Behavioral Treatment for Speech and Language in Primary Progressive Aphasia and Primary Progressive Apraxia of Speech: A Systematic Review.

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 Design Scale or the Physiotherapy Evidence Database - PsycBITE Rating 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.

Neuropathological fingerprints of survival, atrophy and language in primary progressive aphasia.

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.

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

Nosology of Primary Progressive Aphasia and the Neuropathology of Language.

Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration (FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.

Prevalence of amyloid-ß pathology in distinct variants of primary progressive aphasia.

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

A Life Participation Approach to Primary Progressive Aphasia Intervention.

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.

Functional Connectivity is Reduced in Early-stage Primary Progressive Aphasia When Atrophy is not Prominent.

Primary progressive aphasia (PPA) is a clinical syndrome of language decline caused by neurodegenerative pathology. Although language impairments in PPA are typically localized via the morphometric assessment of atrophy, functional changes may accompany or even precede detectable structural alterations, in which case resting state functional connectivity (RSFC) could provide an alternative approach. The goal of this study was to determine whether language network RSFC is reduced in early-stage PPA when atrophy is not prominent. We identified 10 individuals with early-stage agrammatic variant of PPA with no prominent cortical thinning compared with nonaphasic controls. RSFC between 2 nodes of the language network and 2 nodes of the default mode network were compared between agrammatic variant of PPA and healthy control participants. Language network connectivity was comparable with controls among patients with milder agrammatism, but was significantly reduced in patients with more pronounced agrammatism. No group differences were observed in default mode network connectivity, demonstrating specificity of findings. In early stages of PPA when cortical atrophy is not prominent, RSFC provides an alternative method for probing the neuroanatomic substrates of language impairment. RSFC may be of particular utility in studies on early interventions for neurodegenerative disease, either to identify anatomic targets for intervention or as an outcome measure of therapeutic efficacy.

The Wernicke conundrum and the anatomy of language comprehension in primary progressive aphasia.

Wernicke's aphasia is characterized by severe word and sentence comprehension impairments. The location of the underlying lesion site, known as Wernicke's area, remains controversial. Questions related to this controversy were addressed in 72 patients with primary progressive aphasia who collectively displayed a wide spectrum of cortical atrophy sites and language impairment patterns. Clinico-anatomical correlations were explored at the individual and group levels. These analyses showed that neuronal loss in temporoparietal areas, traditionally included within Wernicke's area, leave single word comprehension intact and cause inconsistent impairments of sentence comprehension. The most severe sentence comprehension impairments were associated with a heterogeneous set of cortical atrophy sites variably encompassing temporoparietal components of Wernicke's area, Broca's area, and dorsal premotor cortex. Severe comprehension impairments for single words, on the other hand, were invariably associated with peak atrophy sites in the left temporal pole and adjacent anterior temporal cortex, a pattern of atrophy that left sentence comprehension intact. These results show that the neural substrates of word and sentence comprehension are dissociable and that a circumscribed cortical area equally critical for word and sentence comprehension is unlikely to exist anywhere in the cerebral cortex. Reports of combined word and sentence comprehension impairments in Wernicke's aphasia come almost exclusively from patients with cerebrovascular accidents where brain damage extends into subcortical white matter. The syndrome of Wernicke's aphasia is thus likely to reflect damage not only to the cerebral cortex but also to underlying axonal pathways, leading to strategic cortico-cortical disconnections within the language network. The results of this investigation further reinforce the conclusion that the left anterior temporal lobe, a region ignored by classic aphasiology, needs to be inserted into the language network with a critical role in the multisynaptic hierarchy underlying word comprehension and object naming.

Eye movements as probes of lexico-semantic processing in a patient with primary progressive aphasia.

Eye movement trajectories during a verbally cued object search task were used as probes of lexico-semantic associations in an anomic patient with primary progressive aphasia. Visual search was normal on trials where the target object could be named but became lengthy and inefficient on trials where the object failed to be named. The abnormality was most profound if the noun denoting the object could not be recognized. Even trials where the name of the target object was recognized but not retrieved triggered abnormal eye movements, demonstrating that retrieval failures can have underlying associative components despite intact comprehension of the corresponding noun.

Am I looking at a cat or a dog? Gaze in the semantic variant of primary progressive aphasia is subject to excessive taxonomic capture.

Object naming impairments or anomias are the most frequent symptom in aphasia, and can be caused by a variety of underlying neurocognitive mechanisms. Anomia in neurodegenerative or primary progressive aphasias (PPA) often appears to be based on taxonomic blurring of word meaning: words such as "dog" and "cat" are still recognized generically as referring to animals, but are no longer conceptually differentiated from each other, leading to coordinate errors in word-object matching. This blurring is the hallmark symptom of the "semantic variant" of PPA, who invariably show focal atrophy in the left anterior temporal lobe. In this study we used eye tracking to characterize information processing online (in real time) as non-aphasic controls, semantic and non-semantic PPA participants completed a word-to-object matching task. All participants (including controls) showed taxonomic capture of gaze, spending more time viewing foils that were from the same category as the target compared to unrelated foils, but capture was more extreme in the semantic PPA group. The semantic group showed heightened capture even on trials where they ultimately pointed to the correct target, demonstrating the superiority of eye movements over traditional testing methods in detecting subtle processing impairments. Heightened capture was primarily driven by a tendency to direct gaze back and forth, repeatedly, between a set of related foils on each trial, a behavior almost never shown by controls or non-semantic participants. This suggests semantic PPA participants were accumulating and weighing evidence for a probabilistic rather than definitive mapping between the noun and several candidate objects. Neurodegeneration in PPA thus appears to distort lexical concepts prior to extinguishing them altogether, causing uncertainty in recognition and word-object matching.

