrammatic variant PPA underwent a florbetapir and flortaucpir PET scan, and neuropsychological assessments and magnetic resonance imaging sessions every 6 months. Florbetapir and flortaucpir PET standard uptake value ratios (SUVRs) were quantified from 8 left and right hemisphere brain regions with stereological quantification of amyloid plaques and NFTs from corresponding postmortem sections. Pearson's correlations and measures of asymmetry were used to examine relationships between imaging and autopsy measurements. The three visits prior to death revealed decline of language measures, with marked progression of atrophy. Florbetapir PET presented with an atypical focal pattern of uptake and showed a significant positive correlation with postmortem amyloid plaque density across the 8 regions (r = 0.92; p = 0.001). Flortaucipir PET had a left-lateralized distribution and showed a significant positive correlation with NFT density (r = 0.78; p = 0.023). Flortaucipir PET and NFT density indicated a medial temporal lobe sparing presentation of ADNC, demonstrating that AD does not always target the medial temporal lobe. This study adds additional evidence, in a non-amnestic phenotype of ADNC, that there is a strong correlation between AD PET biomarkers, florbetapir and flortaucipir, with quantitative neuropathology. The atypical and focal presentation of plaque density and florbetapir PET uptake suggests not all amyloid pathology presents as diffuse across neocortex. [ABSTRACT FROM AUTHOR]

Objective: SuperAgers are adults over the age of 80 with superior episodic memory performance and at least average-for-age performance in non-episodic memory domains. This study further characterized the neuropsychological profile of SuperAgers compared to average-for-age episodic memory peers to determine potential cognitive mechanisms contributing to their superior episodic memory performance. Method: Retrospective analysis of neuropsychological test data from 56 SuperAgers and 23 similar-age peers with average episodic memory was conducted. Independent sample t-tests evaluated between-group differences in neuropsychological scores. Multiple linear regression determined the influence of non-episodic memory function on episodic memory scores across participants. Results: As a group, SuperAgers had better scores than their average memory peers on measures of attention, working memory, naming, and speeded set shifting. Scores on tests of processing speed, visuospatial function, verbal fluency, response inhibition, and abstract reasoning did not differ. On an individual level, there was variability among SuperAgers with regard to non-episodic memory performance, with some performing above average-for-age across cognitive domains while others performed in the average-for-age range on non-memory tests. Across all participants, attention and executive function scores explained 20.4% of the variance in episodic memory scores. Conclusions: As a group, SuperAgers outperformed their average memory peers in multiple cognitive domains, however, there was considerable intragroup variability suggesting that SuperAgers' episodic memory strength is not simply related to globally superior cognitive functioning. Attention and executive function performance explained approximately one-fifth of the variance in episodic memory and maybe areas to target with cognitive interventions. [ABSTRACT FROM AUTHOR]

Background: Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials.Method: Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment.Discussion: The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA.Trial Registration: ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia is a neurodegenerative disease that selectively impairs language without equivalent impairment of speech, memory or comportment. In 118 consecutive autopsies on patients with primary progressive aphasia, primary diagnosis was Alzheimer's disease neuropathological changes (ADNC) in 42%, corticobasal degeneration or progressive supranuclear palsy neuropathology in 24%, Pick's disease neuropathology in 10%, transactive response DNA binding proteinopathy type A [TDP(A)] in 10%, TDP(C) in 11% and infrequent entities in 3%. Survival was longest in TDP(C) (13.2 ± 2.6 years) and shortest in TDP(A) (7.1 ± 2.4 years). A subset of 68 right-handed participants entered longitudinal investigations. They were classified as logopenic, agrammatic/non-fluent or semantic by quantitative algorithms. Each variant had a preferred but not invariant neuropathological correlate. Seventy-seven per cent of logopenics had ADNC, 56% of agrammatics had corticobasal degeneration/progressive supranuclear palsy or Pick's disease and 89% of semantics had TDP(C). Word comprehension impairments had strong predictive power for determining underlying neuropathology positively for TDP(C) and negatively for ADNC. Cortical atrophy was smallest in corticobasal degeneration/progressive supranuclear palsy and largest in TDP(A). Atrophy encompassed posterior frontal but not temporoparietal cortex in corticobasal degeneration/progressive supranuclear palsy, anterior temporal but not frontoparietal cortex in TDP(C), temporofrontal but not parietal cortex in Pick's disease and all three lobes with ADNC or TDP(A). There were individual deviations from these group patterns, accounting for less frequent clinicopathologic associations. The one common denominator was progressive asymmetric atrophy overwhelmingly favouring the left hemisphere language network. Comparisons of ADNC in typical amnestic versus atypical aphasic dementia and of TDP in type A versus type C revealed fundamental biological and clinical differences, suggesting that members of each pair may constitute distinct clinicopathologic entities despite identical downstream proteinopathies. Individual TDP(C) participants with unilateral left temporal atrophy displayed word comprehension impairments without additional object recognition deficits, helping to dissociate semantic primary progressive aphasia from semantic dementia. When common and uncommon associations were considered in the set of 68 participants, one neuropathology was found to cause multiple clinical subtypes, and one subtype of primary progressive aphasia to be caused by multiple neuropathologies, but with different probabilities. Occasionally, expected clinical manifestations of atrophy sites were absent, probably reflecting individual peculiarities of language organization. The hemispheric asymmetry of neurodegeneration and resultant language impairment in primary progressive aphasia reflect complex interactions among the cellular affinities of the degenerative disease, the constitutive biology of language cortex, familial or developmental vulnerabilities of this network and potential idiosyncrasies of functional anatomy in the affected individual. [ABSTRACT FROM AUTHOR]

