Primary progressive aphasia (PPA) is a group of disorders with progressive language impairment. Abnormal behaviour may develop in PPA as the disease evolves, but the clinical features and brain basis of behavioural change in PPA have not been fully defined. 33 PPA patients (9 semantic dementia, SD, 14 progressive nonfluent aphasia, PNFA, 7 logopenic/phonological aphasia, LPA and 3 patients with a PPA syndrome in association with progranulin mutations, GRN-PPA) were assessed using the Neuropsychiatric Inventory to record behavioural changes, as well as volumetric MR imaging. The most common abnormal behaviours in SD were irritability, disinhibition, depression and abnormal appetite, in PNFA apathy, agitation and depression, in LPA anxiety, irritability, agitation and apathy, and in GRN-PPA apathy and irritability. Voxel-based morphometry analysis revealed greater atrophy of right lateral orbitofrontal cortex (OFC) in PPA patients with anxiety, apathy, irritability/lability and abnormal appetite/eating disorders, and greater atrophy of left OFC in those with disinhibition. Areas involved beyond OFC included right dorsolateral prefrontal cortex (apathy), right cingulate (irritability/lability) and left anterior superior and medial temporal lobe (disinhibition). Behavioural abnormalities may be clinically significant in PPA, and these abnormalities are underpinned by atrophy of overlapping frontotemporal networks centred on OFC.
Primary progressive aphasia; Frontotemporal lobar degeneration; Frontotemporal dementia
The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity.
Primary progressive aphasia; DTI; Networks; White matter
The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses. Five of nine patients with LPA had cerebrospinal fluid biomarkers consistent with Alzheimer (AD) pathology (AD-PPA) and 2/9 patients had progranulin (GRN) mutations (GRN-PPA). The LPA group had tissue loss in a widespread left hemisphere network. Compared with PNFA and SD, the LPA group had more extensive involvement of grey matter in posterior temporal and parietal cortices and long association white matter tracts. Overlapping but distinct networks were involved in the AD-PPA and GRN-PPA subgroups, with more anterior temporal lobe involvement in GRN-PPA. The importance of these findings is threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.
Primary progressive aphasia; Frontotemporal dementia; Frontotemporal lobar degeneration; Logopenic aphasia
Primary progressive aphasia (PPA) is a form of dementia caused by frontotemporal lobar degeneration. Unlike aphasia due to stroke, in which the association between particular aphasia profiles and insight has been well characterized, this relationship has not been investigated in PPA. Reduced insight is seen in other neurological conditions, but tends to involve right hemisphere damage, whereas PPA is predominantly a left hemisphere disorder. The aim of the current study was to examine whether fluent aphasia with less meaningful speech output, associated with diminished insight in stroke, is also characteristic of PPA patients with reduced insight. Fourteen PPA patients were studied. Results indicated that reduced information content in speech and poor performance on a nonlanguage test, the Pyramids and Palm Trees test, predicted reduced insight. This study has implications for the anatomical network involved in insight and clinical implications in terms of selecting interventions appropriate for individual patients with PPA.
dementia; primary progressive aphasia; insight; awareness; frontotemporal dementia
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.
To compare the distribution of error types across subgroups of primary progressive aphasia and poststroke aphasia in different vascular locations.
We analyzed naming errors in 49 individuals with acute left hemisphere ischemic stroke and 55 individuals with three variants of primary progressive aphasia. Location of atrophy or ischemic stroke was characterized using MRI.
We found that distribution of error types was very similar across all subgroups, irrespective of the site or etiology of the lesion. The only significant difference across groups was the percentage of circumlocutions (F(7, 96) = 3.02, p = .005). Circumlocution errors were highest among logopenic variant PPA (24%) and semantic variant PPA (24%). Semantic coordinate errors were common in all groups, probably because they can arise from disruption of different cognitive processes underlying naming and, therefore, from different locations of brain damage.
