Cases Of Primary Progressive Aphasia Research Articles

Data-driven subtypes of mixed semantic-logopenic primary progressive aphasia: Linguistic features, biomarker profiles and brain metabolic patterns

Mixed primary progressive aphasia (mPPA) accounts for a substantial proportion of primary progressive aphasia (PPA) cases. However, the lack of a standardised definition of this condition has resulted in misclassification of PPA cases. In this study, we enrolled 55 patients diagnosed with PPA, comprising 12 semantic variant (svPPA), 23 logopenic variant (lvPPA), and 20 mPPA cases with linguistic characteristics consistent with both svPPA and lvPPA (s/lvPPA). All patients underwent language assessments, evaluation of Alzheimer's disease biomarkers (via cerebrospinal fluid analysis or Amyloid-PET), and 18F-FDG-PET brain scans. An agglomerative hierarchical clustering (AHC) analysis based on linguistic characteristics revealed two distinct clusters within the s/lvPPA group: cluster k1 (n = 10) displayed an AD-like biomarker profile, with lower levels of Aβ42 and Aβ42/Aβ40 ratio, along with higher levels of t-tau and p-tau compared to cluster k2 (n = 10). Interestingly, k1 exhibited linguistic features that were similar to those of svPPA. Both clusters exhibited extensive temporoparietal hypometabolism. These findings support the hypothesis that a subgroup of s/lvPPA may represent a clinical manifestation of AD-related PPA.

Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias

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

Amygdalar pathology in early neuropsychiatric phenotypes due to 3R‐Pick disease

AbstractBackgroundPersons with dementia syndromes such as primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD) often develop neuropsychiatric symptoms (NPS). Various neurodegenerative diseases may cause PPA or bvFTD, including frontotemporal lobar degeneration (FTLD) with 3‐repeat tau pathology (Pick disease, “PiD”). Limbic regions implicated in mood and behavior, such as the amygdala, are highly impacted in FTLD with PiD. This study quantified Pick bodies and activated microglia in the amygdala of individuals with antemortem diagnosis of PPA or bvFTD and postmortem PiD neuropathology and examined associations with initial NPS.MethodWe identified 16 right‐handed cases from the Northwestern University Alzheimer’s Disease Research Center brain bank with bvFTD (N = 8) or PPA (N = 8) due to PiD with unilateral amygdala tissue (basolateral region) available. Fifteen cases had data on 12 NPS assessed via the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q) from their earliest visit. We performed AT‐8 or HLA‐DR immunohistochemistry on amygdala sections to visualize Pick bodies or HLA‐DR+ activated microglia, respectively. We quantified the density of Pick bodies per mm3 via modified unbiased stereology and used HALO software (Indica Labs) to quantify percent area of HLA‐DR immunopositivity. We assessed differences between clinical groups via Welch’s t‐test (Pick bodies) or repeated‐measures two‐way ANOVA (HLA‐DR). Pearson clinicopathologic correlations were examined between Pick bodies or HLA‐DR immunopositivity and initial endorsement of total (out of 12) or behavioral/comportmental (apathy, disinhibition, motor stereotypies, or appetite disturbance) NPI‐Q symptoms.ResultAmygdalar Pick body densities were similar between PPA (M = 28,822/mm3) and bvFTD (M = 29,114/mm3) cases. Compared to bvFTD, PPA cases trended towards a lower percent area of HLA‐DR immunopositivity (5.54% vs. 2.39%, p&lt;0.10). There was no significant relationship between Pick Body density and initial NPIQ symptoms endorsed across all cases. However, area of HLA‐DR immunopositivity was positively correlated with initial endorsement of total (r = 0.47, p&lt;0.10) and behavioral/comportmental (r = 0.54, p&lt;0.05) NPI‐Q symptoms.ConclusionOur findings suggest that microglial pathology in the amygdala contributes to early neuropsychiatric presentations in PiD, particularly symptoms reflective of behavioral/comportmental disturbance. Future study will investigate the impact of neuronal size and density in the amygdala on NPS in these dementia syndromes due to PiD.

56 Stereological Densities of Neuronal Tau Inclusions in Corticobasal Degeneration are Anatomically Distinct in PPA vs bvFTD

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

Assessment tools accuracy for classification and diagnosis of Primary Progressive Aphasia: A systematic review and meta-analysis protocol.