Objective: Primary progressive aphasia (PPA) is a dementia syndrome characterized by initial development of progressive language deficits in the absence of impairment in other cognitive domains. It has historically been difficult to assess the presence or nature of true memory deficits in this population due to interference from language disturbance on task performance. The Three Words Three Shapes test (3W3S) is a relatively easy memory task that evaluates both verbal and nonverbal memory within the same modality and assesses different aspects of memory, including incidental encoding, effortful encoding, delayed recall, and recognition. Persons with PPA show a material-specific dissociation in performance on 3W3S; specifically, deficits in incidental encoding and recall are limited to verbal, not nonverbal material, in PPA, with preserved recognition of both types of information. However, it is unknown whether this pattern persists over time as the disease progresses. Participants and Methods: Participants were 73 participants enrolled in an observational PPA research study at the Mesulam Center for Cognitive Neurology and Alzheimer's Disease (Mage = 66.75 years, SD = 6.77; Meducation = 16.11 years, SD = 2.38; 51% female). Participants were subtyped as semantic (n = 15), logopenic (n = 27), or agrammatic PPA (n = 31) based on Gorno-Tempini et al., 2011, using 3W3S and other neuropsychological measures as described previously. Participants were followed at 2-year intervals and tests were administered longitudinally. All participants in the current study had 3W3S scores from at least two research visits collected between September 2012 and September 2022. Results: There were no significant baseline group differences on 3W3S performance, except for better incidental encoding in the logopenic than the semantic group for shapes (p =.040) and words (p =.043). We then conducted a mixed measures ANOVAs to determine baseline within-person comparisons between words vs shapes. Within individuals, performance on incidental encoding, effortful encoding, and recognition was worse for words than shapes (p s <.01). There was an interaction between material and group for delayed recall (p <.001) such that there was a significantly larger discrepancy between word and shape recall in the semantic (Mdiff = -9.14) compared to logopenic (M diff = -3.07) and agrammatic groups (Mdiff = -2.13). Repeated measures ANOVAs determined changes in scores over time collapsed across PPA subtypes. Incidental encoding (ps = <.01), effortful encoding (ps <.05), and delayed recall (p s <.01) declined for both words and shapes over time. Copy and recognition of words (ps <.05), but not shapes declined over time. Conclusions: The current results are consistent with prior findings of relative preservation of memory for nonverbal compared to verbal material in PPA as measured by 3W3S, especially in the semantic subtype. Learning and recall of words and shapes declined over time in all groups, whereas there was selective decline in copy and recognition of words compared to shapes. These results provide evidence of differential patterns of decline in certain aspects of memory over time in PPA and highlight the relative preservation of memory in this language-focused dementia even over time. [ABSTRACT FROM AUTHOR]