Asymmetry and heterogeneity of Alzheimer's and frontotemporal pathology in primary progressive aphasia.

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.

Words and objects at the tip of the left temporal lobe in primary progressive aphasia.

Eleven of 69 prospectively enrolled primary progressive aphasics were selected for this study because of peak atrophy sites located predominantly or exclusively within the anterior left temporal lobe. Cortical volumes in these areas were reduced to less than half of control values, whereas average volume elsewhere in the left hemisphere deviated from control values by only 8%. Failure to name objects emerged as the most consistent and severe deficit. Naming errors were attributed to pure retrieval failure if the object could not be named even when the denoting word was understood, the object recognized and the two accurately matched. Surprisingly many of the naming errors reflected pure retrieval failures, without discernible semantic or associative component. The remaining set of errors had associative components. These errors reflected the inability to define the word denoting the object more often than the inability to define the nature of the pictured object. In a separate task where the same object had to be linked to verbal or non-verbal associations, performance was abnormal only in the verbal format. Excessive taxonomic interference was observed for picture-word, but not picture-picture, matching tasks. This excessive interference reflected a blurring of intra- rather than inter-category distinctions as if the acuity of word-object associations had been diminished so that correspondences were easier to recognize at generic than specific levels. These dissociations between verbal and non-verbal markers of object knowledge indicate that the reduced neural mass at peak atrophy sites of the left temporal tip, accounting for half or more of the presumed premorbid volume, was unlikely to have contained domain-independent semantic representations of the type that would be expected in a strictly amodal hub. A more likely arrangement entails two highly interactive routes--a strongly left lateralized temporosylvian language network for verbal concepts, and a presumably more bilateral or right-sided inferotemporal/fusiform object recognition network, which remained relatively spared because peak atrophy sites were concentrated on the left. The current results also suggest that the left anterior temporal neocortex should be inserted into the language network where it is likely to play a major role in selecting verbal labels for objects and mediating the progression of word comprehension from generic to specific levels of precision.

Measuring Multidimensional Aspects of Health in the Oldest Old Using the NIH Toolbox: Results From the ARMADA Study.

OBJECTIVE: The percentage of older adults living into their 80s and beyond is expanding rapidly. Characterization of typical cognitive performance in this population is complicated by a dearth of normative data for the oldest old. Additionally, little attention has been paid to other aspects of health, such as motor, sensory, and emotional functioning, that may interact with cognitive changes to predict quality of life and well-being. The current study used the NIH Toolbox (NIHTB) to determine age group differences between persons aged 65-84 and 85+ with normal cognition. METHOD: Participants were recruited in two age bands (i.e., 65-84 and 85+). All participants completed the NIHTB Cognition, Motor, Sensation, and Emotion modules. Independent-samples t-tests determined age group differences with post-hoc adjustments using Bonferroni corrections. All subtest and composite scores were then regressed on age and other demographic covariates. RESULTS: The 65-84 group obtained significantly higher scores than the 85+ group across all cognitive measures except oral reading, all motor measures except gait speed, and all sensation measures except pain interference. Age remained a significant predictor after controlling for covariates. Age was not significantly associated with differences in emotion scores. CONCLUSIONS: Results support the use of the NIHTB in persons over 85 with normal cognition. As expected, fluid reasoning abilities and certain motor and sensory functions decreased with age in the oldest old. Inclusion of motor and sensation batteries is warranted when studying trajectories of aging in the oldest old to allow for multidimensional characterization of health.

Neural mechanisms of object naming and word comprehension in primary progressive aphasia.

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.

Youthful memory capacity in old brains: anatomic and genetic clues from the Northwestern SuperAging Project.

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 age-matched 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 ɛ4 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.

Behavioural interventions for enhancing life participation in behavioural variant frontotemporal dementia and primary progressive aphasia.

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.

Memory Resilience in Alzheimer Disease With Primary Progressive Aphasia.