Semantic errors are common among all types of primary progressive aphasia and poststroke aphasia, and the type of error depends in part on the location of damage.
naming errors; stroke aphasia; primary progressive aphasia
In an era of disease-modifying treatments, the non-fluent/agrammatic variant of primary progressive aphasia (naPPA) may help screen for a specific cause of neurodegenerative disease. However, there are controversies surrounding the identification of naPPA. This review describes the characteristic features associated with this discrete, young-onset neurodegenerative condition. Patients with naPPA have a distinct limitation in language emphasizingtheir poor grammatical comprehension and expression, as well as a disorder of speech sound production. Imaging studies associate an impairment of this uniquely human language capacity with disruption of a large-scale neural network centered in left inferior frontal and anterior-superior temporal regions. This corresponds to thepathologic burden of disease anatomically focused in left inferior frontal and anterior-superior temporal regions. A review of the histopathology underlying naPPA relates this condition to frontotemporal lobar degeneration spectrum pathology involving the microtubule-associated protein tau in a majority of cases. While much work remains to be done, these observations point to unique clinical-pathological correlations that can advance care for an important class of diseases while supplementing our knowledge of human cognitive neuroscience.
Primary progressive aphasia (PPA) is a neurodegenerative disorder with language impairment as the primary feature. Different subtypes have been described and the 3 best characterized are progressive nonfluent aphasia (PNFA), semantic dementia (SD) and logopenic/phonological aphasia (LPA). Of these subtypes, LPA is most commonly associated with Alzheimer's disease (AD) pathology. However, the features of PPA associated with AD have not been fully defined. Here we retrospectively identified 14 patients with PPA and either pathologically confirmed AD or cerebrospinal fluid (CSF) biomarkers consistent with AD. Analysis of neurological and neuropsychological features revealed that all patients had a syndrome of LPA with relatively nonfluent spontaneous speech, phonemic errors, and reduced digit span; most patients also had impaired verbal episodic memory. Analysis of the pattern of cortical thinning in these patients revealed left posterior superior temporal, inferior parietal, medial temporal, and posterior cingulate involvement and in patients with more severe disease, increasing involvement of left anterior temporal and frontal cortices and right hemisphere areas in the temporo-parietal junction, posterior cingulate, and medial temporal lobe. We propose that LPA may be a “unihemispheric” presentation of AD, and discuss this concept in relation to accumulating evidence concerning language dysfunction in AD.
Frontotemporal dementia; Frontotemporal lobar degeneration; Primary progressive aphasia; Logopenic aphasia; Progressive nonfluent aphasia; Alzheimer's disease
Prosody has been little studied in the primary progressive aphasias (PPAs), a group of neurodegenerative disorders presenting with progressive language impairment.
Here we conducted a systematic investigation of different dimensions of prosody processing (acoustic, linguistic and emotional) in a cohort of 19 patients with nonfluent PPA syndromes (11 with progressive nonfluent aphasia, PNFA; five with progressive logopenic/phonological aphasia, LPA; three with progranulin-associated aphasia, GRN-PPA) compared with a group of healthy older controls. Voxel-based morphometry (VBM) was used to identify neuroanatomical associations of prosodic functions.
Broadly comparable receptive prosodic deficits were exhibited by the PNFA, LPA and GRN-PPA subgroups, for acoustic, linguistic and affective dimensions of prosodic analysis. Discrimination of prosodic contours was significantly more impaired than discrimination of simple acoustic cues, and discrimination of intonation was significantly more impaired than discrimination of stress at phrasal level. Recognition of vocal emotions was more impaired than recognition of facial expressions for the PPA cohort, and recognition of certain emotions (in particular, disgust and fear) was relatively more impaired than others (sadness, surprise). VBM revealed atrophy associated with acoustic and linguistic prosody impairments in a distributed cortical network including areas likely to be involved in perceptual analysis of vocalisations (posterior temporal and inferior parietal cortices) and working memory (fronto-parietal circuitry). Grey matter associations of emotional prosody processing were identified for negative emotions (disgust, fear, sadness) in a broadly overlapping network of frontal, temporal, limbic and parietal areas.
Taken together, the findings show that receptive prosody is impaired in nonfluent PPA syndromes, and suggest a generic early perceptual deficit of prosodic signal analysis with additional relatively specific deficits (recognition of particular vocal emotions).