Purpose: The use of telepractice in the field of communication disorders offers an opportunity to provide care for those with primary progressive aphasia (PPA). The Western Aphasia Battery–Revised (WAB-R) is used for differential diagnosis, to assess severity of aphasia, and to identify a language profile of strengths and challenges. Telehealth administration of the WAB-R is supported for those with chronic aphasia due to stroke but has not yet been systematically explored in neurodegenerative dementia syndromes. To fill this gap, in-person and telehealth performance on the WAB-R from participants with mild to moderate PPA was compared. Method: Nineteen participants with mild to moderate PPA were administered the WAB-R in person and over videoconferencing. Videoconferencing administration included modifications to the testing protocol to ensure smooth completion of the assessment. Subtest and Aphasia Quotient (WAB-AQ) summary scores were compared using concordance coefficients to measure the relationship between the administration modes. Results: In-person and telehealth scores showed strong concordance for the WAB-AQ, Auditory Verbal Comprehension subtest, and Naming & Word Finding subtest. The Spontaneous Speech test summary score had slightly lower concordance, indicating the need for caution when comparing these scores across administration modes. Conclusion: These findings support extending the use of telehealth administration of the WAB-R via videoconferencing to those with mild to moderate PPA given appropriate modifications to testing protocol. [ABSTRACT FROM AUTHOR]

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes. [ABSTRACT FROM AUTHOR]

The neurodegenerative diseases underlying primary progressive aphasia have preferred but not invariant clinical associations. Mesulam et al. reveal that tauopathies most frequently lead to agrammatism, Alzheimer pathology to impaired word retrieval, and TDP type C pathology to impaired word comprehension. The common denominator is greater degeneration of the language-dominant hemisphere.Fifty-eight autopsies of patients with primary progressive aphasia are reported. Twenty-three of these were previously described (Mesulam et al., 2008) but had their neuropathological diagnoses updated to fit current criteria. Thirty-five of the cases are new. Their clinical classification was guided as closely as possible by the 2011 consensus guidelines (Gorno-Tempini et al., 2011). Tissue diagnoses included Alzheimer’s disease in 45% and frontotemporal lobar degeneration (FTLD) in the others, with an approximately equal split between TAR DNA binding protein 43 proteinopathies and tauopathies. The most common and distinctive feature for all pathologies associated with primary progressive aphasia was the asymmetric prominence of atrophy, neuronal loss, and disease-specific proteinopathy in the language-dominant (mostly left) hemisphere. The Alzheimer’s disease pathology in primary progressive aphasia displayed multiple atypical features. Males tended to predominate, the neurofibrillary pathology was more intense in the language-dominant hemisphere, the Braak pattern of hippocampo-entorhinal prominence was tilted in favour of the neocortex, and the APOE e4 allele was not a risk factor. Mean onset age was under 65 in the FTLD as well as Alzheimer’s disease groups. The FTLD-TAR DNA binding protein 43 group had the youngest onset and fastest progression whereas the Alzheimer’s disease and FTLD-tau groups did not differ from each other in either onset age or progression rate. Each cellular pathology type had a preferred but not invariant clinical presentation. The most common aphasic manifestation was of the logopenic type for Alzheimer pathology and of the agrammatic type for FTLD-tau. The progressive supranuclear palsy subtype of FTLD-tau consistently caused prominent speech abnormality together with agrammatism whereas FTLD-TAR DNA binding protein 43 of type C consistently led to semantic primary progressive aphasia. The presence of agrammatism made Alzheimer’s disease pathology very unlikely whereas the presence of a logopenic aphasia or word comprehension impairment made FTLD-tau unlikely. The association of logopenic primary progressive aphasia with Alzheimer’s disease pathology was much more modest than has been implied by results of in vivo amyloid imaging studies. Individual features of the aphasia, such as agrammatism and comprehension impairment, were as informative of underlying pathology as more laborious subtype diagnoses. At the single patient level, no clinical pattern was pathognomonic of a specific neuropathology type, highlighting the critical role of biomarkers for diagnosing the underlying disease. During clinical subtyping, some patients were unclassifiable by the 2011 guidelines whereas others simultaneously fit two subtypes. Revisions of criteria for logopenic primary progressive aphasia are proposed to address these challenges. [ABSTRACT FROM PUBLISHER]

