Search

Syntactic deficits are not a core symptom of the semantic variant of primary progressive aphasia (svPPA). However, some studies indicate syntactic impairments that deteriorate with progress of the disease. The study addresses the presence of a syntactic deficit and its association with clinical, neuropsychological, neuroanatomical and demographic variables. Nine individuals with svPPA were tested with a cognitive screening test (Addenbrooke’s Cognitive Examination, ACE-R), a language screening test (Boston Diagnostic Aphasia Examination—BDAE) and a syntactic test (object question elicitation). Additionally, the regional cerebral flow was measured with brain single-photon emission computed tomography (SPECT). The results indicated significant impairment in the production of object questions for some patients. Performance on these clauses was not predicted by the ACE-R or by hypoperfusion in the language areas. While there was no evidence for an effect of disease duration on syntactic performance, the results reveal a potential effect of the age of symptom onset. Furthermore, the results reveal a significant association between the performance in BDAE and the years of education and production of object questions. Overall, these results indicate a significant specific deficit in syntax for some patients with svPPA and highlight the importance of the premorbid educational status for the progress of the disease.

IntroductionIdentifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.MethodsNinety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes.ResultsNIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss.DiscussionThe NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype–phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD. [ABSTRACT FROM AUTHOR]

Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype–phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD.

We present the preliminary study of the 42-item Semantic Memory Test (SMT-42), a test developed to distinguish semantic variant primary progressive aphasia (svPPA) from the other variants: logopenic (lPPA) and nonfluent/agrammatic (naPPA). The test requires the patient to retrieve the conceptual features of items belonging to different lexical categories. In the first study, we administered the French version of the SMT-42 to a population of healthy subjects and to patients with svPPA matched to a subgroup of the healthy subjects. In the second study, we administered the SMT-42 to four groups of patients (with svPPA, lPPA, naPPA and Alzheimer's disease [AD], respectively) to study its capacity to differentiate patients suffering from svPPA from the other patients. In the first study, 109 healthy subjects were included, 15 of whom were paired with 15 subjects presenting with svPPA. In the second study, designed to compare groups presenting a primary progressive aphasia variant and AD, 12 subjects with svPPA, 6 with naPPA and 9 with lPPA were included, along with 21 subjects with AD. The subjects presenting a semantic deficit were clearly distinguished from the others by their results on the SMT-42 (svPPA: mean = 30.0 (5.9); lPPA: mean = 37.8 (3.3), d = 1.5, p = 0.002; naPPA: mean = 39.8 (1.9), d = 1.89, p = 0.001; AD: mean = 38.5 (2.4), d = 1.63, p < 0.001); (svPPA: median = 31; lPPA: median = 38, U = 9, p = 0.002; naPPA: median = 40.5, U = 1.5, p = 0.001; AD: median = 39, U = 13.5, p < 0.001). The SMT-42 is simple, rapidly administered (3 minutes on average), easily scored and has good sensitivity, and it appears to be an effective tool for semantic screening in routine clinical practice. [ABSTRACT FROM AUTHOR]

Primary progressive aphasias (PPA) are neurodegenerative diseases clinically characterized by an early and relatively isolated language impairment. Three main clinical variants, namely the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA) have been described, each with specific linguistic/cognitive deficits, corresponding anatomical and most probable pathological features. Since the discovery and the development of diagnostic criteria for the PPA variants by the experts in the field, significant progress has been made in the understanding of these diseases. This review aims to provide an overview of the literature on each of the PPA variant in terms of their clinical, anatomical and pathological features, with a specific focus on recent findings. In terms of clinical advancements, recent studies have allowed a better characterization and differentiation of PPA patients based on both their linguistic and non-linguistic profiles. In terms of neuroimaging, techniques such as diffusion imaging and resting-state fMRI have allowed a deeper understanding of the impact of PPA on structural and functional connectivity alterations beyond the well-defined pattern of regional gray matter atrophy. Finally, in terms of pathology, despite significant advances, clinico-pathological correspondence in PPA remains far from absolute. Nonetheless, the improved characterization of PPA has the potential to have a positive impact on the management of patients. Improved reliability of diagnoses and the development of reliable in vivo biomarkers for underlying neuropathology will also be increasingly important in the future as trials for etiology-specific treatments become available.