OBJECTIVE: To determine whether memory is preserved longitudinally in primary progressive aphasia (PPA) associated with Alzheimer disease (AD) and to identify potential factors that maintain memory despite underlying neurofibrillary degeneration of mediotemporal memory areas. METHODS: Longitudinal memory assessment was done in 17 patients with PPA with autopsy or biomarker evidence of AD (PPA-AD) and 14 patients with amnestic dementia of the Alzheimer type with AD at autopsy (DAT-AD). RESULTS: In PPA-AD, episodic memory, tested with nonverbal items, was preserved at the initial testing and showed no decline at retesting 2.35 ± 0.78 years later, at which time symptoms had been present for 6.26 ± 2.21 years. In contrast, language functions declined significantly during the same period. In DAT-AD, both verbal memory and language declined with equal severity. Although imaging showed asymmetric left-sided mediotemporal atrophy in PPA-AD, autopsy revealed bilateral hippocampo-entorhinal neurofibrillary degeneration at Braak stages V and VI. Compared to DAT-AD, however, the PPA-AD group had lower incidence of APOE ε4 and of mediotemporal TAR DNA-binding protein 43 (TDP-43) pathology. CONCLUSIONS: Memory preservation in PPA is not just an incidental finding at onset but a core feature that persists for years despite the hippocampo-entorhinal AD neuropathology that is as severe as that of DAT-AD. Asymmetry of mediotemporal atrophy and a lesser impact of APOE ε4 and of TDP-43 on the integrity of memory circuitry may constitute some of the factors underlying this resilience. Our results also suggest that current controversies on memory in PPA-AD reflect inconsistencies in the diagnosis of logopenic PPA, the clinical variant most frequently associated with AD. CLINICALTRIALSGOV IDENTIFIER: NCT00537004 and NCT03371706.

Modularity and granularity across the language network-A primary progressive aphasia perspective.

Tests of grammar, repetition and semantics were administered to 62 prospectively enrolled right-handed participants with primary progressive aphasia (PPA). Structural brain images were obtained at the time of testing. Regression analyses uncovered 3 clearly delineated non-overlapping left hemisphere clusters where cortical thinning (atrophy) was significantly correlated with impaired performance. A morphosyntactic cluster associated with the grammaticality of sentence construction was located predominantly within the middle and inferior frontal gyri; a phonolexical cluster associated with language repetition was located in the temporoparietal junction; a lexicosemantic cluster associated with object naming and single word comprehension was located within the middle and anterior parts of the temporal lobe and extended into insular, orbitofrontal, and mediotemporal cortices. Commonality analyses were undertaken to explore whether these three clusters were as modular as indicated by the regression analyses or whether some underlying functional granularity could be uncovered. Modularity was defined as the exclusive association of an anatomical cluster with a single type of language task whereas granularity was defined as the association of a single anatomical cluster with more than one type of language task. The commonality analyses revealed a predominantly modular organization with quantitatively minor instances of inter-cluster granularity. The results also reconfirmed previous work on PPA which had shown that Wernicke's area is not essential for word comprehension, that naming impairments can be based either on deficits of lexical retrieval or word comprehension, and that the essential substrates of word comprehension encompass much wider areas of the temporal lobe than the temporal pole. The anatomy of the language network has traditionally been explored through patients with focal cerebrovascular accidents and experiments based on functional activation. Investigations on PPA are showing that focal neurodegenerations can add new perspectives to existing models of the language network.

Speech and Language Presentations of FTLD-TDP Type B Neuropathology.

Four right-handed patients who presented with an isolated impairment of speech or language had transactive response DNA-binding protein of 43 kDa (TDP-43) type B pathology. Comportment and pyramidal motor function were preserved at presentation. Three of the cases developed axial rigidity and oculomotor findings late in their course with no additional pyramidal or lower motor neuron impairments. However, in all 4 cases, postmortem examination disclosed some degree of upper and lower motor neuron disease (MND) pathology in motor cortex, brainstem, and spinal cord. Although TDP-43 type B pathology is commonly associated with MND and behavioral variant frontotemporal dementia, it is less recognized as a pathologic correlate of primary progressive aphasia and/or apraxia of speech as the presenting syndrome. These cases, taken together, contribute to the growing heterogeneity in clinical presentations associated with TDP pathology. Additionally, 2 cases demonstrated left anterior temporal lobe atrophy but without word comprehension impairments, shedding light on the relevance of the left temporal tip for single-word comprehension.

Familial language network vulnerability in primary progressive aphasia.

OBJECTIVE: To investigate evidence of the potential role of early cortical vulnerability in the development of primary progressive aphasia (PPA). METHOD: A woman with a diagnosis of PPA and her 9 adult siblings, 7 with developmental language disabilities, underwent neuropsychological testing, structural MRI, and resting-state fMRI. Whole-exome sequencing was conducted for genes associated with dyslexia or with neurodegenerative dementia. RESULTS: The siblings demonstrated lower verbal than nonverbal cognitive test scores in a developmental dyslexia pattern. On structural MRI, although the siblings did not differ from controls in total brain volume, the left hemisphere language area volume was significantly smaller than the right. Furthermore, cortical connectivity between the left superior temporal area, previously identified as the region of peak atrophy in the proband early in the course of illness, and adjacent language network components, including the planum temporale, was decreased in the siblings. No distinctive genetic signatures were identified. CONCLUSION: This report further supports the hypothesis that at least some cases of PPA may be based on a familial language network vulnerability that interferes with the acquisition of language in some members and that makes the language network a locus of least resistance to the effects of an independently late-arising neurodegenerative disease in others. This association offers a conceptual model to explain why identical neurodegenerative diseases may selectively target the language network in some individuals while targeting networks that regulate memory or behavior in others. The genetic basis for this vulnerability remains to be determined.