Frontotemporal Dementia Phenotype Research Articles

Automatic classification of AD pathology in FTD phenotypes using natural speech.

Screening for Alzheimer's disease neuropathologic change (ADNC) in individuals with atypical presentations is challenging but essential for clinical management. We trained automatic speech-based classifiers to distinguish frontotemporal dementia (FTD) patients with ADNC from those with frontotemporal lobar degeneration (FTLD). We trained automatic classifiers with 99 speech features from 1 minute speech samples of 179 participants (ADNC=36, FTLD=60, healthy controls [HC]=89). Patients' pathology was assigned based on autopsy or cerebrospinal fluid analytes. Structural network-based magnetic resonance imaging analyses identified anatomical correlates of distinct speech features. Our classifier showed 0.88 0.03 area under the curve (AUC) for ADNC versusFTLD and 0.93 0.04 AUC for patients versusHC. Noun frequency and pause rate correlated with gray matter volume loss in the limbic and salience networks, respectively. Brief naturalistic speech samples can be used for screening FTD patients for underlying ADNC in vivo. This work supports the future development of digital assessment tools for FTD. We trained machine learning classifiers for frontotemporal dementia patients using natural speech. We grouped participants by neuropathological diagnosis (autopsy) or cerebrospinal fluid biomarkers. Classifiers well distinguished underlying pathology (Alzheimer's disease vs. frontotemporal lobar degeneration) in patients. We identified important features through an explainable artificial intelligence approach. This work lays the groundwork for a speech-based neuropathology screening tool.

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia.

We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

In vivo PET classification of tau pathologies in patients with frontotemporal dementia.

Frontotemporal dementia refers to a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of frontotemporal dementia at an individual level have hitherto not been successful. In this study, we aim to classify patients with frontotemporal dementia based on topologies of tau protein aggregates captured by PET with 18F-florzolotau (aka 18F-APN-1607 and 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer's disease as well as in non-Alzheimer's disease tauopathies. Twenty-six patients with frontotemporal dementia, 15 with behavioural variant frontotemporal dementia and 11 with other frontotemporal dementia phenotypes, and 20 age- and sex-matched healthy controls were included in this study. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively. By combining visual and quantitative analyses of PET images, the patients with behavioural variant frontotemporal dementia were classified into the following subgroups: (i) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = 3), (ii) predominant tau accumulations in posterior cortical and subcortical structures indicative of four-repeat tauopathies (n = 4); (iii) amyloid and tau accumulations consistent with Alzheimer's disease (n = 4); and (iv) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localizations of brain atrophy did not significantly differ among the identified behavioural variant frontotemporal dementia subgroups. The patients with other frontotemporal dementia phenotypes were also classified into similar subgroups. The results suggest that PET with 18F-florzolotau potentially allows the classification of each individual with frontotemporal dementia on a neuropathological basis, which might not be possible by symptomatic and volumetric assessments.

Identifying clinical phenotypes of frontotemporal dementia in post-9/11 era veterans using natural language processing.

Frontotemporal dementia (FTD) encompasses a clinically and pathologically diverse group of neurodegenerative disorders, yet little work has quantified the unique phenotypic clinical presentations of FTD among post-9/11 era veterans. To identify phenotypes of FTD using natural language processing (NLP) aided medical chart reviews of post-9/11 era U.S. military Veterans diagnosed with FTD in Veterans Health Administration care. A medical record chart review of clinician/provider notes was conducted using a Natural Language Processing (NLP) tool, which extracted features related to cognitive dysfunction. NLP features were further organized into seven Research Domain Criteria Initiative (RDoC) domains, which were clustered to identify distinct phenotypes. Veterans with FTD were more likely to have notes that reflected the RDoC domains, with cognitive and positive valence domains showing the greatest difference across groups. Clustering of domains identified three symptom phenotypes agnostic to time of an individual having FTD, categorized as Low (16.4%), Moderate (69.2%), and High (14.5%) distress. Comparison across distress groups showed significant differences in physical and psychological characteristics, particularly prior history of head injury, insomnia, cardiac issues, anxiety, and alcohol misuse. The clustering result within the FTD group demonstrated a phenotype variant that exhibited a combination of language and behavioral symptoms. This phenotype presented with manifestations indicative of both language-related impairments and behavioral changes, showcasing the coexistence of features from both domains within the same individual. This study suggests FTD also presents across a continuum of severity and symptom distress, both within and across variants. The intensity of distress evident in clinical notes tends to cluster with more co-occurring conditions. This examination of phenotypic heterogeneity in clinical notes indicates that sensitivity to FTD diagnosis may be correlated to overall symptom distress, and future work incorporating NLP and phenotyping may help promote strategies for early detection of FTD.