Background: It is important to make accurate clinical diagnosis of frontotemporal lobar degeneration (FTLD), which in turn, leads to future therapic approaches. The FTLD cases are frequently inaccurately identified, but the frequency of this misidentification according to the underlying pathological subtypes is still unclear.Objective: We aimed to quantify the accuracy of behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) diagnoses by both the patients' referring physicians and hospital expert psychiatrists, and we investigated whether the physicians' and psychiatrists' diagnostic patterns are associated with a specific neuropathology.Methods: We retrospectively analyzed the cases of a series of Japanese patients with pathologically diagnosed FTLD (n = 55): the bvFTD group (n = 47) consisted of patients with FTLD-tau (n = 20), FTLD-TDP (TAR DNA-binding protein of 43-kDA) (n = 19), and FTLD-FUS (fused in sarcoma) (n = 8). The svPPA patients (n = 8) all had FTLD-TDP.Results: Only 31% of the patients' referring physicians mentioned FTD syndrome. The referring psychiatrists and neurologists showed similar diagnostic accuracy. High diagnostic accuracy was observed for the TDP pathology group (mainly svPPA patients). The FTLD-FUS patients were more likely to be diagnosed as having a psychiatric disorder by referring physicians. The hospital expert psychiatrists' accuracy for identifying FTLD-tau pathology was low.Conclusion: The results of our analyses revealed a specific diagnostic pattern associated with particular FTLD pathological subtypes, which will help to improve non-specialists' diagnostic ability. [ABSTRACT FROM AUTHOR]

Some patients with primary progressive aphasia (PPA) present with various types of hearing deficits. Research on the auditory function and speech sounds in PPA, including temporal, phonemic, and prosodic processing, revealed impairment in some of these auditory processes. Many patients with PPA who present with impaired word recognition subsequently developed non-fluent variant PPA. Herein, we present a patient with semantic variant PPA (svPPA) who demonstrated impaired verbal word discrimination. Audiological examinations revealed normal auditory brainstem responses and slightly impaired pure-tone perception. By contrast, verbal word discrimination and monosyllable identification were impaired, and temporal auditory acuity deteriorated. Analyses of brain magnetic resonance images revealed a significant decrease in the gray matter volume in bilateral superior temporal areas, predominantly on the left, compared with those of patients with typical svPPA, which appeared to be associated with impaired word recognition in our patient. [ABSTRACT FROM AUTHOR]

Background and purpose: Q336H is a rare MAPT mutation, previously found in a single patient with behavioral variant frontotemporal dementia and tau pathology (Pick bodies). Here, we describe the clinical characteristics of two members of a new family carrying the Q336H MAPT mutation. Methods: Clinical, genetic, and neuroradiological assessment and follow‐up of the proband were made. Results: At age 37 years, the proband developed naming and object recognition impairment, due to a lack of knowledge. After 3 years, he developed behavioral disorders. Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography showed the involvement of the left temporal pole. A diagnosis of semantic variant primary progressive aphasia (svPPA) was made. At follow‐up after 6 and 12 months, a rapid worsening of cognitive deficits occurred. His parent presented, at age 65 years, slowly progressive memory deficits without behavioral impairment, and, on MRI, evidence of mesial temporal atrophy, consistent with a clinical diagnosis of Alzheimer disease (AD). Conclusions: This is the second family carrying the MAPT Q336H mutation reported so far. We showed that svPPA and AD‐like phenotype can be associated with this mutation. A wide clinical variability exists at the intrafamilial level for Q336H MAPT mutation, pointing to genetic and/or environmental influencing factors on disease expression. We also confirmed that svPPA can be associated with MAPT mutations, suggesting that this gene should be analyzed also in patients with svPPA, especially with early onset. In addition, an AD‐like phenotype may be associated with this mutation, suggesting its different effects on protein misfolding and aggregation. [ABSTRACT FROM AUTHOR]

Some patients with primary progressive aphasia (PPA) present with various types of hearing deficits. Research on the auditory function and speech sounds in PPA, including temporal, phonemic, and prosodic processing, revealed impairment in some of these auditory processes. Many patients with PPA who present with impaired word recognition subsequently developed non-fluent variant PPA. Herein, we present a patient with semantic variant PPA (svPPA) who demonstrated impaired verbal word discrimination. Audiological examinations revealed normal auditory brainstem responses and slightly impaired pure-tone perception. By contrast, verbal word discrimination and monosyllable identification were impaired, and temporal auditory acuity deteriorated. Analyses of brain magnetic resonance images revealed a significant decrease in the gray matter volume in bilateral superior temporal areas, predominantly on the left, compared with those of patients with typical svPPA, which appeared to be associated with impaired word recognition in our patient.