Abstract: This study evaluates spelling errors in the three subtypes of primary progressive aphasia (PPA): agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S). Forty-one PPA patients and 36 age-matched healthy controls were administered a test of spelling. The total number of errors and types of errors in spelling to dictation of regular words, exception words and nonwords, were recorded. Error types were classified based on phonetic plausibility. In the first analysis, scores were evaluated by clinical diagnosis. Errors in spelling exception words and phonetically plausible errors were seen in PPA-S. Conversely, PPA-G was associated with errors in nonword spelling and phonetically implausible errors. In the next analysis, spelling scores were correlated to other neuropsychological language test scores. Significant correlations were found between exception word spelling and measures of naming and single word comprehension. Nonword spelling correlated with tests of grammar and repetition. Global language measures did not correlate significantly with spelling scores, however. Cortical thickness analysis based on MRI showed that atrophy in several language regions of interest were correlated with spelling errors. Atrophy in the left supramarginal gyrus and inferior frontal gyrus (IFG) pars orbitalis correlated with errors in nonword spelling, while thinning in the left temporal pole and fusiform gyrus correlated with errors in exception word spelling. Additionally, phonetically implausible errors in regular word spelling correlated with thinning in the left IFG pars triangularis and pars opercularis. Together, these findings suggest two independent systems for spelling to dictation, one phonetic (phoneme to grapheme conversion), and one lexical (whole word retrieval). [Copyright &y& Elsevier]

Primary progressive aphasia (PPA) is a neurodegenerative syndrome that causes a gradual atrophy of the left hemisphere language network, leading to impairments of object naming (anomia) and word comprehension. In 33 human subjects with PPA, object naming and word comprehension were explored with N400 potentials elicited by picture-word or picture-picture matching tasks. Two mechanisms of impairment were identified. In one group of patients, where the object name could be recognized but not retrieved during verbal naming, N400s in picture-word trials were also abnormal, revealing an associative basis for retrieval anomia. In these patients, a putative prephonological signal (i.e., lemma) evoked by the object picture appears to have become too weak to elicit retrieval, but not necessarily too weak to support the informationally less taxing process of recognition. A second group of PPA patients showed more severe naming deficits--the object name was neither verbalized nor recognized. Furthermore, nouns of the same category (but not those of other object categories) could not be identified as mismatches. This blurring of intracategory but not intercategory differentiation of word meaning was correlated with anterior temporal atrophy, predominantly in the left hemisphere, especially along the superior temporal gyrus. Although not part of the classic language network, this area appears critical for proceeding from generic to specific levels of word comprehension and object naming. N400 abnormalities emerged for lexical (picture-word) but not nonverbal (picture-picture) associations, supporting a dual-route rather than amodal organization of object concepts. [ABSTRACT FROM AUTHOR]

Objective: Primary progressive aphasia (PPA) is a dementia syndrome characterized early in its course by gradual dissolution of language and is associated with asymmetric atrophy in the language-dominant hemisphere (usually left). In contrast, behavioral variant frontotemporal dementia (bvFTD) is a dementia syndrome characterized by a progressive early decline in personality and comportment and is associated with relatively symmetric or rightward predominant bifrontal atrophy. This study analyzed the regional and hemispheric distributions of neuronal tau inclusions of the corticobasal degeneration variant of FTLD-tau pathology (FTLD-CBD) in individuals with PPA or bvFTD. The goal was to establish clinicopathologic concordance between FTLD-CBD and behavioral/comportmental vs aphasic dementia syndromes. Participants and Methods: Seven participants were clinically diagnosed with PPA and 6 were diagnosed with bvFTD. All had FTLD-CBD as the principal neuropathologic diagnosis at postmortem study. Sections from the following cortical regions were stained immunohistochemically with AT-8 to visualize neuronal tau inclusions: bilateral middle frontal gyrus (MFG), inferior parietal lobule (IPL), superior temporal gyrus (STG); and unilateral occipital cortex (OCC). Bilateral anterior temporal lobes (ATL) were analyzed in PPA cases only. Unbiased stereological analysis was performed to compare regional and hemispheric distributions between and within PPA vs. bvFTD groups. Results: Overall neocortical (MFG+STG+IPL) tau densities were significantly greater in the PPA group compared to the bvFTD group (p<0.05). Within the bvFTD group, the highest densities of tau inclusions were observed in the right MFG (mean=6,871.17; SD=3,220). In the PPA group, highest densities were observed in the left ATL (mean=9,901.81; SD=6,871). There was leftward hemispheric asymmetry of tau inclusions in IPL, STG and ATL which trended towards significance in the latter (p=0.083). Cortical distributions were symmetric or rightward predominant within the bvFTD group. Occipital cortex was devoid of inclusions. Conclusions: Preliminary stereological findings of FTLD-CBD tau inclusions suggest that the distributions of pathologic tau are different across two distinct clinical dementia phenotypes. The presence of left-sided neuronal tau inclusions in PPA is concordant with the aphasic phenotype whereas symmetric and frontal-predominant densities in bvFTD are consistent with comportmental dysfunction. [ABSTRACT FROM AUTHOR]