Introduction. Primary Progressive Aphasia (PPA) is a syndrome characterized by progressive decline in language function. There are three main PPA syndromes, each one features different language profiles and neuropathologic substrates. Although there are current clinical diagnostic criteria for PPA categorization, the utility of these requires evaluation(s) by specialized staff and the administration of extensive cognitive batteries. A diagnostic tool for PPA is not currently standardized, though some batteries have been developed and/or validated exclusively for PPA categorization. We aim to describe which cognitive/aphasia diagnostic tool has the best accuracy for PPA diagnosis and categorization. Methods and Analysis. MEDLINE (PubMed), EMBASE and Web of Science databases will be searched using adequate search strategies. Studies including original data of possible, probable, and definite PPA cases according to current clinical diagnostic criteria for PPA will be included. Inclusion criteria will be 1) Studies describing data of a cognitive/aphasia clinical battery including at least one test measure (e.g., specificity, positive predictive values, etc.) and 2) PPA diagnosis according to current clinical criteria as the reference standard. Two reviewers will perform the screening and data extraction. Quality assessment will be performed according to the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) guidelines. This systematic review protocol is reported as stated by with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) 2015 statement. Dissemination. Findings of this systematic review protocol will be disseminated through a publication in a peer-reviewed journal. Results will be helpful to improve the diagnosis and classification of PPA syndromes.

Differential vulnerability of the dentate gyrus to tauopathies in dementias

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

Comorbid Neurodegeneration in Primary Progressive Aphasia: Clinicopathological Correlations in a Single-Center Study.

Introduction Primary progressive aphasia (PPA) is a clinically variable syndrome manifesting as slow progressive loss of speech and language with multiple underlying neurodegenerative pathologies. Materials and Methods We included data from nine PPA patients with available autopsies. We then retrospectively reviewed all available medical records, neuropsychology, and MRI results to confirm the corresponding subtypes of PPA and compared them with postmortem neuropathological results. Results Clinical presentations corresponded to the nonfluent/agrammatic variant in six cases, the semantic variant in one case, the logopenic variant in one case, and the mixed variant (concomitant nonfluent/agrammatic plus semantic variant) in one case. Patients with a broader clinical presentation, i.e., combining manifestations of one PPA subtype and symptoms of another PPA variant, had autopsy comorbidities showing multiple neurodegenerative disorders. Of the nine subjects enrolled in the study, Alzheimer's disease (AD) was found in eight cases; however, in only one case, AD was detected as an isolated neuropathological substrate of PPA. In eight brain samples, different comorbid neuropathologies were detected: three cases with comorbid AD and dementia with Lewy bodies, two cases with comorbid AD and TDP-43 pathology, one case with comorbid AD and complex tauopathies, and one case with comorbid AD with both tau and TDP-43 deposits. Finally, one case had comorbid tau and TDP-43 pathology but without comorbid AD pathology. Conclusions Our observation suggests that PPA cases could be more heterogeneous in their etiology than previously thought and underlying neurodegenerative comorbidities should be considered in routine practice, especially if the clinical presentation of PPA is atypical.

Rare variants in TP73 in a frontotemporal dementia cohort link this gene with primary progressive aphasia phenotypes.

TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD. We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded). Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia. We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases.

Primary progressive aphasias: clinical and genetic heterogeneity and diagnostic difficulties

This systematic review describes primary progressive aphasia (PPA) variants and includes the authors' own clinical observations. Over 20 genes have now been identified, with mutations that are directly involved in the development of the behavioural variant of frontotemporal dementia, as well as other forms of PPA. Pathomorphological markers of Alzheimer's disease were identified in 76% of cases of logopenic PPA, while signs of frontotemporal dementia associated with TDP-43 were identified in 80% of cases of the semantic variant, and those associated with TDP-43/tau were identified in 64% of cases of agrammatic PPA. The clinical diagnosis of PPA is based on a history of long-term, progressive speech disturbances and identifying a particular variant: agrammatic, semantic or logopenic. The primary variant of the speech disorder cannot be identified in approximately 30% of cases. The focus should be on the main and additional clinical signs (presence of agrammatism, object naming, word comprehension, preserved repetition), as well as neuroimaging (presence of asymmetrical frontal and/or temporal lobe atrophy).&#x0D; The article also provides key aspects of differential diagnosis of the PPA variants, and puts forth a stepwise diagnostic algorithm. It examines features of PPA progression, with possible development of corticobasal syndrome, illustrated by a clinical case. A dissociation between neuroimaging findings and clinical disease variant is also demonstrated to be possible. Different neuropsychological assessments of patients with aphasia and methods of determining the severity of speech dysfunction are presented. Standardized aphasia assessment tools and the adapted PPA severity scale are provided.

Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C.