We report four cases depicting the heterogeneity of Alzheimer's disease (AD) associated with pure AD pathology. Case 1 was a 77‐year‐old man with a false positive diagnosis of dementia with Lewy bodies with reduced dopamine transporter uptake activity of the striatum but no Lewy body pathology. There were tau deposits in the large neurons in the putamen, which may be related to the development of parkinsonism. Case 2 was an AD patient in his early 30s who presented with a psychotic episode and a cognitive decline, and later developed myoclonus and seizures. He demonstrated considerable amyloid‐beta deposits in the cerebral cortex, including cotton wool plaques, basal ganglia, and cerebellum. Tau deposits were also abundant in the cerebral neocortex, hippocampus, basal ganglia, and brain stem. Case 3 was a 60‐year‐old woman who exhibited typical symptoms characteristic of the logopenic variant of primary progressive aphasia (lvPPA). Case 4 was a 68‐year‐old man who exhibited the semantic variant of primary progressive aphasia (svPPA) plus repetition impairment, a rare case associated with AD pathology. In addition to tau pathology, astrocytic pathology was prominent in the white matter and cortical layers of the left temporoparietal cortices. While the main AD lesion in case 4 was evaluated by tau accumulation and astrogliosis in the left temporal lobe, that in case 3 in was evaluated by the same points in the left parietal lobe. Within the spectrum of lvPPA, case 4 may be regarded as a temporal variant of lvPPA presenting svPPA. The pathology of PPA associated with AD may have broader clinical manifestations than that in previously described cases. Case 4 also showed pathological features characteristic of cerebral amyloid angiopathy throughout the cerebral cortex. The distribution of tau and astrocytic pathologies in the cerebral cortex, basal ganglia, brain stem, and cerebellum may explain the various symptoms of atypical pure AD patients. [ABSTRACT FROM AUTHOR]

Dementias with predominant language involvement, called primary progressive aphasias provide us with unique insight into systematic breakdown of language in neurodegenerative diseases and the structures and networks involved. Clinical and neuroimaging models quite distinct from those seen in stroke aphasias have evolved. In this short overview, we will discuss the cognitive processes involved in expressive and receptive verbal communication and how these processes are affected in the different variants of primary progressive aphasia producing distinctive clinical patterns. We will also discuss the brain's language network and how different components of the network break down in each of the primary progressive aphasia variants.

Objectives: Frontotemporal lobar degeneration (FTLD) is associated with accumulation of neurodegeneration‐related protein, such as tau, TAR DNA‐binding protein 43 (TDP‐43), or fused in sarcoma protein (FUS). There have been very few systematic studies of the early symptoms of clinical phenotypes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA). Clinical subtypes and the patterns of atrophy reflect protein‐accumulation patterns, but the relationship between early symptoms and pathological findings remains unclear. Methods: We retrospectively investigated the clinical records and examined the neuropathology of 39 bvFTD and 6 svPPA patients to identify symptoms appearing within 2 years of the first clinically apparent changes. Results: The bvFTD group consisted of 13 FTLD‐tau, 18 FTLD‐TDP, and 8 FTLD‐FUS, and the svPPA group consisted of 6 FTLD‐TDP. Age at death is significantly younger in FTLD‐FUS (52.8 ± 12.6; P = 0.0104 < 0.05). Over 50% of bvFTD patients show apathy or inertia, and distinct language features appear early in svPPA. Interestingly, bvFTD and svPPA frequently present additional symptoms, not included in the diagnostic criteria, such as physical signs, reticence, dazed condition, and delusions. Stereotyped behaviors, hyperorality and dietary changes are prominent in FTLD‐FUS, while linguistic deficits are greater in FTLD‐TDP. Conclusions: Specific symptoms tend to appear in the early stage of FTLD in each pathological background. They might reflect the morphological features and pathological progression, and should be helpful in the stratification of patients for future therapeutic trials based on the proteinopathies. [ABSTRACT FROM AUTHOR]

Objective: To assess longitudinal patterns of brain functional MRI (fMRI) activity in a case of prodromal semantic variant of a primary progressive aphasia (svPPA). Methods: Clinical, cognitive and neuroimaging data (T1-weighted and task-based fMRI during silent naming [SN] and object knowledge [OK]) were obtained at baseline, month 8 and month 16 from a 49-year-old lady presenting with anomias and evolving to overt svPPA in 8 months. Results: At baseline, the patient showed isolated anomias and mild left anterior temporal pole atrophy. During SN–fMRI, she showed bilateral temporal and left inferior frontal gyri (iFG) activations. During OK–fMRI, we observed normal performance and the recruitment of bilateral posterior hippocampi, iFG and left middle orbitofrontal gyrus (mOFG). At month 8, the patient received a diagnosis of svPPA and showed isolated right iFG activity during SN–fMRI, and a borderline performance during OK–fMRI together with a disappearance of mOFG recruitment. At the last visit (after 7-month language therapy), the patient showed a stabilization of naming disturbances, and, compared to previous visits, an increased left iFG recruitment during SN–fMRI. During OK–fMRI, she performed abnormally and did not show the activity of mOFG and iFG. Across all visits, brain atrophy remained stable. Conclusions: This case report showed longitudinal fMRI patterns during semantic-related tasks from prodromal to overt svPPA. Frontal brain recruitment may represent a compensatory mechanism in patients with early svPPA, which is likely to be reinforced by language-therapy. Brain fMRI is more sensitive compared with structural MRI to detect progressive brain changes associated with disease and treatment. [ABSTRACT FROM AUTHOR]