Primary progressive aphasia; Frontotemporal dementia; Frontotemporal lobar degeneration; Logopenic aphasia; Progranulin; Prosody
Primary progressive aphasia (PPA) results from an asymmetric degeneration of the language dominant (usually left) hemisphere and can be associated with the pathology of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). This study aimed to investigate whether the anatomic distribution of TDP-43 inclusions displayed a corresponding leftward asymmetry in a patient with PPA with a mutation in the progranulin gene and FTLD pathology.
Brain tissue from a 65-year-old patient with PPA and progranulin mutation was analyzed using immunohistochemical methods for TDP-43. Analysis was performed in the superior temporal gyrus, inferior temporal gyrus, inferior parietal lobule, orbitofrontal cortex, entorhinal cortex, and dentate gyrus. Neuronal intranuclear inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites were quantified using modified stereologic analysis. Analysis of variance was used to determine significant effects.
All 3 types of inclusions predominated on the left side of analyzed cortical regions. They were also more frequent in language areas than in memory-related areas.
These results demonstrate a phenotypically concordant distribution of abnormal TDP-43 inclusions in primary progressive aphasia (PPA). This contrasts with PPA cases with Alzheimer pathology where no consistent leftward asymmetry of neurofibrillary degeneration or amyloid deposition has been demonstrated despite the leftward asymmetry of the atrophy, and where neurofibrillary tangles show a greater density in memory than language areas despite the predominantly aphasic phenotype. This case suggests that the TDP-43 inclusions in PPA–frontotemporal lobar degeneration are more tightly linked to neuronal death and dysfunction than neurofibrillary and amyloid deposits in PPA–Alzheimer disease.
= Alzheimer disease;
= anterior part of inferior parietal lobule;
= dentate gyrus;
= dystrophic neurite;
= entorhinal cortex;
= frontotemporal lobar degeneration;
= inferior temporal gyrus;
= neuronal cytoplasmic inclusion;
= neuronal intranuclear inclusion;
= orbitofrontal cortex;
= posterior part of inferior parietal lobule;
= primary progressive aphasia;
= superior temporal gyrus.
Many patients with primary progressive aphasia (PPA) are impaired in syntactic production. Because most previous studies of expressive syntax in PPA have relied on quantitative analysis of connected speech samples, which is a relatively unconstrained task, it is not well understood which specific syntactic structures are most challenging for these patients. We used an elicited syntactic production task to identify which syntactic structures pose difficulties for 31 patients with three variants of PPA: non-fluent/agrammatic, semantic and logopenic. Neurodegenerative and healthy age-matched participants were included as controls. As expected, non-fluent/agrammatic patients made the most syntactic errors. The structures that resulted in the most errors were constructions involving third person singular present agreement, and constructions involving embedded clauses. Deficits on this elicited production task were associated with atrophy of the left posterior inferior frontal gyrus.
syntax; production; primary progressive aphasia; voxel-based morphometry
Primary progressive aphasia (PPA) is a neurodegenerative disorder with no effective pharmacological treatment. Cognition-based interventions are adequate alternatives, but their benefit has not been thoroughly explored. Our aim was to study the effect of speech and language therapy (SLT) on naming ability in PPA.
An open parallel prospective longitudinal study involving two centers was designed to compare patients with PPA submitted to SLT (1 h/week for 11 months) with patients receiving no therapy. Twenty patients were enrolled and undertook baseline language and neuropsychological assessments; among them, 10 received SLT and 10 constituted an age- and education-matched historical control group. The primary outcome measure was the change in group mean performance on the Snodgrass and Vanderwart naming test between baseline and follow-up assessments.
Intervention and control groups did not significantly differ on demographic and clinical variables at baseline. A mixed repeated measures ANOVA revealed a significant main effect of therapy (F(1,18) = 10.763; p = 0.005) on the performance on the Snodgrass and Vanderwart naming test.
Although limited by a non-randomized open study design with a historical control group, the present study suggests that SLT may have a benefit in PPA, and it should prompt a randomized, controlled, rater-blind clinical trial.
Primary progressive aphasia; Dementia; Cognitive rehabilitation; Speech and language therapy
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).
