Primary Progressive Aphasia: Toward a Pathophysiological Synthesis.

PURPOSE OF REVIEW: The term primary progressive aphasia (PPA) refers to a diverse group of dementias that present with prominent and early problems with speech and language. They present considerable challenges to clinicians and researchers. RECENT FINDINGS: Here, we review critical issues around diagnosis of the three major PPA variants (semantic variant PPA, nonfluent/agrammatic variant PPA, logopenic variant PPA), as well as considering 'fragmentary' syndromes. We next consider issues around assessing disease stage, before discussing physiological phenotyping of proteinopathies across the PPA spectrum. We also review evidence for core central auditory impairments in PPA, outline critical challenges associated with treatment, discuss pathophysiological features of each major PPA variant, and conclude with thoughts on key challenges that remain to be addressed. New findings elucidating the pathophysiology of PPA represent a major step forward in our understanding of these diseases, with implications for diagnosis, care, management, and therapies.

A Meta-Analysis of Neuropsychological Functioning in the Logopenic Variant of Primary Progressive Aphasia: Comparison with the Semantic and Non-Fluent Variants.

OBJECTIVES: The logopenic variant of primary progressive aphasia (lvPPA) has disparate pathological and anatomical features when compared to the semantic (svPPA) and non-fluent (nfvPPA) variants of PPA. As such, there is increasing need for measures that improve diagnostic accuracy particularly when etiology-specific treatments become available. In the current study, we used meta-analytic methods to establish the neuropsychological profile of lvPPA and compare it to recent findings in svPPA and nfvPPA. METHODS: We extracted neuropsychological data from 51 publications representing 663 lvPPA patients and 1379 controls. We calculated Hedges' g effect sizes for nine domains of neuropsychological functioning in lvPPA and assessed the influence of demographic, disease, and task characteristics on effect size magnitude. Results obtained in lvPPA were compared to findings in svPPA and nfvPPA. RESULTS: In lvPPA, the magnitude of deficits in attention, math, visuospatial memory, and executive functioning were as prominent as language deficits. Within the language domain, lvPPA patients demonstrated greater naming than repetition deficits. Compared to svPPA and nfvPPA, lvPPA patients demonstrated greater neuropsychological deficits overall and greater impairment on attention, math, and visual set-shifting tests. CONCLUSIONS: Tests of attention, delayed visuospatial memory, visual set-shifting, and math distinguish lvPPA from svPPA and nfvPPA likely reflecting the posterior temporoparietal atrophy observed early in the course of lvPPA. These findings support the inclusion of these measures in the clinical neuropsychological assessment of lvPPA and underscore the need for additional clinicopathological and longitudinal studies of arithmetic and visuospatial memory across the PPA variants.

Tau accumulation in two patients with frontotemporal lobe degeneration showing different types of aphasia using 18F-THK-5351 positron emission tomography: a case report.

ABSTRACTTau deposits in Alzheimer's disease and corticobasal syndrome have been reported using 18F-THK-5351 positron emission tomography (PET). To our knowledge, our study is the first to demonstrate tau deposits in patients with frontotemporal lobe degeneration (FTLD), using 18F-THK-5351 PET. This case report presents two patients, both of whom showed positive Tau deposition using 18F-THK-5351 PET. One patient was diagnosed with semantic variant primary progressive aphasia (PPA) and the other diagnosed with logopenic variant PPA. Our results suggest an association in the pathology of Alzheimer's disease, corticobasal syndrome, and FTLD, and could plan more effective clinical care in advance.

Imaging correlations of tau, amyloid, metabolism, and atrophy in typical and atypical Alzheimer's disease.

INTRODUCTION: Neuroimaging modalities can measure different aspects of the disease process in Alzheimer's disease, although the relationship between these modalities is unclear. METHODS: We assessed subject-level regional correlations between tau on [18F]AV-1451 positron emission tomography (PET), ß amyloid on Pittsburgh compound B PET, hypometabolism on [18F] fluorodeoxyglucose PET, and cortical thickness on magnetic resonance imaging in 96 participants with typical and atypical Alzheimer's disease presentations. We also assessed how correlations between modalities varied according to age, presenting syndrome, tau-PET severity, and asymmetry. RESULTS: [18F]AV-1451 uptake showed the strongest regional correlation with hypometabolism. Correlations between [18F]AV-1451 uptake and both hypometabolism and cortical thickness were stronger in participants with greater cortical tau severity. In addition, age, tau asymmetry, and clinical diagnosis influenced the strength of the correlation between [18F]AV-1451 uptake and cortical thickness. DISCUSSION: These findings support a close relationship between tau and hypometabolism in Alzheimer's disease but show that correlations between neuroimaging modalities vary across participants.