Dementias with predominant language involvement, called primary progressive aphasias provide us with unique insight into systematic breakdown of language in neurodegenerative diseases and the structures and networks involved. Clinical and neuroimaging models quite distinct from those seen in stroke aphasias have evolved. In this short overview, we will discuss the cognitive processes involved in expressive and receptive verbal communication and how these processes are affected in the different variants of primary progressive aphasia producing distinctive clinical patterns. We will also discuss the brain's language network and how different components of the network break down in each of the primary progressive aphasia variants. [ABSTRACT FROM AUTHOR]

Primary progressive aphasia (PPA) results from selective neurodegeneration mainly in the areas of the language-dominant hemisphere, disrupting processes whose proper functioning is ensured by a complex language network in the brain, localized mainly in the cortex but also in subcortical and deeper brain areas. Speech/ language defi cits are the fi rst and long-term dominant problem in the initial stage of the disease, causing signifi cant impairment in activities of everyday life in PPA patients. We summarize the most important aspects of PPA with special emphasis on the characteristics of three PPA variants - the nonfl uent/agrammatic, semantic and logopenic variants - and primary apraxia of speech are described in terms of linguistic defi cits and co-occurring cognitive disorders (neuropsychological aspects) and neuropsychiatric disorders, especially behavioral disorders. We provide information that can help to identify key symptoms more rapidly in clinical practice. The clinical picture of PPA is complemented by localization of brain atrophy on MRI and also by summarizing specifi c PPA neuropathology. [ABSTRACT FROM AUTHOR]

Differential patterns of white matter disruption have recently been reported in the non-fluent (nfvPPA) and semantic (svPPA) variants of primary progressive aphasia (PPA). No single measure is sufficient to distinguish between the PPA variants, but connected speech allows for the quantification of multiple measures. The aim of the present study was to further investigate the white matter correlates associated with connected speech features in PPA. We examined the relationship between white matter metrics and connected speech deficits using an automated analysis of transcriptions of connected speech and diffusion tensor imaging in language-related tracts. Syntactic, lexical, and semantic features were automatically extracted from transcriptions of topic-directed interviews conducted with groups of individuals with nfvPPA or svPPA as well as with a group of healthy controls. A principal component analysis was performed in order to reduce the number of language measures and yielded a five-factor solution. The results indicated that nfvPPA patients differed from healthy controls on a syntactic factor, and svPPA patients differed from controls on two semantic factors. However, the patient groups did not differ on any factor. Moreover, a correlational analysis revealed that the lexical richness factor was significantly correlated with radial diffusivity in the left inferior longitudinal fasciculus, which suggests that semantic deficits in connected speech reflect a disruption of this ventral pathway, and which is largely consistent with the results of previous studies. Using an automated approach for the analysis of connected speech combined with probabilistic tractography, the present findings demonstrate that nfvPPA patients are impaired relative to healthy controls on syntactic measures and have increased radial diffusivity in the left superior longitudinal fasciculus, whereas the svPPA group was impaired on lexico-semantic measures relative to controls and showed increased radial diffusivity in the uncinate and inferior longitudinal fasciculus bilaterally.

The article describes the semantic flexibility inherent in the verbs of movement, which allows you to in detail and fully cover with lexical means the entire sphere of extra-linguistic reality related to the processes of movement. The variation of values resulting from the appearance of new differential features is represented; changes in the ratio of the semantic significance of various features of one lexico-semantic variant changes in the sphere of reality – an object that moves or is experiencing movement itself under the influence of extraneous forces; expansion of meaning that allows nominating other areas of reality; generalization of the meaning of verbs to the extent that it becomes universal, having lost connection with any particular type of movement, type of environment or method of movement; phraseological transfer of values. It is argued that these semantic phenomena cause a process of secondary nominations, the emergence of nominative-derived verbs.