Dementia; Primary Progressive Aphasia; Agraphia; Cortical atrophy; Frontotemporal dementia
We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E ε4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.
The objective of this study is to determine which cognitive processes underlying spelling are most affected in the three variants of Primary Progressive Aphasia (PPA): Logopenic variant primary progressive aphasia (lvPPA), Semantic variant primary progressive aphasia (svPPA), and Nonfluent variant primary progressive aphasia (nfvPPA).
23 PPA patients were administered The Johns Hopkins Dysgraphia Battery to assess spelling. Subtests evaluate for effects of word frequency, concreteness, word length, grammatical word class, lexicality (words vs. pseudowords), and “regularity” by controlling for the other variables. Significant effects of each variable were identified with chi square tests. Responses on all spelling to dictation tests were scored by error type. 16 of the 23 subjects also had a high resolution MRI brain scan to identify areas of atrophy.
We identified 4 patterns of spelling that could be explained by damage to one or more cognitive processes underlying spelling. Nine patients (3 unclassifiable, 4 with lvPPA, 2 with svPPA) had dysgraphia explicable by impaired access to lexical representations, with reliance on sublexical phonology-to-orthography conversion (POC). Two patients (with nfvPPA) showed dysgraphia explicable by impaired access to lexical representations and complete disruption of sublexical POC. Seven patients (4 with lvPPA, 1 with svPPA, 2 unclassifiable) showed dysgraphia explicable by impaired access to lexical-semantic representations and/or lexical representations with partially spared sublexical POC mechanisms. Five patients (1 with nfvPPA, 2 with svPPA, 1 with lvPPA, and 1 unclassifiable) showed dysgraphia explicable by impairment of the graphemic buffer.
Any cognitive process underlying spelling can be affected in PPA. Predominance of phonologically plausible errors, more accurate spelling of regular words than irregular words, and more accurate spelling of pseudowords than words (indicating spared POC mechanisms) may indicate a low probability of progression to nfvPPA.
Primary Progressive Aphasia; dysgraphia; spelling errors; neuroimaging; aphasia
To estimate the quantity of informal care associated with neuropsychiatric symptoms in older adults with cognitive impairment
The Aging, Demographics, and Memory Study
A sample (n=450) of adults aged 71 and older with cognitive impairment drawn form the Health and Retirement Study
The presence of neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, apathy, elation, anxiety, disinhibition, irritation, and aberrant motor behaviors) was identified using the Neuropsychiatric Inventory. Cognitive category (normal, cognitive impairment without dementia [CIND], or dementia) was assigned by a consensus panel. The hours per week of active help and supervision were ascertained by informant questionnaire.
Among older adults with CIND or dementia, those with no neuropsychiatric symptoms received an average of 10.2 hours of active help and 10.9 hours of supervision per week from informal caregivers. Those with 1 or 2 neuropsychiatric symptoms received an additional 10.0 hours of active help and 12.4 hours of supervision per week, while those with 3 or more symptoms received an additional 18.2 hours of active help and 28.7 hours of supervision per week (p < .001). The presence of irritation (14.7 additional hours) was associated with the greatest number of additional hours of active help. The presence of aberrant motor behaviors (17.7 additional hours) and disinhibition (17.5 additional hours) were associated with the greatest number of additional hours of supervision.
Neuropsychiatric symptoms among those with CIND or dementia are associated with a significant increase in the provision of informal care. This care represents a significant time commitment for families and a significant economic cost to society.