APOE ε4 influences ß-amyloid deposition in primary progressive aphasia and speech apraxia.

BACKGROUND: Apolipoprotein E ε4 (APOE ε4) is a risk factor for ß-amyloid deposition in Alzheimer's disease dementia. Its influence on ß-amyloid deposition in speech and language disorders, including primary progressive aphasia (PPA), is unclear. METHODS: One hundred thirty subjects with PPA or progressive speech apraxia underwent APOE genotyping and Pittsburgh compound B (PiB) PET scanning. The relationship between APOE ε4 and PiB status, as well as severity and regional distribution of PiB, was assessed. RESULTS: Forty-five subjects had an APOE ε4 allele and 60 subjects were PiB-positive. The odds ratio for a subject with APOE ε4 being PiB-positive compared with a subject without APOE ε4 being PiB-positive was 10.2 (95% confidence interval, 4.4-25.5; P < .0001). The APOE ε4 allele did not influence regional PiB distribution or severity. CONCLUSION: APOE ε4 increases the risk of ß-amyloid deposition in PPA and progressive speech apraxia but does not influence regional ß-amyloid distribution or severity.

Primary progressive aphasia: six questions in search of an answer.

Here, we review recent progress in the diagnosis and management of primary progressive aphasia-the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there-and is syndromic diagnosis even useful? Are these truly 'language-led' dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies.

Atypical clinical variants of Alzheimer's disease: are they really atypical?

Alzheimer's disease (AD) is a neuropathological disorder defined by the deposition of the proteins, tau and ß-amyloid. Alzheimer's disease is commonly thought of as a disease of the elderly that is associated with episodic memory loss. However, the very first patient described with AD was in her 50's with impairments in multiple cognitive domains. It is now clear that AD can present with multiple different non-amnestic clinical variants which have been labeled as atypical variants of AD. Instead of these variants of AD being considered "atypical," I propose that they provide an excellent disease model of AD and reflect the true clinical heterogeneity of AD. The atypical variants of AD usually have a relatively young age at onset, and they show striking cortical tau deposition on molecular PET imaging which relates strongly with patterns of neurodegeneration and clinical outcomes. In contrast, elderly patients with AD show less tau deposition on PET, and neuroimaging and clinical outcomes are confounded by other age-related pathologies, including TDP-43 and vascular pathology. There is also considerable clinical and anatomical heterogeneity across atypical and young-onset amnestic variants of AD which reflects the fact that AD is a disease that causes impairments in multiple cognitive domains. Future studies should focus on careful characterization of cognitive impairment in AD and consider the full clinical spectrum of AD, including atypical AD, in the design of research studies investigating disease mechanisms in AD and clinical treatment trials, particularly with therapeutics targeting tau.

Beyond language impairment: Profiles of apathy in primary progressive aphasia.

Primary progressive aphasia (PPA) is characterised by predominant language and communication impairment. However, behavioural changes, such as apathy, are increasingly recognised. Apathy is defined as a reduction in motivation and goal-directed behaviour. Recent theoretical models have suggested that apathy can be delineated into multiple dimensions: executive apathy (i.e., deficits in maintaining goals and organisation), emotional apathy (i.e., emotional blunting and indifference) and initiation apathy (i.e., reduced self-initiation). Whether the nature of apathy differs between clinical variants of PPA, and across early and late disease stages, remains to be established. Here, carers/informants of 20 semantic variant PPA (svPPA), 15 non-fluent variant PPA (nfvPPA), 16 logopenic variant PPA (lvPPA) and 25 healthy older controls completed the Dimensional Apathy Scale to quantify executive, emotional and initiation apathy. Voxel-based morphometry was used to identify associations between dimensions of apathy and regions of grey matter intensity decrease. Our behavioural results showed greater executive and initiation apathy in late svPPA than in late nfvPPA patients, while late svPPA had greater emotional apathy than both late nfvPPA and late lvPPA groups. Executive and initiation apathy were significantly higher than premorbid levels in all PPA subtypes, while elevated emotional apathy was only seen in early and late svPPA. Distinct neural correlates were identified across apathy dimensions. Executive apathy correlated with grey matter intensity of the left dorsolateral prefrontal and inferior parietal cortices; emotional apathy with the left medial prefrontal, insular and cerebellar regions; and initiation apathy with right parietal areas. Our findings are the first to reveal evidence of the dimensional nature of apathy in PPA, with different clinical signatures observed for each subtype. From a clinical standpoint, these results will inform the development of targeted interventions for specific aspects of apathy which emerge in PPA.