Introduction: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. Methods: Ninety‐three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH‐EXAMINER) and the UDS neuropsychological battery. Linear mixed‐effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. Results: NIH‐EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH‐EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. Discussion: The NIH‐EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint. [ABSTRACT FROM AUTHOR]

Primary progressive aphasias (PPA) are neurodegenerative diseases clinically characterized by an early and relatively isolated language impairment. Three main clinical variants, namely the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA) have been described, each with specific linguistic/cognitive deficits, corresponding anatomical and most probable pathological features. Since the discovery and the development of diagnostic criteria for the PPA variants by the experts in the field, significant progress has been made in the understanding of these diseases. This review aims to provide an overview of the literature on each of the PPA variant in terms of their clinical, anatomical and pathological features, with a specific focus on recent findings. In terms of clinical advancements, recent studies have allowed a better characterization and differentiation of PPA patients based on both their linguistic and non-linguistic profiles. In terms of neuroimaging, techniques such as diffusion imaging and resting-state fMRI have allowed a deeper understanding of the impact of PPA on structural and functional connectivity alterations beyond the well-defined pattern of regional gray matter atrophy. Finally, in terms of pathology, despite significant advances, clinico-pathological correspondence in PPA remains far from absolute. Nonetheless, the improved characterization of PPA has the potential to have a positive impact on the management of patients. Improved reliability of diagnoses and the development of reliable in vivo biomarkers for underlying neuropathology will also be increasingly important in the future as trials for etiology-specific treatments become available.

Primary progressive aphasia (PPA) comprises a heterogeneous group of neurodegenerative conditions that can be classified in three cliniconeuroanatomic syndromes. Limited information exists, however, about patterns of neuropathologic spreading and microscopic changes underpinning each syndrome. We performed an analysis of a longitudinal in vivo cohort and a postmortem PPA cohort to investigate neurodegeneration over time and to quantify microscopic changes in key language brain areas. The longitudinal analyses demonstrated distinctive patterns of topological extension of brain atrophy. Although semantic variant (sv-PPA) showed an eccentric pattern, nonfluent and/or agrammatic (nfv-PPA) and logopenic (lv-PPA) variants showed additional multifocal extension. The quantitative pathology showed that sv-PPA had neuronal loss and thinning in BA 38, whereas nfv-PPA showed thinning in BA 44/45 and evidence of microscopic involvement in BA 40/22. Although lv-PPA showed neuronal loss focused on BA 40/22, imaging results demonstrated widespread left-sided brain atrophy. These analyses provide an account of the pathologic process whereby each variant has stereotypical patterns of brain atrophy extension, which is largely determined by the specific pathologic type. [ABSTRACT FROM AUTHOR]

Introduction According to its classic definition, the morpheme is the smallest meaning unit of language. Accessing the meaning of derivational morphemes helps to understand new or unfamiliar words. The aim of this study was to explore the impact of semantic impairment on the comprehension of derivational morphemes in a group of individuals with semantic variant primary progressive aphasia (svPPA). A few studies report results for derivational morphology in svPPA (Kavé, Heinik, & Biran, 2012; Meteyard & Patterson, 2009) but they did not specifically examine the comprehension of derivational morphemes. Methods Seven French-speaking individuals with svPPA and 14 age, sex and education matched individuals completed a word-to-definition matching task. Targets and foils (2), matched for token frequency, consisted in morphologically complex, semantically transparent words, formed with the base word included in the definition. The task included 6 definition formats and 6 items per format (36 in total). For example, in items with the definition format “De manière [mot de base]” (“In a [base word] way”), targets were formed with the suffix “-ment” which approximately translates to “-ly” in English. Definitions were presented both orally through headphones and visually on a computer screen. Participants had to choose the word that matched the definition by pressing on a button within an eight seconds delay. Because derived words can be processed as a whole and not as a base and an affix, participants were also submitted to a pseudo-word-to-definition matching task in which the correct answer could only be selected by understanding the target morpheme. Each pseudo-word (36) was built in respect to a word item and the foils were formed with the same affixes as their real word counterparts. Results The results of one svPPA participant were excluded from the analysis for the pseudo-word condition because of uncertainty regarding her understanding of the instructions. As shown in Table 1, individuals with svPPA were slower and less accurate in selecting words and pseudo-words that matched a definition. Within group comparisons showed that the control group was faster to choose the correct answer for words than for pseudo-words, while the svPPA group did not show such an advantage. Conclusion The results of the word condition alone cannot rule out the possibility that errors in the svPPA group were caused by difficulty in understanding words rather than in processing derivational morphemes. However, the lexical context provided in this condition did not speed-up the performance of svPPA individuals as it did in the control group. Most importantly, results from the pseudo-word condition showed that in the svPPA group, the association between the morpheme and its meaning was not performed as readily and reliably as in the control group. These results support the involvement of semantic memory in morphological processing.