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD. [ABSTRACT FROM AUTHOR]

Objective: The Montreal Cognitive Assessment (MoCA) is a popular and simple-to-administer screening instrument to detect cognitive impairment. The MoCA generates a total score and six domain-specific index scores: (1) Memory, (2) Executive Functioning, (3) Attention, (4) Language, (5) Visuospatial, and (6) Orientation. It is unclear whether these MoCA scores can differentiate between distinct clinical dementia syndromes. This study compared MoCA Index scores between amnestic dementia of the Alzheimer's type (DAT) and primary progressive aphasia (PPA), a language-based dementia. Method: Baseline MoCA data were analyzed from 33 DAT, 37 PPA, and 83 cognitively normal individuals enrolled in the Clinical Core of the Northwestern Alzheimer's Disease Center. A one-way analysis of covariance adjusted for age was used to compare MoCA scores among groups. A logistic regression model was implemented to observe individual likelihood of group affiliation based on MoCA Index scores. Results: The mean MoCA total score was significantly higher in controls compared to both patient groups (p <.001) but did not differ between DAT and PPA groups. However, in accordance with salient clinical features commonly observed in DAT versus PPA, Memory and Orientation Index scores were lowest in the DAT group (p <.001), whereas Language and Attention Index scores were lowest in the PPA group (p <.001). Multivariate logistic regression analysis showed that the individual effects of Memory (p =.001), Language (p =.002), and Orientation (p =.025) Indices were significant. Conclusions: MoCA Index scores can help differentiate among distinct cognitive syndromes, suggesting it may be a useful brief screening tool to detect domain-specific cognitive impairment. [ABSTRACT FROM AUTHOR]

Impaired sentence comprehension is observed in the three major subtypes of PPA, with distinct performance patterns relating to impairments in comprehending complex sentences in the agrammatic (PPA-G) and logopenic (PPA-L) variants and word comprehension in the semantic subtype (PPA-S). However, little is known about basic combinatory processes during sentence comprehension in PPA, such the integration of verbs with their subject and object(s) (verb-argument integration). The present study used visual-world eye-tracking to examine real-time verb-argument integration in individuals with PPA (12 with PPA-G, 10 with PPA-L, and 6 with PPA-S) and neurotypical older adults (15). Two baseline experiments probed eye movement control , using a non-linguistic task, and noun comprehension, respectively. Two verb-argument integration experiments examined the effects of verb meaning on (a) lexical access of the verb's direct object (argument access) and (b) selection of a semantically-appropriate direct object (argument selection), respectively. Eye movement analyses were conducted only for trials with correct behavioral responses, allowing us to distinguish accuracy and online processing. The eye movement control experiment revealed no significant impairments in PPA, whereas the noun comprehension experiment revealed reduced accuracy and eye-movement latencies in PPA-S, and to a lesser extent PPA-G. In the argument access experiment, verb meaning facilitated argument access normally in PPA-G and PPA-L; in PPA-S, verb-meaning effects emerged on an atypical time course. In the argument selection experiment, significant impairments in accuracy were observed only in PPA-G, accompanied by markedly atypical eye movement patterns. This study revealed two distinct patterns of impaired verb-argument integration in PPA. In PPA-S, impaired verb-argument integration was observed in the argument access experiment, indicating impairments in basic semantic combinatory processes which likely relate to damage in ventral language pathways. In contrast, listeners with PPA-G showed marked impairments of argument selection, likely relating to damage to left inferior frontal regions. • The study examined verb-argument integration in primary progressive aphasia (PPA). • Eye-tracking (ET) was used to measure language processing and oculomotor control. • ET data revealed impaired language processing but intact oculomotor control in PPA. • Semantic PPA (PPA-S) was associated with impaired verb-argument access. • Agrammatic PPA (PPA-G) was associated with impaired verb-argument selection. [ABSTRACT FROM AUTHOR]