Longitudinal volumetric changes in amygdala subregions in frontotemporal dementia.

Amygdala atrophy has been found in frontotemporal dementia (FTD), yet the specific changes of its subregions across different FTD phenotypes remain unclear. The aim of this study was to investigate the volumetric alterations of the amygdala subregions in FTD phenotypes and how they evolve with disease progression. Patients clinically diagnosed with behavioral variant FTD (bvFTD) (n = 20), semantic dementia (SD) (n = 20), primary nonfluent aphasia (PNFA) (n = 20), Alzheimer's disease (AD) (n = 20), and 20 matched healthy controls underwent whole brain structural MRI. The patient groups were followed up annually for up to 3.5years. Amygdala nuclei were segmented using FreeSurfer, corrected by total intracranial volumes, and grouped into the basolateral, superficial, and centromedial subregions. Linear mixed effects models were applied to identify changes in amygdala subregional volumes over time. At baseline, bvFTD, SD, and AD displayed global amygdala volume reduction, whereas amygdala volume appeared to be preserved in PNFA. Asymmetrical amygdala atrophy (left > right) was most pronounced in SD. Longitudinally, SD and PNFA showed greater rates of annual decline in the right basolateral and superficial subregions compared to bvFTD and AD. The findings provide comprehensive insights into the differential impact of FTD pathology on amygdala subregions, revealing distinct atrophy patterns that evolve over disease progression. The characterization of amygdala subregional involvement in FTD and their potential role as biomarkers carry substantial clinical implications.

Automatic classification of underlying AD vs. FTLD pathology in people with clinical Frontotemporal Dementia using digital speech markers

AbstractBackgroundRecent studies show promising results using speech features to automatically distinguish patients with amnestic Alzheimer’s disease (AD) from healthy controls (HC). However these studies exclude atypical presentations of AD, which present with linguistic and/or behavioral impairments that clinically overlap with frontotemporal dementia (FTD). A clinically meaningful challenge is distinguishing underlying AD pathology from frontotemporal lobar degeneration (FTLD) pathology in people presenting with an FTD phenotype. We used digital speech features to automatically classify patients with clinical FTD with as to underlying AD or FTLD pathology.MethodWe extracted 90 lexical and 9 acoustic features from one‐minute picture descriptions produced by 179 participants using our previously validated automated pipelines (Table 1). All patients presented clinically with FTD and had AD or FTLD pathology based on either autopsy or CSF (AD: CSF pTau/Aβ42³0.1 and tTau/Aβ42³0.34). Extracted features included part‐of‐speech, unique words per 100 words, several lexical characteristics, and acoustic/durational measures. Support Vector Machine (SVM), Random Forest (RF), and Multilayer Perceptron (MLP) classifiers were trained for two tasks: 1) AD vs. FTLD pathology and 2) all patients vs. HC. Five feature sets were tested: Set 1 (baseline): demographics+MMSE, Set 2: speech only, Set 3: speech+demographics, Set 4: speech+MMSE, Set 5: speech+demographics+MMSE. Features were selected using the elastic net regression with 10‐fold validations; the best performance models were reported after hyperparameter tuning.ResultDistinguishing AD from FTLD, the MLP model trained with speech had the highest AUC (0.88; accuracy = 83%) (Table 2). The RF model trained with speech and MMSE showed similar performance (accuracy = 84%, AUC = 0.85). Verb counts had the highest feature importance (FI) values in the MLP model trained with speech, followed by noun length. Distinguishing all patients from HC, the MLP model trained with speech only had the highest accuracy (93%; AUC = 0.93) (Table 3). The MLP model trained with speech and MMSE showed a comparable result (accuracy = 92%, AUC = 0.94). Unique adjective counts had the highest FI in the MLP model trained with speech, followed by word length.ConclusionSpeech models outperformed baseline models and showed comparable results with speech+MMSE. Features extracted from brief speech samples are valuable in automatically distinguishing AD from FTLD pathology, and FTD from HC.