neuropsychiatric symptoms; informal caregiving; cognitive impairment
Degeneration of language regions in the dominant hemisphere can result in primary progressive aphasia (PPA), a clinical syndrome characterized by progressive deficits in speech and/or language function. Recent studies have identified three variants of PPA: progressive non-fluent aphasia (PNFA), semantic dementia (SD) and logopenic progressive aphasia (LPA). Each variant is associated with characteristic linguistic features, distinct patterns of brain atrophy, and different likelihoods of particular underlying pathogenic processes, which makes correct differential diagnosis highly clinically relevant. Evaluation of linguistic behavior can be challenging for non-specialists, and neuroimaging findings in single subjects are often difficult to evaluate by eye. We investigated the utility of automated structural MR image analysis to discriminate PPA variants (N=86) from each other and from normal controls (N=115). T1 images were preprocessed to obtain modulated grey matter (GM) images. Feature selection was performed with principal components analysis (PCA) on GM images as well as images of lateralized atrophy. PC coefficients were classified with linear support vector machines, and a cross-validation scheme was used to obtain accuracy rates for generalization to novel cases. The overall mean accuracy in discriminating between pairs of groups was 92.2%. For one pair of groups, PNFA and SD, we also investigated the utility of including several linguistic variables as features. Models with both imaging and linguistic features performed better than models with only imaging or only linguistic features. These results suggest that automated methods could assist in the differential diagnosis of PPA variants, enabling therapies to be targeted to likely underlying etiologies.
Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. BPSD constitute a major component of the dementia syndrome irrespective of its subtype. They are as clinically relevant as cognitive symptoms as they strongly correlate with the degree of functional and cognitive impairment. BPSD include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite changes. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness, and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, misuse of medication, and increased health care costs. Although these symptoms can be present individually it is more common that various psychopathological features co-occur simultaneously in the same patient. Thus, categorization of BPSD in clusters taking into account their natural course, prognosis, and treatment response may be useful in the clinical practice. The pathogenesis of BPSD has not been clearly delineated but it is probably the result of a complex interplay of psychological, social, and biological factors. Recent studies have emphasized the role of neurochemical, neuropathological, and genetic factors underlying the clinical manifestations of BPSD. A high degree of clinical expertise is crucial to appropriately recognize and manage the neuropsychiatric symptoms in a patient with dementia. Combination of non-pharmacological and careful use of pharmacological interventions is the recommended therapeutic for managing BPSD. Given the modest efficacy of current strategies, there is an urgent need to identify novel pharmacological targets and develop new non-pharmacological approaches to improve the adverse outcomes associated with BPSD.
behavioral and psychological symptoms; dementia; neuropsychiatric symptoms; Alzheimer’s disease
The left posterior inferior frontal cortex (IFC) is important for syntactic processing, and has been shown in many functional imaging studies to be differentially recruited for the processing of syntactically complex sentences relative to simpler ones. In the non-fluent variant of primary progressive aphasia (PPA), degeneration of the posterior IFC is associated with expressive and receptive agrammatism, however the functional status of this region in non-fluent PPA is not well understood. Our objective was to determine whether the atrophic posterior IFC is differentially recruited for the processing of syntactically complex sentences in non-fluent PPA. Using structural and functional magnetic resonance imaging, we quantified tissue volumes and functional responses to a syntactic comprehension task in eight patients with non-fluent PPA, compared to healthy age-matched controls. In controls, the posterior IFC showed more activity for syntactically complex sentences than simpler ones, as expected. In non-fluent PPA patients, the posterior IFC was atrophic and, unlike controls, showed an equivalent level of functional activity for syntactically complex and simpler sentences. This abnormal pattern of functional activity was specific to the posterior IFC: the mid superior temporal sulcus, another region modulated by syntactic complexity in controls, showed normal modulation by complexity in patients. A more anterior inferior frontal region was recruited by patients, but did not support successful syntactic processing. We conclude that in non-fluent PPA, the posterior IFC is not only structurally damaged, but is also functionally abnormal, suggesting a critical role for this region in the breakdown of syntactic processing in this syndrome.
syntactic processing; primary progressive aphasia; progressive non-fluent aphasia; inferior frontal gyrus; superior temporal sulcus; functional magnetic resonance imaging
Primary progressive aphasia (PPA) has been proposed to comprise 3 discrete clinical subtypes: semantic, agrammatic/nonfluent, and logopenic. Recent consensus recommendations suggest a diagnostic framework based primarily on clinical and neuropsychological findings to classify these variants. Our objective was to evaluate the extent to which patients with PPA would conform to the proposed tripartite system and whether the clustering pattern of elements of the linguistic profile suggests discrete clinical syndromes.
