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INTRODUCTION Frontotemporal dementia (FTD) with right anterior temporal lobe (rATL) predominance lacks universally agreed‐upon diagnostic criteria. This study validated the Amsterdam diagnostic tree (ADT) for right temporal variant FTD (rtvFTD) and the diagnostic criteria for semantic behavioral variant FTD (sbvFTD), examining clinical, behavioral, and imaging differences. METHODS The study included 138 patients with behavioral variant FTD and 87 with semantic variant primary progressive aphasia who had 3D T1‐weighted magnetic resonance imaging scans. The participants were grouped into rtvFTD and sbvFTD by respective imaging criteria. RESULTS We identified 42 rtvFTD and 20 sbvFTD patients. ADT showed 81% sensitivity and 29% specificity, whereas sbvFTD criteria had 45% sensitivity and 55% specificity. DISCUSSION The unfavorable validation of both diagnostic criteria in Korean FTD patients may result from socio‐cultural differences, the lack of standardized tools for assessing abnormal behaviors, and the retrospective nature of the study. The perspectives on rATL also differed between the two studies. Highlights Frontotemporal dementia (FTD) with right anterior temporal lobe (rATL) predominance is a controversial FTD syndrome, also referred to as right temporal variant FTD (rtvFTD), or right predominant semantic variant primary progressive aphasia. Two clinical criteria for rATL have been proposed: One is the Amsterdam diagnostic tree for rtvFTD and the other is for semantic behavioral variant FTD (sbvFTD). Our validation study suggested the need for standardized tools and highlighted theoretical distinctions between rtvFTD and sbvFTD.

Conceptual knowledge reflects our multi-modal ‘semantic database’. As such, it brings meaning to all verbal and non-verbal stimuli, is the foundation for verbal and non-verbal expression and provides the basis for computing appropriate semantic generalizations. Multiple disciplines (e.g. philosophy, cognitive science, cognitive neuroscience and behavioural neurology) have striven to answer the questions of how concepts are formed, how they are represented in the brain and how they break down differentially in various neurological patient groups. A long-standing and prominent hypothesis is that concepts are distilled from our multi-modal verbal and non-verbal experience such that sensation in one modality (e.g. the smell of an apple) not only activates the intramodality long-term knowledge, but also reactivates the relevant intermodality information about that item (i.e. all the things you know about and can do with an apple). This multi-modal view of conceptualization fits with contemporary functional neuroimaging studies that observe systematic variation of activation across different modality-specific association regions dependent on the conceptual category or type of information. A second vein of interdisciplinary work argues, however, that even a smorgasbord of multi-modal features is insufficient to build coherent, generalizable concepts. Instead, an additional process or intermediate representation is required. Recent multidisciplinary work, which combines neuropsychology, neuroscience and computational models, offers evidence that conceptualization follows from a combination of modality-specific sources of information plus a transmodal ‘hub’ representational system that is supported primarily by regions within the anterior temporal lobe, bilaterally.

Objectives: The Addenbrooke’s Cognitive Examination (ACE) is a common cognitive screening test for dementia. Here, we examined the relationship between the most recent version (ACE-III) and its predecessor (ACE-R), determined ACE-III cutoff scores for the detection of dementia, and explored its relationship with functional ability. Methods: Study 1 included 199 dementia patients and 52 healthy controls who completed the ACE-III and ACE-R. ACE-III total and domain scores were regressed on their corresponding ACE-R values to obtain conversion formulae. Study 2 included 331 mixed dementia patients and 87 controls to establish the optimal ACE-III cutoff scores for the detection of dementia using receiver operator curve analysis. Study 3 included 194 dementia patients and their carers to investigate the relationship between ACE-III total score and functional ability. Results: Study 1: ACE-III and ACE-R scores differed by ≤1 point overall, the magnitude varying according to dementia type. Study 2: a new lower bound cutoff ACE-III score of 84/100 to detect dementia was identified (compared with 82 for the ACE-R). The upper bound cutoff score of 88/100 was retained. Study 3: ACE-III scores were significantly related to functional ability on the Clinical Dementia Rating Scale across all dementia syndromes, except for semantic dementia. Conclusions: This study represents one of the largest and most clinically diverse investigations of the ACE-III. Our results demonstrate that the ACE-III is an acceptable alternative to the ACE-R. In addition, ACE-III performance has broader clinical implications in that it relates to carer reports of functional impairment in most common dementias. (JINS, 2018, 24, 854–863)

Frontotemporal dementia encompasses a group of clinical syndromes defined pathologically by degeneration of the frontal and temporal lobes. Historically, these syndromes have been challenging to diagnose, with an average of about three years between the time of symptom onset and the initial evaluation and diagnosis. Research in the field of neuroimaging has revealed numerous biomarkers of the various frontotemporal dementia syndromes, which has provided clinicians with a method of narrowing the differential diagnosis and improving diagnostic accuracy. As such, neuroimaging is considered a core investigative tool in the evaluation of neurodegenerative disorders. Furthermore, patterns of neurodegeneration correlate with the underlying neuropathological substrates of the frontotemporal dementia syndromes, which can aid clinicians in determining the underlying etiology and improve prognostication. This review explores the advancements in neuroimaging and discusses the phenotypic and pathologic features of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia, as seen on structural magnetic resonance imaging and positron emission tomography.