The auditory phenotype of behavioural variant frontotemporal dementia

AbstractBackgroundPatients with behavioural variant frontotemporal dementia commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people.MethodThe QSTAC was administered to 15 patients with behavioural variant frontotempoal dementia, 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultAfter accounting for nonverbal executive and peripheral hearing performance, patients with behavioural variant frontotemporal dementia showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with behavioural variant frontotemporal dementia were further differentiated from primary progressive aphasia patients on their performance across QSTAC (sound recognition and localisation) subtests.ConclusionBehavioural variant frontotemporal dementia has a distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.

Sporadic behavioral phenotype of Right Temporal Variant of Frontotemporal Dementia: a case report

AbstractBackgroundThere are two subtypes of the right Temporal Variant of Frontotemporal Dementia (rtv‐FTD). Semantic dementia (SMD) phenotype is defined by negative familiar history, word‐finding, anomia, comprehension difficulties, prosopagnosia, and topographagnosia. The behavioral frontotemporal dementia (bvFTD) phenotype is defined by personality changes, inappropriate behaviors, positive family history, and relatively poor performance on neurobehavioral testing with better performance on confrontational naming tests. (1) We present a rare interesting case.MethodWe describe the clinical and imaging features of a man who presented a sporadic behavioral phenotype of rtv‐FTD, showing negative genetic results.ResultA 62‐year‐old man with 8 years of progressive behavioral impairment. He showed personality changes, and compulsive‐like / ritualistic behaviors such as excessive unpurposed accumulation of items, washing hands repeatedly every five minutes, and walking and wandering repeatedly in circles. He also had hiperorality, cravings for sweet foods, social cognition impairment, associated with loss of empathy, and inappropriate social behavior (hypersexuality, verbal aggressivity to unrelated people, and talking bad words to neighbors with no reason). After years he followed with mild to moderate apathy. The neuropsychological evaluation showed impairment of executive functioning, episodic memory impairment, and MMSE 19/30. The neurological exam was unremarkable, and the familiar history was negative. Brain MRI revealed frontotemporal atrophy with a marked asymmetry in the right temporal lobe. The genetic testing was negative, illustrating and sporadic case.ConclusionTheoretically, rtv‐FTD is considered a right variant of semantic phenotype, and the general assumption is that is also a sporadic disorder. Although the behavioral phenotype of rtv‐FTD normally has a genetic basis, showing positive family history, It can be presented as a sporadic disorder with non‐familial variants of FTD, as in this case. (2)

57 Traumatic Brain Injury and Concussion in Patients with Frontotemporal Dementia Spectrum Diagnoses

Objective:Traumatic brain injury (TBI) and concussion are associated with increased dementia risk. Accurate TBI/concussion exposure estimates are relatively unknown for less common neurodegenerative conditions like frontotemporal dementia (FTD). We evaluated lifetime TBI and concussion frequency in patients diagnosed with a range of FTD spectrum conditions and related prior head trauma to cavum septum pellucidum (CSP) characteristics observable on MRI.Participants and Methods:We administered the Ohio State University TBI Identification and Boston University Head Impact Exposure Assessment to 108 patients (age 69.5 ± 8.0, 35% female, 93% white or unknown race) diagnosed at the UCSF Memory and Aging Center with one of the following FTD or related conditions: behavioral variant frontotemporal dementia (N=39), semantic variant primary progressive aphasia (N=16), nonfluent variant PPA (N=23), corticobasal syndrome (N=14), or progressive supranuclear palsy (N=16). Data were also obtained from 217 controls (“HC”; age 76.8 ± 8.0, 53% female, 91% white or unknown race). CSP characteristics were defined based on width or “grade” (0-1 vs. 2+) and length of anterior-posterior separation (millimeters). We first describe frequency of any and multiple (2+) prior TBI based on different but commonly used definitions: TBI with loss of consciousness (LOC), TBI with LOC or posttraumatic amnesia (LOC/PTA), TBI with LOC/PTA or other symptoms like dizziness, nausea, “seeing stars,” etc. (“concussion”). TBI/concussion frequency was then compared between FTD and HC using chi-square. Associations between TBI/concussion and CSP characteristics were analyzed with chi-square (CSP grade) and Mann-Whitney U tests (CSP length). We explored sex differences due to typically higher rates of TBI among males.Results:History of any TBI with LOC (FTD=20.0%, HC=19.2%), TBI with LOC/PTA (FTD:32.2%, HC=31.5%), and concussion (FTD: 50.0%, HC=44.3%) was common but not different between study groups (p’s>.4). In both FTD and HC, prior TBI/concussion was nominally more frequent in males but not significantly greater than females. Frequency of repeat TBI/concussion (2+) also did not differ significantly between FTD and HC (repeat TBI with LOC: 6.7% vs. 3.3%, TBI with LOC/PTA: 12.2% vs. 10.3%, concussion: 30.2% vs. 28.7%; p’s>.2). Prior TBI/concussion was not significantly related to CSP grade or length in the total sample or within the FTD or HC groups.Conclusions:TBI/concussion rates depend heavily on the symptom definition used for classifying prior injury. Lifetime symptomatic TBI/concussion is common but has an unclear impact on risk for FTD-related diagnoses. Larger samples are needed to appropriately evaluate sex differences, to evaluate whether TBI/concussion rates differ between specific FTD phenotypes, and to understand the rates and effects of more extensive repetitive head trauma (symptomatic and asymptomatic) in patients with FTD.

Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease.

Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. To evaluate psychopharmacological medication use at the time of FTD diagnosis. Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group. Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

The involvement of language-associated networks, tracts, and cortical regions in frontotemporal dementia and amyotrophic lateral sclerosis: Structural and functional alterations.

Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality-of-life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS-FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied. A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language-associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS-FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72-negative ALS-FTD, C9orf72-positive ALS-FTD, behavioral-variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke' areas and FC along the FAT was also specifically assessed. Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language-associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS-FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72-negative ALS-FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72-positive ALS-FTD patients do not. Language-associated tracts and networks are not only affected in language-variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype.

Facial expression recognition deficits in frontotemporal dementia and Alzheimer's disease: a meta-analytic investigation of effects of phenotypic variant, task modality, geographical region and symptomatic specificity.

Deficits in social cognition may be present in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Here, we conduct a qualitative synthesis and meta-analysis of facial expression recognition studies in which we compare the deficits between both disorders. Furthermore, we investigate the specificity of the deficit regarding phenotypic variant, domain-specificity, emotion category, task modality, and geographical region. The results reveal that both FTD and AD are associated with facial expression recognition deficits, that this deficit is more pronounced in FTD compared to AD and that this applies for the behavioral as well as for language FTD-variants, with no difference between the latter two. In both disorders, overall emotion recognition was most frequently impaired, followed by recognition of anger in FTD and by fear in AD. Verbal categorization was the most frequently used task, although matching or intensity rating tasks may be more specific. Studies from Oceania revealed larger deficits. On the other hand, non-emotional control tasks were more impacted by AD than by FTD. The present findings sharpen the social cognitive phenotype of FTD and AD, and support the use of social cognition assessment in late-life neuropsychiatric disorders.

Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease.

Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer's disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

The contribution of thalamic pathology to the clinical manifestations of frontotemporal dementia phenotypes (P5-12.004)

<h3>Objective:</h3> To systematically characterise thalamus pathology in frontotemporal dementia (FTD) phenotypes <h3>Background:</h3> FTD is classically associated with distinctive cortical atrophy patterns. However, the spectrum of cognitive and behavioural manifestations in FTD arise from multi-synaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit; the anterior cingulate circuit; and the orbitofrontal circuit. <h3>Design/Methods:</h3> Thalamus pathology was quantitatively evaluated at a nuclear, vertex and morphometric level in a prospective, multimodal imaging study using a standardised neuroimaging protocol. 10 patients with behavioural FTD (bvFTD), 15 patients with non-fluent variant primary progressive aphasia (nfvPPA) and 5 patients with semantic variant PPA (svPPA) were evaluated with reference to 100 healthy controls. All patients underwent detailed clinical and neuropsychological profiling and whole-genome sequencing. <h3>Results:</h3> Volumetric analyses revealed widespread bilateral thalamic nuclear volume loss in bvFTD; selective bilateral with left-sided predominant thalamic degeneration was captured in nfvPPA; and more focal, left-lateralised thalamic volume loss identified in svPPA. Vertex analyses showed diffuse thalamic surface changes in bvFTD and nfvPPA, but not svPPA. Morphometric analyses demonstrated extensive symmetric intra-thalamic changes in nfvPPA, and mostly right-sided changes in both bvFTD and svPPA. <h3>Conclusions:</h3> FTD is associated with considerable focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei associated with behaviour and language functions are preferentially involved. FTD is not solely associated with cortical atrophy. The manifestations of FTD are likely to stem from cortico-subcortical circuitry dysfunction and not exclusively driven by focal cortical changes. <b>Disclosure:</b> Dr. McKenna has nothing to disclose. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Teva. Dr. Bede has nothing to disclose.