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

Metabolic positron-emission tomography/magnetic resonance imaging in primary progressive aphasia and frontotemporal lobar degeneration subtypes: Reassessment of expected [18F]-fluorodeoxyglucose uptake patterns.

Clinical assessment of frontotemporal lobar degeneration (FTLD)/primary progressive aphasia (PPA) patients is challenging, given that common cognitive assessments rely extensively on language. Since asymmetry in neuroimaging biomarkers is often described as a central finding in these patients, our study evaluated [18F]-fluorodeoxyglucose (FDG) uptake patterns in patients meeting clinical and imaging criteria for FTLD, with emphasis on PPA. Fifty-one subjects underwent brain [18F]-FDG positron-emission tomography/magnetic resonance imaging (PET/MRI) as part of their routine clinical workup for dementia and neurodegenerative disease. Images were obtained using a Siemens Biograph mMR integrated 3T PET/MRI scanner. PET surface maps and fusion fluid-attenuated inversion recovery-PET images were generated utilizing MIMneuro software. Two board-certified neuroradiologists and one nuclear medicine physician blinded to patient history classified each FTLD/PPA subtype and assessed for left- versus right-side dominant hypometabolism. Qualitative and semiquantitative assessment demonstrated 18 cases of PPA, 16 behavioral variant frontotemporal dementia (bvFTD), 12 corticobasal degeneration, and 5 progressive supranuclear palsy. Among the 18 PPA subjects (11 svPPA, 5 lvPPA, and 2 agPPA), 12 (67%) demonstrated left-dominant hypometabolism and 6 (33%) right-dominant hypometabolism. While existing literature stresses left-dominant hypometabolism as a key imaging feature in the PPA subtypes, a third of our cases demonstrated right-dominant hypometabolism, suggesting that emphasis should be placed on the functionality of specific brain regions affected, rather than left versus right sidedness of hypometabolism patterns.

Qualitative and Quantitative Analyses of Brain 18Fluoro-Deoxy-Glucose Positron Emission Tomography in Primary Progressive Aphasia

Background: A primary progressive aphasia (PPA) diagnosis is generally based on clinical criteria, but often symptoms and signs may overlap in the different forms. Recent data have evidenced that brain ¹⁸fluoro-deoxy-glucose positron emission tomography (¹⁸F-FDG PET) could support the clinical diagnosis, since specific metabolic patterns are described for the different variants. Aims: We further evaluated the usefulness of ¹⁸F-FDG PET, by both visual qualitative (QL) and quantitative (QN) methods in the initial diagnosis of PPA, focusing on the classification of different variants. Moreover, we also analyzed the role of ¹⁸F-FDG PET in clarifying the association of PPA with the early phase of Alzheimer’s disease (AD) or frontotemporal (FTD) dementias. Methods: We consecutively enrolled 35 patients with clinical symptoms of aphasia, suspect of or attributable to PPA. Patients were classified into two groups: 18 cases with clinical symptoms of aphasia but normal neuropsychological tests and an unclear classification of a specific PPA variant (group A) and 17 cases with clinical and neuropsychological signs attributable to PPA with an uncertain differential diagnosis between AD and FTD (group B). All patients underwent brain ¹⁸F-FDG PET/CT, and images were evaluated both by QL and QN, the latter applying an automated analysis program that produced brain regional metabolicmaps and normal age-matched control group comparative analysis (zscore). Results: ¹⁸F-FDG PET showed different patterns of bilateral cortical hypometabolism in the two groups. The combined use of QL and QN permitted to achieved a correct PPA variant diagnosis in 8 of 18 (44.4%) cases of group A and in 14 of 17 (82.3%) of group B, while only QN could support the correct classification of PPA variants in 10 of 18 (55.6%) cases of group A and in 3 of 17 (17.7%) cases of group B in whom the procedure better localized the hypometabolic areas. Conclusions: Brain ¹⁸F-FDG PET had an elevated performance in the early diagnosis of PPA variants and in the advanced PPA AD/FTD classification. QL clarified the development of AD or FTD in advanced PPA cases and supported the differential diagnosis of a PPA variant in a few early cases. QN ¹⁸F-FDG PET evaluation better contributed to the early diagnosis of an unclear metabolic pattern. To correctly identify all cases, patients with diffuse cortical hypometabolism were also included. Larger series are necessary to confirm these data.

The underacknowledged PPA-ALS: A unique clinicopathologic subtype with strong heritability.