The neuropathologic basis of in vivo cortical atrophy in clinical dementia syndromes remains poorly understood. This includes primary progressive aphasia (PPA), a language‐based dementia syndrome characterized by asymmetric cortical atrophy. The neurofibrillary tangles (NFTs) and amyloid‐ß plaques (APs) of Alzheimer's disease (AD) can cause PPA, but a quantitative investigation of the relationships between NFTs, APs and in vivo cortical atrophy in PPA‐AD is lacking. The present study measured cortical atrophy from corresponding bilateral regions in five PPA‐AD participants with in vivo magnetic resonance imaging scans 7–30 months before death and acquired stereologic estimates of NFTs and dense‐core APs visualized with the Thioflavin‐S stain. Linear mixed models accounting for repeated measures and stratified by hemisphere and region (language vs. non‐language) were used to determine the relationships between cortical atrophy and AD neuropathology and their regional selectivity. Consistent with the aphasic profile of PPA, left language regions displayed more cortical atrophy (P = 0.01) and NFT densities (P = 0.02) compared to right language homologues. Left language regions also showed more cortical atrophy (P < 0.01) and NFT densities (P = 0.02) than left non‐language regions. A subset of data was analyzed to determine the predilection of AD neuropathology for neocortical regions compared to entorhinal cortex in the left hemisphere, which showed that the three most atrophied language regions had greater NFT (P = 0.04) and AP densities (P < 0.01) than the entorhinal cortex. These results provide quantitative evidence that NFT accumulation in PPA selectively targets the language network and may not follow the Braak staging of neurofibrillary degeneration characteristic of amnestic AD. Only NFT densities, not AP densities, were positively associated with cortical atrophy within left language regions (P < 0.01) and right language homologues (P < 0.01). Given previous findings from amnestic AD, the current study of PPA‐AD provides converging evidence that NFTs are the principal determinants of atrophy and clinical phenotypes associated with AD. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes characterized by progressive decline in language or speech. There is a growing number of studies investigating speech-language interventions for PPA/PPAOS. An updated systematic evaluation of the treatment evidence is warranted to inform best clinical practice and guide future treatment research. We systematically reviewed the evidence for behavioral treatment for speech and language in this population. Reviewed articles were published in peer-reviewed journals through 31 May 2021. We evaluated level of evidence, reporting quality, and risk of bias using a modified version of the American Speech-Language Hearing Association (ASHA) Levels of Evidence, an appraisal point system, additional reporting quality and internal/external validity items, and, as appropriate, the Single Case Experimental DesignScale or the Physiotherapy Evidence Database – PsycBITERating Scale for Randomized and Non-Randomized Controlled Trials. Results were synthesized using quantitative summaries and narrative review. A total of 103 studies reported treatment outcomes for 626 individuals with PPA; no studies used the diagnostic label PPAOS. Most studies evaluated interventions for word retrieval. The highest-quality evidence was provided by 45 experimental and quasi-experimental studies (16 controlled group studies, 29 single-subject designs). All (k = 45/45) reported improvement on a primary outcome measure; most reported generalization (k = 34/43), maintenance (k = 34/39), or social validity (k = 17/19) of treatment for at least one participant. The available evidence supports speech-language intervention for persons with PPA; however, treatment for PPAOS awaits systematic investigation. Implications and limitations of the evidence and the review are discussed. [ABSTRACT FROM AUTHOR]

According to the literature on PPA, however, word comprehension is impaired when peak cortical neurodegeneration (i.e. atrophy) is centred in the anterior temporal lobe (ATL) rather than PTL. If ATL atrophy causes comprehension impairment because it deafferents PTL, where Wernicke's area is located, why doesn't atrophy in PTL lead to the same outcome? The article by Matchin, Ouden, Hickok, Hillis, Bonilha and Fridriksson[1] is written to discredit our work on the anatomy of word comprehension in patients with primary progressive aphasia (PPA).[2],[3] For reasons stated below, we believe that the authors have missed their target by a long shot. [Extracted from the article]