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

Background/Aims: Semantic dementia (SD) is a clinical subclassification of frontotemporal lobar degeneration. Patients with ‘pure SD’ present with semantic memory impairment preceding the frontal symptoms, and there have been no reports of familial cases. Methods: We evaluated the clinical features of, and performed neuropsychological examinations on, the proband and two affected family members. Then we performed neuroimaging and genetic analysis of MAPT and other dementia-related genes in the proband. Results: All three cases had semantic memory impairment with loss of word meanings as the primary early symptom. We diagnosed all cases as pure SD and identified a P301L mutation in the MAPT gene of the proband. Conclusion: Although the P301L mutation identified here has been previously described as pathogenic for frontotemporal dementia with parkinsonism-17 (FTDP-17), the proband and his two affected relatives showed different clinical symptoms from those of typical FTDP-17 cases who carry the P301L mutation. Pathologically, pure SD usually shows a TAR DNA-binding protein proteinopathy, but the molecular understanding of SD is not well established. Although our cases were clinically pure SD, the proband has a tau gene mutation, which would lead to tauopathy. These findings suggest that reconsideration of the molecular understanding of SD is warranted.

Background Prosodic deficits in neurodegenerative diseases are often studied through a left‐right hemispheric framework, particularly focusing on pitch control. Emerging evidence, however, suggests prosodic processing may also follow dorsal‐ventral organizational principles tied to different time windows of signal variation. For example, most studies of pitch consider variation overall, and have tied this to frontal pathways. However, speakers can also change median pitch, or key, between intervals of speech to signify a change of context or emphasis, which requires semantic knowledge usually mediated by ventral pathways. This study explored pitch variation across conversational speech intervals in individuals with behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia and semantic behavioral variant FTD (svPPA/sbvFTD), conditions primarily affecting dorsal and ventral pathways, respectively. Methods We recorded ten‐minute semi‐structured conversations between 76 participants (31 bvFTD, 16 svPPA, 11 sbvFTD, 18 healthy controls) and study partners using lavalier microphones in the Berkeley Psychophysiology Laboratory. Uninterrupted speech intervals were manually labeled and analyzed in Praat. Python, assisted by Claude (AI), was used for statistical analyses. Pitch variability was quantified as the standard deviation of median interval pitch, reflecting slower‐scale prosodic modulation tied to conversational context shifts. Results A between‐group ANOVA revealed marginal statistical insignificance (F=2.181, p = 0.098). However, pre‐specified analyses by pathway involvement showed that dorsal pathway disruption (FTD) was associated with significantly greater pitch variation compared to ventral pathway disruption (svPPA/rsvPPA) (t=2.351, p = 0.022, Cohen's d=0.629). Conclusion These results suggest that prosodic key across conversational intervals is differentially impacted by dorsal versus ventral pathway degeneration. This supports theories of dorsal‐ventral distinctions in the temporal processing of speech and enhances our understanding of how distinct neural pathways regulate prosodic control within different time windows.

Apathy is inherently multidimensional and can be deconstructed in terms of its effect on goal-oriented behaviour, cognitive engagement, or emotional responsiveness. 5,6 Therefore, a potential confounding factor is that the assessment of apathy as a unitary construct via the Neuropsychiatric Inventory might obscure important treatment effects on different apathy dimensions. [...]the primary mechanism of action of oxytocin might differ by frontotemporal dementia subtype, as previous studies have revealed distinct motivational profiles across frontotemporal dementia syndromes. Importantly, although a global dampening of motivation is evident in people with behavioural variant frontotemporal dementia, behavioural inertia and economy of cognitive effort seem particularly important in driving functional decline in this syndrome. 2 By contrast, anhedonia has emerged as a prominent yet overlooked feature of the motivational disturbances seen in people with semantic dementia, 7 and one which is closely linked to the emergence of ritualistic and repetitive behaviours. 8,9 Adopting a one-size-fits-all approach to apathy treatment, which seeks to boost goal-directed behaviour in a generalised manner, might have the unintended consequences of producing an upswing in stereotypical behaviours in people with semantic dementia. [...]apathy likely follows a dynamic trajectory, evolving with progression of frontotemporal dementia.

The anterior temporal lobes (ATL) have become a key brain region of interest in cognitive neuroscience founded upon neuropsychological investigations of semantic dementia (SD). The purposes of this investigation are to generate a single unified model that captures the known cognitive-behavioural variations in SD and map these to the patients’ distribution of frontotemporal atrophy. Here we show that the degree of generalised semantic impairment is related to the patients’ total, bilateral ATL atrophy. Verbal production ability is related to total ATL atrophy as well as to the balance of left > right ATL atrophy. Apathy is found to relate positively to the degree of orbitofrontal atrophy. Disinhibition is related to right ATL and orbitofrontal atrophy, and face recognition to right ATL volumes. Rather than positing mutually-exclusive sub-categories, the data-driven model repositions semantics, language, social behaviour and face recognition into a continuous frontotemporal neurocognitive space. Semantic dementia patients present with a core semantic impairment and variations of language, behavioural and face recognition abilities. Here, the authors build a unified multidimensional model to capture all these graded symptoms and map them to the variations in the patients’ frontotemporal atrophy.

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