To assess the incidence, heritability, and neuropathology of primary progressive aphasia (PPA) with amyotrophic lateral sclerosis (ALS) in a large Australian cohort. A total of 130 patients with a primary nonfluent variant of PPA (nfvPPA) or semantic variant of PPA (svPPA) were assessed for concomitant ALS and a strong family history of neurodegenerative diseases (Goldman score ≤3). Neuropathologic examination was carried out in 28% (n = 36) of these PPA and PPA-ALS cases that had come to autopsy. ALS was identified in 18% of patients with nfvPPA and 5% of patients with svPPA. PPA-ALS but not PPA was found to have a strong family history. At autopsy, frontotemporal lobar degeneration (FTLD)-TDP was identified in 100% of nfvPPA-ALS cases, 100% of svPPA-ALS cases, 24% of nfvPPA cases, and 78% of svPPA cases. Clinicopathologic assessments revealed a significant association between a strong family history and underlying FTLD-TDP pathology. Pathogenic mutations in known frontotemporal dementia (FTD)/ALS genes were identified in 100% of these familial PPA cases but only 50% of familial PPA-ALS cases, suggesting the involvement of novel genetic variants in this underacknowledged phenotype. The present study identified ALS in 12% of a large cohort of patients with nfvPPA and svPPA, which is comparable to the 10%-15% reported in FTD overall, indicating that a third of patients with FTD-ALS will have a predominant language profile. These findings highlight the importance of assessing for ALS in PPA, particularly since this is the only PPA phenotype in which a perfect clinicopathologic association has been reported in to date.

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia.

Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P<0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P<0.05). White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy.

Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia

The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. Clinical, cognitive, neuroimaging, and pathology results. Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET-positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11-labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease.

PROMINENT MICROGLIAL ACTIVATION IN CORTICAL WHITE MATTER IS SELECTIVELY ASSOCIATED WITH CORTICAL ATROPHY IN PRIMARY PROGRESSIVE APHASIA

AIMS Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. METHODS Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. RESULTS Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05). CONCLUSIONS White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy.

Reading impairment in neurodegenerative diseases: a multiple single-case study

ABSTRACTBackground: Reading impairment is frequently associated with neurodegenerative diseases, such as Alzheimer disease (AD), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). Notwithstanding the clinical relevance of reading processes in these conditions, only a relatively small number of studies have been published on this topic so far.Aims: We investigated the reading impairment in patients with different types of neurodegenerative diseases. In the light of the marked variability in pathological changes affecting brain areas potentially relevant to reading, it could be hypothesised that these neurodegenerative conditions may lead to different patterns of reading impairment.Methods & Procedures: Three groups of patients (AD, PPA, and PCA) and a control sample of neurologically healthy participants were examined with five tasks to test the ability to read and to repeat words and nonwords, as well as with an auditory and visual lexical decision task.Outcomes & Results: No specific pattern emerged as strongly diagnostic of a specific degenerative disease. Overall, AD and PPA patients were significantly more impaired in reading nonwords than words. Lexical decision impairment in the visual modality appears to be related to PCA, while a similar deficit in the auditory modality is more suggestive of AD. A multiple single-case analysis on the reading performance was run to identify the distribution of different kinds of dyslexia: phonological dyslexia occurred in 50% of patients affected by PCA: it occurred less often in patients affected by AD (15.8%) and PPA (16.7%). Surface dyslexia occurred only in one case of AD. Age of acquisition was predictive of the reading performance for AD patients, but not for PCA and PPA patients.Conclusions: Phonological dyslexia predominates in PCA. Surface dyslexia occurred only in one AD patient. Reading nonwords was predominantly impaired in AD and PPA cases. Impairment in visual lexical decision was associated with PCA, whereas a lexical decision deficit in the auditory modality emerged in AD. Data indicate the importance of extensive testing of reading and input lexical abilities in neurodegenerative diseases.

Neuropathologic Associations of Learning and Memory in Primary Progressive Aphasia.