Logopenic aphasia due to Lewy body disease dramatically improved with donepezil.

•Pathological basis of primary progressive aphasia is heterogeneous.•Logopenic primary progressive aphasia can precede dementia with Lewy bodies (DLB).•Cholinesterase inhibitor can improve logopenic aphasia with DLB.

The Landscape Montage Technique for diagnosing frontotemporal dementia starting as primary progressive aphasia: a case report.

BACKGROUND: The Landscape Montage Technique was originally developed by Hisao Nakai, a Japanese psychiatrist, to pursue the possibility and application of a psychotherapeutic approach using drawing for patients with schizophrenia. Drawing was initially adopted to evaluate patients with an impaired ability for verbal expression, particularly for the diagnosis and treatment of patients with schizophrenia. Since its development, the Landscape Montage Technique has been utilized in various clinical settings throughout Japan. This study aimed to evaluate the psychiatric conditions of a patient diagnosed as having primary progressive aphasia using the Landscape Montage Technique at a 3-year follow-up. CASE PRESENTATION: We present the case of a 64-year-old, right-handed Japanese woman initially diagnosed as having logopenic variant primary progressive aphasia or logopenic aphasia. At a 3-year follow-up, logopenic aphasia progressed to behavioral variant frontotemporal dementia or frontotemporal dementia. According to her husband, she began to have speech difficulties approximately 5 years before her first visit. The results of neurocognitive tests suggested mild cognitive impairment or early stages of dementia. Her clinical dementia rating score was 0.5, suggesting a diagnosis of mild cognitive impairment. She had a Raven's Colored Progressive Matrices score of 31 out of 36, which indicated a nonverbal cognitive ability that was greater than the 90th percentile for her age. The Japanese Standard Language Test of Aphasia, which was performed at two points during the follow-up, indicated the possibility for a diagnosis of primary progressive aphasia given the progression of her aphasia. Based on her clinical symptoms and Japanese Standard Language Test of Aphasia results, a diagnosis of logopenic variant primary progressive aphasia was established. Magnetic resonance imaging revealed severe predominant left frontal and anterior temporal atrophy, as well as bilateral parietal atrophy. Amyloid beta deposition was negative. At the 3-year follow-up, logopenic variant primary progressive aphasia had progressed to behavioral variant frontotemporal dementia. However, the Landscape Montage Technique allowed for the diagnosis of behavioral variant frontotemporal dementia only 2 years after baseline. CONCLUSIONS: The present study showed that the Landscape Montage Technique can be useful for diagnosing behavioral variant frontotemporal dementia that starts as logopenic variant primary progressive aphasia at earlier stages.

Correlates of anomia in non-semantic variants of primary progressive aphasia converge over time.

To track neural correlates of naming performance with disease progression, we estimated key areas affected in nonfluent/agrammatic (nfvPPA) and logopenic (lvPPA) primary progressive aphasia variants over time and changes in naming correlates over time. Twenty-nine non-semantic PPA participants (17 nfvPPA and 12 lvPPA) were selected based upon current diagnostic criteria and PiB-PET status and conducted a confrontation-naming task and a structural MRI. Linear mixed-effect models implemented in FreeSurfer were used for tracking cortical thickness and epicenters of atrophy over time. Using averaged cortical thickness of epicenters and naming performance as variables of interest, two sets of multivariate analyses were conducted to compare atrophy progression and naming correlates across groups. While all PPA participants demonstrated naming deterioration and progressive cortical thinning in the left temporal lobe and the left inferior frontal gyrus, the lvPPA cohort showed greater naming deterioration and thinning in the left posterior inferior parietal cortex over time than it did the nfvPPA cohort. The multivariate analyses confirmed a widespread cortical thinning in lvPPA over time, but a more rapid thinning in the right superior frontal gyrus of nfvPPA participants. Impaired naming correlated with common cortical regions in both groups. These regions included the left anterior superior temporal gyrus and the posterior middle temporal gyrus, which was primarily affected in lvPPA. Non-semantic PPA variants initially present with separate epicenters of atrophy and different spatial-temporal patterns of neurodegeneration over time, but the common involvement in key cortical regions of the left temporal lobe accounts for naming deterioration in both groups.