A total of 46 patients with PPA were prospectively recruited to the Cambridge Longitudinal Study of PPA. Sufficient data were collected to assess all consensus-proposed diagnostic domains. By comparing patients' performances against those of 30 age- and education-matched healthy volunteers, z scores were calculated, and values of 1.5 SDs outside control participants' means were considered abnormal. Raw test scores were used to undertake a principal factor analysis to identify the clustering pattern of individual measures.
Of the patients, 28.3%, 26.1%, and 4.3% fitted semantic, nonfluent/agrammatic, and logopenic categories respectively, and 41.3% did not fulfill the diagnostic recommendations for any of the 3 proposed variants. There was no significant between-group difference in age, education, or disease duration. Furthermore, the outcome of the factor analysis was in keeping with discrete semantic and nonfluent/agrammatic syndromes but did not support a logopenic variant.
Taken together, the results of this prospective data-driven study suggest that although a substantial proportion of patients with PPA have neither the semantic nor the nonfluent variants, they do not necessarily conform to a discrete logopenic variant.
Classical aphasiology, based on the study of stroke sequelae, fuses speech fluency and grammatical ability. Nonfluent (Broca's) aphasia often is accompanied by agrammatism; whereas in the fluent aphasias grammatical deficits are not typical. The assumption that a similar relationship exists in primary progressive aphasia (PPA) has led to the dichotomization of this syndrome into fluent and nonfluent subtypes.
This study compared elements of fluency and grammatical production in the narrative speech of individuals with PPA to determine if they can be dissociated from one another.
Speech samples from 37 individuals with PPA, clinically assigned to agrammatic (N=11), logopenic (N=20) and semantic (N=6) subtypes, and 13 cognitively healthy control participants telling the “Cinderella Story” were analyzed for fluency (i.e., words per minute (WPM) and mean length of utterance in words (MLU-W)) and grammaticality (i.e., the proportion of grammatically correct sentences, open-to-closed-class word ratio, noun-to-verb ratio, and correct production of verb inflection, noun morphology, and verb argument structure.) Between group differences were analyzed for each variable. Correlational analyses examined the relation between WPM and each grammatical variable, and an off-line measure of sentence production.
Outcomes And Results
Agrammatic and logopenic groups both had lower scores on the fluency measures and produced significantly fewer grammatical sentences than did semantic and control groups. However, only the agrammatic group evinced significantly impaired production of verb inflection and verb argument structure. In addition, some semantic participants showed abnormal open-to-closed and noun-to-verb ratios in narrative speech. When the sample was divided on the basis of fluency, all the agrammatic participants fell in the nonfluent category. The logopenic participants varied in fluency but those with low fluency showed variable performance on measures of grammaticality. Correlational analyses and scatter plots comparing fluency and each grammatical variable revealed dissociations within PPA participants, with some nonfluent participants showing normal grammatical skill.
Grammatical production is a complex construct comprised of correct usage of several language components, each of which can be selectively affected by disease. This study demonstrates that individuals with PPA show dissociations between fluency and grammatical production in narrative speech. Grammatical ability, and its relationship to fluency, varies from individual to individual, and from one variant of PPA to another, and can even be found in individuals with semantic PPA in whom a fluent aphasia is usually thought to accompany preserved ability to produce grammatical utterances.
To estimate the prevalence of neuropsychiatric symptoms and examine their association with functional limitations.
The Aging, Demographics, and Memory Study (ADAMS).
A sample of adults aged 71 and older (N = 856) drawn from Health and Retirement Study (HRS), a nationally representative cohort of U.S. adults aged 51 and older.
The presence of neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, apathy, elation, anxiety, disinhibition, irritation, and aberrant motor behaviors) was identified using the Neuropsychiatric Inventory. A consensus panel in the ADAMS assigned a cognitive category (normal cognition; cognitive impairment, no dementia (CIND); mild, moderate, or severe dementia). Functional limitations, chronic medical conditions, and sociodemographic information were obtained from the HRS and ADAMS.