Introduction. The semantic variant of primary progressive aphasia (svPPA) is characterized by a progressive deterioration of semantic memory, associated with word comprehension and naming deficits (Gorno-Tempini et al., 2011). Patients with svPPA also show acquired surface dyslexia and dysgraphia. According to the 'dual-route' model, reading aloud (Coltheart, 1978) and spelling (Ellis, 1982) of nonwords are achieved by resorting to a nonlexical and non semantic route, through the application of grapheme-phoneme conversion (GPC) rules. The aim of the present study was to examine the performance of two individuals with svPPA in tasks tapping consistent GPC rules of two types: a) non-contextual GPC rules (n-cGPC) in which each grapheme has only one unequivocal phonemic correspondence; 2) context-sensitive GPC rules (c-sGPC) in which the pronunciation or spelling is determined by the preceding or following letters (e.g. C and G, which are consistently pronounced /k/ and /g/, change to /s/ and /ʒ/ before the letters E and I). Method. Participants. We report the performance of two French-speaking patients (NG and ND) that fulfilled clinical and imaging-supported criteria for svPPA. Both presented with surface dyslexia and dysgraphia. Each of them was matched by age, gender and education to three normal controls. Tasks and procedure. NG and ND were administered the following experimental tasks comprising bisyllabic and trisyllabic words and nonwords with n-cGPC and c-sGPC rules, placed at the beginning, the middle or the end of the stimulus: 1) regular word and nonword reading; 2) adding a missing letter in words and nonwords: the patients were asked to complete stimuli by a letter to make them correspond to the word or nonword pronounced by the experimenter (for n-cGPC rules, the missing letter was randomly chosen; for c-sGPC rules, one of the letters of the context was missing); 3) rhyme judgement of nonwords: stimuli were auditorily presented and the patients had to indicate if they rhymed or not (for c-sGPC stimuli, in non-rhyming pairs, the difference between nonwords implied one of the context letters). Results. As shown in Table 1, NG and ND's performance was well preserved in tasks with words and nonwords with n-cGPC rules. However, ND was impaired in all tasks with c-sGPC rules, whilst NG's performance was affected for c-sGPC stimuli only in the rhyming task. Discussion. The processing of regular words and nonwords is assumed to be unimpaired in svPPA since their production do not necessary rely on the lexical-semantic route of reading and spelling. In the present study, this hypothesis was confirmed for n-cGPC rules only. However, both patients presented with difficulty in c-sGPC stimuli. This pattern of performance, never reported before in svPPA, questions the possible role of semantic memory in the reading and spelling of stimuli comprising consistent but contextual GPC rules.

Individuals suffering from the semantic variant of primary progressive aphasia (svPPA) show semantic degradation and impaired lexical decision (LD) (Rogers, Lambon Ralph, Hodges, & Patterson, 2004). The PDP-triangle model states that written word recognition depends on the interaction between perceptual and conceptual processing, i.e. orthography-to-semantics (O-S) mappings. Thus semantic impairment should affect normal recognition. Additionally, the pseudohomophone (PsH) effect in LD is traduced in longer latencies and more errors for pseudowords that sound like a real word (roZe), as compared to pseudowords that do not (rone). This effect is considered a marker of phonological activation in LD (Braun, Hutzler, Ziegler, Dambacher, & Jacobs, 2009) since a PsH will activate an existing phonological representation, creating a conflict between orthography-phonology (O-P). The aim of this study was to examine the performance of patients with svPPA in a LD task with PsHs. We predicted that patients should be impaired because of a deficit in O-S mappings. However, O-P mappings are assumed to be intact in svPPA and a PsH effect should be found for patients, as described for normals. Method Participants. Eight French-speaking patients that fulfilled clinical and imaging-supported criteria for svPPA (Gorno-Tempini et al., 2011) were matched by age, gender and education to 16 normal controls. Stimuli. LD task with (1) irregular- and (2) regular-words, (3) PsH and (4) pseudowords (n=60 per condition). All conditions were matched by length (in letters and phonemes), bigram frequency and N-size. Conditions 1-3 were additionally matched by frequency and imageability. Procedure. Stimuli were randomly presented on a laptop using the DMDX software. Each participant was asked to decide whether stimuli were real words. Data analysis. ANOVAs were carried out with RTs and errors as dependent variables and type of stimuli as repeated measures and participant group as between subject factor using SPSS-19. Simple effects were studied with paired t-tests. Results For both RTs and errors: (a) svPPA patients were significantly slower and more error-prone than controls; (b) the effects of lexicality and PsHs were found for controls only. Discussion The results in controls reproduce those found in literature (Braun et al., 2009). The general impairment and the lack of lexicality effect are also in line with current literature on svPPA and are likely explained by semantic impairment (Rogers et al., 2004). Interestingly, the novel result here is the absence of PsH effect in svPPA. This suggests that phonology is not correctly activated and that O-P mappings are also impaired in svPPA.