Primary progressive aphasia: a clinical approach.

The primary progressive aphasias are a heterogeneous group of focal 'language-led' dementias that pose substantial challenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including 'clinical pearls' that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic 'roadmap'. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers.

Quantitative assessment of grammar in amyloid-negative logopenic aphasia.

Logopenic primary progressive aphasia (lvPPA) typically results from underlying Alzheimer's disease, but subjects have been reported that do not show beta-amyloid (Aß) deposition. These subjects do not differ on neurological and speech-language testing from Aß-positive lvPPA, but they impressionistically show increased grammatical deficits. We performed a quantitative linguistic analysis of grammatical characteristics in Aß-negative lvPPA compared to Aß-positive lvPPA and agrammatic PPA, which is characterized by increased grammatical difficulties. Aß-negative lvPPA used fewer function words and correct verbs but more syntactic and semantic errors compared to Aß-positive lvPPA. These measures did not differ between Aß-negative lvPPA and agPPA. Both lvPPA cohorts showed a higher mean length of utterance, more complex sentences, and fewer nouns than agPPA. Aß-negative lvPPA subjects appear unique and share linguistic features with both agPPA and Aß-positive lvPPA. Quantitative language analysis in lvPPA may be able to distinguish those with and without Aß deposition.

Patterns of Neuropsychological Dysfunction and Cortical Volume Changes in Logopenic Aphasia.

BACKGROUND: Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA). OBJECTIVE: This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles. METHODS: We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses. RESULTS: We identified three clusters characterized as lvPPA with no neurocognitive impairment (n = 5), lvPPA with mild neurocognitive deficits (n = 23), and lvPPA with marked cognitive deficits (n = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups. CONCLUSIONS: LvPPA patients without cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA.

Episodic and working memory function in Primary Progressive Aphasia: A meta-analysis.

OBJECTIVE: The distinction between Primary Progressive Aphasia (PPA) variants remains challenging for clinicians, especially for the non-fluent (nfv-PPA) and the logopenic variants (lv-PPA). Previous research suggests that memory tests might aid this differentiation. This meta-analysis compares memory function among PPA variants. METHOD: Effects sizes were extracted from 41 studies (N = 849). Random-effects models were used to compare performance on episodic and working memory tests among PPA patients and healthy controls, and between the PPA variants. RESULTS: Memory deficits were frequently observed in PPA compared to controls, with large effect sizes for lv-PPA (Hedges' g = -2.04 [-2.58 to -1.49]), nfv-PPA (Hedges' g = -1.26 ([-1.60 to -0.92], p < .001)), and the semantic variant (sv-PPA; Hedges' g = -1.23 [-1.50 to -0.97]). Sv-PPA showed primarily verbal memory deficits, whereas lv-PPA showed worse performance than nfv-PPA on both verbal and non-verbal memory tests. CONCLUSIONS: Memory deficits were more pronounced in lv-PPA compared to nfv-PPA. This suggests that memory tests may be helpful to distinguish between these PPA variants.

Sensitivity of Speech Output to Delayed Auditory Feedback in Primary Progressive Aphasias.