The semantic variant of primary progressive aphasia (PPA-S) is diagnosed based on impaired single-word comprehension, but nonverbal impairments in face and object recognition can also be present, particularly in later disease stages. PPA-S is associated with focal atrophy in the left anterior temporal lobe (ATL), often accompanied by a lesser degree of atrophy in the right ATL. According to a dual-route account, the left ATL is critical for verbal access to conceptual knowledge while nonverbal access to conceptual knowledge depends upon the integrity of right ATL. Consistent with this view, single-word comprehension deficits in PPA-S have consistently been linked to the degree of atrophy in left ATL. In the current study we examined object processing and cortical thickness in 19 patients diagnosed with PPA-S, to evaluate the hypothesis that nonverbal object impairments would instead be determined by the amount of atrophy in the right ATL. All patients demonstrated inability to access conceptual knowledge on standardized tests with word stimuli: they were unable to match spoken words with their corresponding pictures on the Peabody Picture Vocabulary Test. Only a minority of patients, however, performed abnormally on an experimental thematic verification task, which requires judgments as to whether pairs of object pictures are thematically-associated, and does not rely on auditory or visual word input. The entire PPA-S group showed cortical thinning in left ATL, but atrophy in right ATL was more prominent in the subgroup with low verification scores. Thematic verification scores were correlated with cortical thickness in the right rather than left ATL, an asymmetric mapping which persisted when controlling for the degree of atrophy in the contralateral hemisphere. These results are consistent with a dual-route account of conceptual knowledge: breakdown of the verbal left hemispheric route produces an aphasic syndrome, which is only accompanied by visual object processing impairments when the nonverbal right hemispheric route is also compromised. [ABSTRACT FROM AUTHOR]

Objective: To quantitatively determine the density and distribution of activated microglia across cortical regions and hemispheres in the brains of primary progressive aphasia (PPA) participants with pathological diagnoses of frontotemporal lobar degeneration with transactive response DNA-binding protein-43 (TDP-43) inclusions and to examine the relationships between microglial densities, patterns of focal atrophy, (TDP-43) inclusions, and clinical phenotype.Methods: Activated microglia and TDP-43 inclusions were visualized in whole-hemisphere brain sections using immunohistochemical methods from five participants with PPA-TDP. Unbiased stereology was used to bilaterally quantify human leuckocyte antigen/D related-positive activated microglia and TDP-43 inclusions across five language-related regions. Density and distribution of both markers were compared across cortical regions and hemispheres, and their relationships to patterns of focal atrophy and clinical phenotype were determined.Results: Activated microglia displayed asymmetric distribution favoring the language-dominant hemisphere, consistent with greater postmortem and/or in vivo atrophy in that hemisphere, in PPA-TDP. In one participant with no asymmetric atrophy, quantitative distribution of microglia also lacked asymmetry. Patterns of microglial activation also showed variation that favored areas of high atrophy in regions affiliated with language function, demonstrating concordance between patterns of microglial activation, atrophy, and clinical phenotype. TDP-43 also showed higher inclusion densities in areas of high atrophy than in regions with low atrophy, but no clear relationship with microglia density at a regional level.Interpretation: The initial activation of microglia is most likely a response to cortical abnormalities in PPA-TDP, which contribute to atrophy. The patterns of microglial activation, TDP-43 inclusion deposition, atrophy, and clinical phenotype suggest that activated microglia may make unique contributions to cortical thinning and TDP-43 inclusion formation. Ann Neurol 2018;83:1096-1104. [ABSTRACT FROM AUTHOR]

Objectives: The Northwestern University SuperAging Program studies a rare cohort of individuals over age 80 with episodic memory ability at least as good as middle-age adults to determine what factors contribute to their elite memory performance. As psychological well-being is positively correlated with cognitive performance in older adults, the present study examined whether aspects of psychological well-being distinguish cognitive SuperAgers from their cognitively average-for-age, same-age peers. Method: Thirty-one SuperAgers and 19 cognitively average-for-age peers completed the Ryff 42-item Psychological Well-Being questionnaire, comprised of 6 subscales: Autonomy, Positive Relations with Others, Environmental Mastery, Personal Growth, Purpose in Life, and Self-Acceptance. Results: The groups did not differ on demographic factors, including estimated premorbid intelligence. Consistent with inclusion criteria, SuperAgers had better episodic memory scores. Compared to cognitively average-for-age peers, SuperAgers endorsed greater levels of Positive Relations with Others. The groups did not differ on other PWB-42 subscales. Discussion: While SuperAgers and their cognitively average-for-age peers reported similarly high levels of psychological well-being across multiple dimensions, SuperAgers endorsed greater levels of positive social relationships. This psychological feature could conceivably have a biological relationship to the greater thickness of the anterior cingulate gyrus and higher density of von Economo neurons previously reported in SuperAgers. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia (PPA) is clinically defined by an initial loss of language function and preservation of other cognitive abilities, including episodic memory. While PPA primarily affects the left-lateralized perisylvian language network, some clinical neuropsychological tests suggest concurrent initial memory loss. The goal of this study was to test recognition memory of objects and words in the visual and auditory modality to separate language-processing impairments from retentive memory in PPA. Individuals with non-semantic PPA had longer reaction times and higher false alarms for auditory word stimuli compared to visual object stimuli. Moreover, false alarms for auditory word recognition memory were related to cortical thickness within the left inferior frontal gyrus and left temporal pole, while false alarms for visual object recognition memory was related to cortical thickness within the right-temporal pole. This pattern of results suggests that specific vulnerability in processing verbal stimuli can hinder episodic memory in PPA, and provides evidence for differential contributions of the left and right temporal poles in word and object recognition memory. [ABSTRACT FROM AUTHOR]