The dementia syndrome of primary progressive aphasia (PPA) can be caused by 1 of several neuropathologic entities, including forms of frontotemporal lobar degeneration (FTLD) or Alzheimer disease (AD). Although episodic memory is initially spared in this syndrome, the subtle learning and memory features of PPA and their neuropathologic associations have not been characterized. To detect subtle memory differences on the basis of autopsy-confirmed neuropathologic diagnoses in PPA. Retrospective analysis was conducted at the Northwestern Cognitive Neurology and Alzheimer's Disease Center in August 2015 using clinical and postmortem autopsy data that had been collected between August 1983 and June 2012. Thirteen patients who had the primary clinical diagnosis of PPA and an autopsy-confirmed diagnosis of either AD (PPA-AD) or a tau variant of FTLD (PPA-FTLD) and 6 patients who had the clinical diagnosis of amnestic dementia and autopsy-confirmed AD (AMN-AD) were included. Scores on the effortless learning, delayed retrieval, and retention conditions of the Three Words Three Shapes test, a specialized measure of verbal and nonverbal episodic memory. The PPA-FTLD (n = 6), PPA-AD (n = 7), and AMN-AD (n = 6) groups did not differ by demographic composition (all P > .05). The sample mean (SD) age was 64.1 (10.3) years at symptom onset and 67.9 (9.9) years at Three Words Three Shapes test administration. The PPA-FTLD group had normal (ie, near-ceiling) scores on all verbal and nonverbal test conditions. Both the PPA-AD and AMN-AD groups had deficits in verbal effortless learning (mean [SD] number of errors, 9.9 [4.6] and 14.2 [2.0], respectively) and verbal delayed retrieval (mean [SD] number of errors, 6.1 [5.9] and 12.0 [4.4], respectively). The AMN-AD group had additional deficits in nonverbal effortless learning (mean [SD] number of errors, 10.3 [4.0]) and verbal retention (mean [SD] number of errors, 8.33 [5.2]), which were not observed in the PPA-FTLD or PPA-AD groups (all P < .005). This study identified neuropathologic associations of learning and memory in autopsy-confirmed cases of PPA. Among patients with clinical PPA syndrome, AD neuropathology appeared to interfere with effortless learning and delayed retrieval of verbal information, whereas FTLD-tau pathology did not. The results provide directions for future research on the interactions between limbic and language networks.

Behavioral Evolution of Progressive Semantic Aphasia in Comparison with Nonfluent Aphasia

Background: Patients with primary progressive aphasia (PPA) usually develop significant behavioral disturbances with progression of the disease. We tested our clinical observation that development of disruptive agitation is more likely in semantic than in nonfluent PPA and examined which clinical variables could be associated with this behavior. Methods: We retrospectively analyzed neuropsychiatric scores and the need for behavioral treatments in semantic PPA (n = 41) and nonfluent PPA (n = 39) cases and compared first (1-3 years since the onset of symptoms) and last (5-13 years since the onset) evaluations. Clinical variables and laterality of temporal atrophy were associated with symptoms in semantic PPA cases. Results: The semantic PPA group developed more frequent (p = 0.03) and intense agitation (p = 0.0008) and had a greater need for antipsychotic drugs (p = 0.001) than the nonfluent PPA group. Presence of agitation was clearly associated with psychotic symptoms (delusions/hallucinations) but was not associated with gender, age at onset, duration of the disease, or laterality of temporal atrophy. In contrast, nonfluent PPA cases were more frequently depressed and treated with antidepressants (p = 0.0007). There were no differences in anxiety, irritability, apathy, perseverations, hyperorality, or abnormal motor behavior. Conclusions: Semantic PPA in advanced disease is frequently associated with agitation and psychotic symptoms with fewer mood symptoms, while nonfluent PPA maintains a high prevalence of depression. This implies different treatment and care and support needs for each group.

18F-FDG PET Improves Diagnosis in Patients with Focal-Onset Dementias.

Alzheimer disease is the cause of up to one-third of cases of primary progressive aphasia or corticobasal syndrome. The primary objective of this study was to determine the accuracy of 18F-FDG PET metabolic imaging for the detection of Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome. A cohort of patients (n=94), including those with an expert clinical diagnosis of logopenic (n=19), nonfluent (n=16), or semantic (n=13) variants of primary progressive aphasia, corticobasal syndrome (n=14), or Alzheimer disease (n=24), underwent 18F-FDG metabolic and 11C-labeled Pittsburgh compound B (11C-PiB) amyloid PET brain imaging. 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays were classified as revealing Alzheimer disease or "other" by interpreters who were unaware of the clinical assessments and 11C-PiB PET results. 11C-PiB PET imaging was considered to be the diagnostic reference standard, with a threshold standardized uptake value ratio of 1.5 being indicative of Alzheimer disease pathology. To address possible bias from subgroup selection for the Alzheimer disease binary classifier, we calculated both conventional and balanced accuracies. Diagnoses of Alzheimer disease based on 18F-FDG PET resulted in 84% accuracy (both conventional and balanced). In comparison, diagnoses based on clinical assessments resulted in 65% conventional accuracy and 67% balanced accuracy. Brain 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays accurately detected Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome as focal-onset dementias. In such diagnostically challenging cohorts, (18)F-FDG PET imaging can provide more accurate diagnoses, enabling more appropriate therapy.