Background: Three variants of primary progressive aphasia (PPA) have been currently characterized: non fluent/agrammatic (nfv-PPA), semantic (sv-PPA), and logopenic variant (lv-PPA). lv-PPA is most commonly associated with Alzheimer's disease (AD), while nfv-PPA and sv-PPA are related to frontotemporal lobar degeneration. Objective: We aimed to determine whether cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), total tau protein (t-tau), and phosphorylated tau (p-tau), frequently abnormal in AD, could constitute a useful tool in the PPA diagnostic work up, in order to identify subjects with an underlying AD pathology. Methods: We measured CSF biomarker levels in a group of twenty-eight patients, fourteen lv-PPA, nine nfv-PPA, and five sv-PPA. Results: Since there were no significant differences in any of the parameters investigated between nfv-PPA and sv-PPA, the two groups were considered as one (nfv/sv-PPA). At diagnosis, lv-PPA were older than nfv/sv-PPA patients (mean values: 70.7 versus 64.6 years, p = 0.02). CSF biomarker mean concentrations were significantly different in lv-PPA versus nfv/sv-PPA patients (p = 0.000): Aβ42 350.64 versus 661.64 ng/L; tau 631.21 versus 232.71 ng/L; p-tau 101 versus 38.21 ng/L. According to the recent AD diagnostic criteria, (Cummings et al., 2013) eleven lv-PPA and only one nfv/sv-PPA showed a liquoral pattern typical for AD. Finally lv-PPA had CSF biomarker levels very similar to a sample of 72 AD patients from our Department. Conclusions: Our data showed that CSF biomarkers can easily and reliably detect those patients with language disorders due to an underlying AD pathology, thus offering the possibility of targeted therapeutic interventions. However, because of the small sample size, such analyses should be reproduced in larger populations of patients to confirm our data. [ABSTRACT FROM AUTHOR]