Forty-three percent of individuals with CIND and 58% of those with dementia exhibited at least one neuropsychiatric symptom. Depression was the most common individual symptom in those with normal cognition (12%), CIND (30%), and mild dementia (25%), whereas apathy (42%) and agitation (41%) were most common in those with severe dementia. Individuals with three or more symptoms and one or more clinically significant symptoms had significantly higher odds of having functional limitations. Those with clinically significant depression had higher odds of activity of daily living limitations, and those with clinically significant depression, anxiety, or aberrant motor behaviors had significantly higher odds of instrumental activity of daily living limitations.
Neuropsychiatric symptoms are highly prevalent in older adults with CIND and dementia. Of those with cognitive impairment, a greater number of total neuropsychiatric symptoms and some specific individual symptoms are strongly associated with functional limitations.
neuropsychiatric symptoms; cognitive impairment; prevalence; functional status
To examine the association of neuropsychiatric symptoms with risk of institutionalization and death.
Analysis of longitudinal data
The Aging, Demographics, and Memory Study (ADAMS)
A sample (n=537) of adults aged 71 or older with cognitive impairment drawn from the Health and Retirement Study (HRS)
The presence of neuropsychiatric symptoms (delusions, hallucinations, agitation, depression, apathy, elation, anxiety, disinhibition, irritation, and aberrant motor behaviors) and caregiver distress were identified using the Neuropsychiatric Inventory. Cognitive category was assigned in the ADAMS by a consensus panel. Date of nursing home placement and death, functional limitations, medical comorbidity, and sociodemographics were obtained from the HRS and ADAMS.
Overall, the presence of 1 or more neuropsychiatric symptoms was not associated with a significantly higher risk for either institutionalization or death during the 5-year study period. However, when assessing each symptom individually, the presence of depression, delusions, and agitation were each associated with a significantly higher risk of institutionalization (HR, 3.06; 95% CI, 1.09-8.59 for depression; HR, 5.74; 95% CI, 1.94-16.96 for clinically significant delusions; HR, 4.70; 95% CI, 1.07-20.70 for clinically significant agitation). The association of delusions and agitation with institutionalization was mediated by caregiver distress. The presence of depression and hallucinations were each associated with a significantly higher mortality (HR, 1.56; 95% CI, 1.08-2.26 for depression; HR, 2.59; 95% CI, 1.09-6.16 for clinically significant hallucinations).
Some, but not all, neuropsychiatric symptoms are associated with a higher risk of institutionalization and death among those with cognitive impairment, and some are additionally influenced by caregiver distress. Interventions that better target and treat the neuropsychiatric symptoms of depression, delusions, agitation, and hallucinations, as well as caregiver distress, may help delay or prevent these negative clinical outcomes.
neuropsychiatric symptoms; caregiver distress; institutionalization; mortality
To provide a quantitative algorithm for classifying primary progressive aphasia (PPA) into agrammatic (PPA-G), semantic (PPA-S) and logopenic (PPA-L) variants, each of which is known to have a different probability of association with Alzheimer’s disease (AD) versus frontotemporal lobar degeneration (FTLD).
Prospectively and consecutively enrolled 16 PPA patients tested with neuropsychological instruments and magnetic resonance imaging (MRI).
University medical center.
PPA patients recruited nationally in the USA as part of a longitudinal study.
A two-dimensional template, reflecting performance on tests of syntax (Northwestern Anagram Test) and lexical semantics (Peabody Picture Vocabulary Test), classified all 16 patients in concordance with a clinical diagnosis that had been made prior to the administration of the quantitative tests. All three subtypes had distinctly asymmetrical atrophy of the left perisylvian language network. Each subtype also had distinctive peak atrophy sites. Only PPA-G had peak atrophy in the IFG (Broca’s area), only PPA-S had peak atrophy in the anterior temporal lobe, and only PPA-L had peak atrophy in area 37.
Once an accurate root diagnosis of PPA is made, subtyping can be quantitatively guided using a two-dimensional template based on orthogonal tasks of grammatical competence and word comprehension. Although the choice of tasks and precise cut-off levels may evolve in time, this set of 16 patients demonstrates the feasibility of using a simple algorithm for clinico-anatomical classification in PPA. Prospective studies will show whether this suptyping can improve the clinical prediction of underlying neuropathology.
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.
Dementia; Frontotemporal dementia; Recognition memory; Language; Semantic processing