Mutations in the gene encoding tau (MAPT) cause frontotemporal dementia spectrum disorders. A rare tau variant p.A152T was reported as a risk factor for frontotemporal dementia spectrum and Alzheimer's disease in an initial case-control study. Such findings need replication in an independent cohort. We analysed an independent multinational cohort comprising 3100 patients with neurodegenerative disease and 4351 healthy control subjects and found p.A152T associated with significantly higher risk for clinically defined frontotemporal dementia and progressive supranuclear palsy syndrome. To assess the functional and biochemical consequences of this variant, we generated transgenic zebrafish models expressing wild-type or A152T-tau, where A152T caused neurodegeneration and proteasome compromise. Impaired proteasome activity may also enhance accumulation of other proteins associated with this variant. We increased A152T clearance kinetics by both pharmacological and genetic upregulation of autophagy and ameliorated the disease pathology observed in A152T-tau fish. Thus, autophagy-upregulating therapies may be a strategy for the treatment for tauopathies. [ABSTRACT FROM AUTHOR]

In the next two decades, there will be advances in the diagnosis and treatment of the disorders of aging that have the potential to change the way speech-language pathologists (SLPs) are trained and provide services to individuals with a continuum of cognitive communication challenges. SLPs will address the needs of the aging adult who continues to reside in the community and desires to maintain an independent and meaningful life, as well as those who require a supportive residential setting to achieve a satisfying quality of life. Evidence-based strategies and intervention approaches for the range of goals that will address the desired functions of a meaningful life for individuals faced with cognitive communicative challenges are outlined. Institutional barriers to the implementation of documented evidence-based approaches will need to be reduced through a variety of organizational and systems changes. The projected outcome of these changes will be the creation of a person-centered culture of care that promotes dignity, choice, and engagement in meaningful activities through the end of life. [ABSTRACT FROM AUTHOR]

The article discusses a study to classify frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) based on the distribution of neuronal cytoplasmic inclusions, dystrophic neurites, and neuronal intranuclear inclusions and mentions the use of TDP-43-ir immunohistochemistry.

Introduction: Eye movement studies can uncover subtle aspects of language processing impairment in individuals with primary progressive aphasia (PPA), who may have difficulty understanding words. This study examined eye movement patterns on a word-object matching task in response to varying levels of word-knowledge in PPA.Methods: Participants with semantic and non-semantic PPA completed an object-matching task, where a word was presented and participants then selected the corresponding pictured object from an array. Afterwards, participants defined words for trials to which they incorrectly pointed. Linear mixed-effects analyses examined fixation differences on targets and related and unrelated foils.Results: On incorrectly-pointed trials, participants demonstrated greater fixation duration on related foils, demonstrating intra-category blurring. For words that could not be defined, there was similar fixation duration on related and unrelated foils, demonstrating inter-category semantic blurring.Discussion: This study demonstrated that fixation patterns reflect varying levels of word knowledge in PPA. [ABSTRACT FROM AUTHOR]

We aimed to determine whether (18) F-florbetapir amyloid positron emission tomography imaging shows a clinically concordant, left-hemisphere-dominant pattern of deposition in primary progressive aphasia (PPA). Elevated cortical amyloid (Aβ(+) ) was found in 19 of 32 PPA patients. Hemispheric laterality of amyloid burden was compared between Aβ(+) PPA and an Aβ(+) amnestic dementia groups (n = 22). The parietal region showed significantly greater left lateralized amyloid uptake in the PPA group than the amnestic group (p < 0.007), consistent with the left lateralized pattern of neurodegeneration in PPA. These results suggest that the cortical distribution of amyloid may have a greater clinical concordance than previously reported. [ABSTRACT FROM AUTHOR]