We aimed to explore the nature of verbal repetition deficits and infer the cognitive systems involved in primary progressive aphasia (PPA) and Alzheimer's disease (AD). A total of 63 patients (13 semantic variant (sv-PPA), 17 nonfluent/agrammatic variant (nfv-PPA), 10 logopenic variant (lv-PPA), 23 AD) and 13 matched healthy controls completed a battery of tests that included naming, word comprehension, digit span, repetition of multisyllabic single words, monosyllabic word span presented under similar and dissimilar phonological conditions, and sentence repetition. All patient groups displayed some level of impairment, however, specific patterns emerged in each variant. Participants with sv-PPA were the least impaired, showing marginal difficulties exclusively for sentence repetition, whereas those with lv-PPA had the worst overall performance. Cases with nfv-PPA showed compromised repetition of multisyllabic and phonologically similar words. The deficit in cases with AD was confined to span tasks. These distinctive patterns of language impairments can assist in the differential diagnosis of PPA variants and point toward the vulnerability of specific cognitive systems in each syndrome. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to report diffusion tensor imaging (DTI) patterns in three patients, each with a different primary progressive aphasia (PPA) variant. Design: One agrammatic PPA, one semantic PPA, and one logopenic PPA subject underwent a magnetic resonance imaging examination including DTI sequences. The fractional anisotropy (FA) value was calculated in regions of interest (ROIs) involved in these three variants (perisylvian region, temporal pole, and parietotemporal junction) for each patient. Left-right FA ratios in each ROI were compared between PPA subjects and a group of three amnestic mild cognitive impairment patients with a cerebrospinal fluid biomarker profile of the Alzheimer type. Results: The FA values were lower in the left hemisphere (p = 0.03). The lowest FA values were observed in the left perisylvian region for the non-fluent/agrammatic subtype PPA patient, in the left anterior temporal lobe for the semantic subtype PPA patient, and in the left parietotemporal junction for the logopenic patient (p = 0.028). The left-right FA ratio in these specific ROIs for each PPA variant was significantly lower than in the amnestic mild cognitive impairment group (p = 0.009). Conclusion: DTI patterns could be an effective new tool for diagnosing PPA and classifying the three variants. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Early-onset Semantic dementia (EOSD) and early-onset Alzheimer's disease (EOAD) are often difficult to clinically differentiate in the early stages of the diseases because of the overlaps of clinical symptoms such as language symptoms. We compared the degree of atrophy in medial temporal structures between the two types of dementia using the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD)., Methods: The participants included 29 (age: 61.7±4.5 years) and 39 (age: 60.2±4.9 years) patients with EOSD and EOAD, respectively. The degree of atrophy in medial temporal structures was quantified using the VSRAD for magnetic resonance imaging data. Receiver operating characteristic (ROC) analysis was performed to distinguish patients with EOSD and EOAD using the mean Z score (Z-score) in bilateral medial temporal structures and the absolute value (laterality score) of the laterality of Z-score (| right-left |) for indicating the degree of asymmetrical atrophy in medial temporal structures., Results: The EOSD group had significantly higher Z and laterality scores than the EOAD group (Zscores: mean ± standard deviation: 3.74±1.05 vs. 1.56±0.81, respectively; P<0.001; laterality score: mean ± standard deviation: 2.35±1.23 vs. 0.68±0.51, respectively; P<0.001). In ROC analysis, the sensitivity and specificity to differentiate EOSD from EOAD by a Z-score of 2.29 were 97% and 85%, respectively and by the laterality score of 1.05 were 93% and 85%, respectively., Conclusion: EOSD leads to more severe and asymmetrical atrophy in medial temporal structures than EOAD. The VSRAD may be useful to distinguish between these dementias that have several clinically similar symptoms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Frontotemporal dementia (FTD) represents the second most frequent early onset of dementia in people younger than 65 years. The main syndromes encompassed by the term FTD are behavioral variant of Frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA) and semantic variant (SD)., Aims: To assess the bvFTD and SD, which represent the most common subtypes of FTD, using visual rating scales., Methods: Brain MRI exams of 77 patients either with bvFTD (n=43) or SD (n=34) were evaluated. The rating scales used were: Global cortical atrophy (GCA), Fazekas Scale: periventricular (PV) and white matter (WM) changes, Koedam rating scale and visual scales regarding specific cortical regions: dorsofrontal (DF), orbitofrontal (OF), anterior cingulate (AC), basal ganglia (BG), anterior- temporal (AT), insula, lateral-temporal (LT), entorhinal (ERC), perirhinal (PRC), anterior fusiform( AF), anterior hippocampus (AHIP) and posterior hippocampus (PHIP). Both Left (L) and Right (R) hemispheres were evaluated., Results: R-OF (p=0.059), L-OF (p<0.0005), L-AT (p=0.047) and L-AHIP (p=0.007) have a statistically significant effect on the variable occurrence of SD compared to bvFTD. The indicators with the highest value of the area under the curve (AUC) were R-AC (0.829), L-OF (0.808), L-AC (0.791) and L-AF (0.778). Highest sensitivity was achieved by R-OF (97%) and L-AF (75%). Highest specificity was achieved by L-OF (95%), L-AT (91%) followed by R-AC (84%). Best combination of sensitivity and specificity was achieved by L-AF (74%-79%), L-OF (56%-95%) and R-OF (97%-42%). Best combination of PPV and NPV was achieved by L-OF (90%-73%), LAT (83%-72%) and R-AC (77%-77%)., Conclusion: Visual rating scales can be a practical diagnostic tool in the characterization of patterns of atrophy in FTLD and may be used as an alternative to highly technical methods of quantification., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hoarding and obsessive-compulsive behaviours (OCB) are well documented symptoms in frontotemporal dementia (FTD). While contemporary models consider hoarding and obsessive-compulsive disorder distinct, the related behaviours have not been separately examined in patients with FTD, and the neuroanatomical correlates of hoarding in patients with FTD have not been previously examined (American Psychiatric Association, 2013; Grisham and Baldwin, 2015; Mataix-Cols et al., 2010)., Methods: Patients with FTD who were evaluated between 2004 and 2018 at our centre were included. Cortical thickness and subcortical volumetric analyses were completed on available T1 high resolution anatomic scans using FreeSurfer., Results: Eighty-seven patients met inclusion criteria, and 49 had scans available for quantitative MRI volumetric analysis. New hoarding behaviours were present in 29% of patients and were more common in the semantic variant subtype of FTD, while 49% of individuals had new or increased OCB. Hoarding behaviours were associated with decreased thickness in a factor comprised of left temporal, insular and anterior cingulate cortices. The presence of OCB was predicted by reduced cortical thickness and volumes in a factor comprised of the anterior cingulate and subcortical volumes in the bilateral amygdala and hippocampus. OCB were associated with greater right temporal cortical thickness in comparison to patients with hoarding., Discussion: The association of the semantic variant with hoarding, together with the observed associations between left temporal atrophy and hoarding indicate that degeneration of the left temporal lobe has a role in the emergence of hoarding in FTD. As in current models of Hoarding disorder and Obsessive-Compulsive disorder, our results suggest that in patients with FTD, hoarding and OCB are clinically and anatomically partially dissociable phenomenon. The results may also help to further elucidate the cognitive processes and neural networks contributing to Hoarding disorder and Obsessive-Compulsive disorder in persons without dementia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Artistic ability and creativity are defining characteristics of human behavior. Behavioral neurology, as a specialty, believes that even the most complex behaviors can be modeled and understood as the summation of smaller cognitive functions. Literature from individuals with specific brain lesions has helped to map out these smaller regions of cognitive abilities. More recently, models based on neurodegenerative conditions, especially from the frontotemporal dementias, have allowed for greater nuanced investigations into the various functional anatomies necessary for artistic behavior and possibly the underlying networks that promote creativity., (© 2013 Elsevier B.V. All rights reserved.)