Delayed auditory feedback (DAF) is a classical paradigm for probing sensori-motor interactions in speech output and has been studied in various disorders associated with speech dysfluency and aphasia. However, little information is available concerning the effects of DAF on degenerating language networks in primary progressive aphasia: the paradigmatic "language-led dementias." Here we studied two forms of speech output (reading aloud and propositional speech) under natural listening conditions (no feedback delay) and under DAF at 200 ms, in a cohort of 19 patients representing all major primary progressive aphasia syndromes vs. healthy older individuals and patients with other canonical dementia syndromes (typical Alzheimer's disease and behavioral variant frontotemporal dementia). Healthy controls and most syndromic groups showed a quantitatively or qualitatively similar profile of reduced speech output rate and increased speech error rate under DAF relative to natural auditory feedback. However, there was no group effect on propositional speech output rate under DAF in patients with nonfluent primary progressive aphasia and logopenic aphasia. Importantly, there was considerable individual variation in DAF sensitivity within syndromic groups and some patients in each group (though no healthy controls) apparently benefited from DAF, showing paradoxically increased speech output rate and/or reduced speech error rate under DAF. This work suggests that DAF may be an informative probe of pathophysiological mechanisms underpinning primary progressive aphasia: identification of "DAF responders" may open up an avenue to novel therapeutic applications.

Retained capacity for perceptual learning of degraded speech in primary progressive aphasia and Alzheimer's disease.

BACKGROUND: Processing of degraded speech is a promising model for understanding communication under challenging listening conditions, core auditory deficits and residual capacity for perceptual learning and cerebral plasticity in major dementias. METHODS: We compared the processing of sine-wave-degraded speech in 26 patients with primary progressive aphasia (non-fluent, semantic, and logopenic variants), 10 patients with typical Alzheimer's disease and 17 healthy control subjects. Participants were required to identify sine-wave words that were more predictable (three-digit numbers) or less predictable (place names). The change in identification performance within each session indexed perceptual learning. Neuroanatomical associations of degraded speech processing were assessed using voxel-based morphometry. RESULTS: Patients with non-fluent and logopenic progressive aphasia and typical Alzheimer's disease showed impaired identification of sine-wave numbers, whereas all syndromic groups showed impaired identification of sine-wave place names. A significant overall identification advantage for numbers over place names was shown by patients with typical Alzheimer's disease, patients with semantic progressive aphasia and healthy control participants. All syndromic groups showed spontaneous perceptual learning effects for sine-wave numbers. For the combined patient cohort, grey matter correlates were identified across a distributed left hemisphere network extending beyond classical speech-processing cortices. CONCLUSIONS: These findings demonstrate resilience of auditory perceptual learning capacity across dementia syndromes, despite variably impaired perceptual decoding of degraded speech and reduced predictive integration of semantic knowledge. This work has implications for the neurobiology of dynamic sensory processing and plasticity in neurodegenerative diseases and for development of novel biomarkers and therapeutic interventions.

Logopenic Aphasia due to a Strategic Stroke: New Evidence from a Single Case.

Among primary progressive aphasias (PPAs), logopenic variant PPA (lv-PPA) is usually related to Alzheimer's disease. Although it has been widely clinically and pathologically evaluated, the topography in LPA is still controversial. We report a patient presenting with a logopenic syndrome due to a strategic lesion located in the superior and middle temporal gyrus and compare our findings with those of a PiB-PET positive lv-PPA patient matched by age, gender, and education. We consider that our study provides new anatomical clues to better understand the cognitive mechanisms underlying the logopenic syndrome.

Music Perception in Dementia.

Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimer's disease (AD, n = 16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n = 5), and progressive nonfluent aphasia (PNFA; n = 9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. Taking working memory performance into account, no specific deficits of musical temporal processing, timbre processing, musical scene analysis, or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation.

Functional neuroanatomy of speech signal decoding in primary progressive aphasias.

The pathophysiology of primary progressive aphasias remains poorly understood. Here, we addressed this issue using activation fMRI in a cohort of 27 patients with primary progressive aphasia (nonfluent, semantic, and logopenic variants) versus 15 healthy controls. Participants listened passively to sequences of spoken syllables in which we manipulated 3-key auditory speech signal characteristics: temporal regularity, phonemic spectral structure, and pitch sequence entropy. Relative to healthy controls, nonfluent variant patients showed reduced activation of medial Heschl's gyrus in response to any auditory stimulation and reduced activation of anterior cingulate to temporal irregularity. Semantic variant patients had relatively reduced activation of caudate and anterior cingulate in response to increased entropy. Logopenic variant patients showed reduced activation of posterior superior temporal cortex to phonemic spectral structure. Taken together, our findings suggest that impaired processing of core speech signal attributes may drive particular progressive aphasia syndromes and could index a generic physiological mechanism of reduced computational efficiency relevant to all these syndromes, with implications for development of new biomarkers and therapeutic interventions.