Frontotemporal dementia: From the clinic to the differential diagnosis

Introduction: Frontotemporal dementia (FTD) is a disease that encompasses several syndromes that differ in their cognitive, behavioral, language signs, and motor phenomena. Only Alzheimer’s disease causes more early-onset dementia cases than FTD. According to World Health Organization (WHO) projections, dementia rates will double every 20 years and reach 115.4 million people in 2050, ranging from 3% to 26%. The FTD spectrum encompasses three variant syndromes, namely the behavioral variant, the semantic variant, and the non-fluent/agrammatical variant. Frontotemporal lobar degeneration is neuropathologically related to the clinical phenotypes of FTD. Therefore, the frontal and temporal lobes suffer from gliosis and selective neuronal loss due to this neurodegenerative condition. Case Report: A 62-year-old doctor with no comorbidities. According to the family, he reports delivering very slowly, which he doesn’t and comes in the processing very efficiently. He claims that he already lost on the street but managed to restore his visuospatial function. He denies changes in his daily life to recent trauma. Neurological examination revealed impaired attention and behavioral changes, impaired short-term memory (mini-mental: 19/30 points), normal laboratory, regular liquor; skull magnetic resonance imaging (MRI) showed mild atrophy in the frontotemporal regions. Decreased activity in areas of the cortex was observed by cerebral perfusion scintigraphy. Conclusion: Therefore, this report is relevant because it correlates a patient with neurological examination and tests with a good indication of FTD; however, the diagnosis can be confirmed with greater accuracy through brain perfusion scintigraphy. It is still possible to observe that although there has been a significant increase in the literature on FTD, its variants and its clinic still need further studies regarding their possible differential diagnoses, mainly related to psychiatric disorders and the behavioral variant of FTD.

Thalamic pathology in frontotemporal dementia: Predilection for specific nuclei, phenotype-specific signatures, clinical correlates, and practical relevance.

Frontotemporal dementia (FTD) phenotypes are classically associated with distinctive cortical atrophy patterns and regional hypometabolism. However, the spectrum of cognitive and behavioral manifestations in FTD arises from multisynaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit, the anterior cingulate circuit, and the orbitofrontal circuit. In this paper, we have reviewed evidence for thalamic pathology in FTD based on radiological and postmortem studies. Original research papers were systematically reviewed for preferential involvement of specific thalamic regions, for phenotype-associated thalamic disease burden patterns, characteristic longitudinal changes, and genotype-associated thalamic signatures. Moreover, evidence for presymptomatic thalamic pathology was also reviewed. Identified papers were systematically scrutinized for imaging methods, cohort sizes, clinical profiles, clinicoradiological associations, and main anatomical findings. The findings of individual research papers were amalgamated for consensus observations and their study designs further evaluated for stereotyped shortcomings. Based on the limitations of existing studies and conflicting reports in low-incidence FTD variants, we sought to outline future research directions and pressing research priorities. FTD is associated with focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei mediating behavioral and language functions are preferentially involved. Given the compelling evidence for considerable thalamic disease burden early in the course of most FTD subtypes, we also reflect on the practical relevance, diagnostic role, prognostic significance, and monitoring potential of thalamic metrics in FTD. Cardinal manifestations of FTD phenotypes are likely to stem from thalamocortical circuitry dysfunction and are not exclusively driven by focal cortical changes.

P.219 Novel clinical phenotype of early-onset amyotrophic lateral sclerosis and frontotemporal dementia with SNCB mutation

The continuum between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is well known spectrum of disease and genetic variability in this overlap has been previously reported. We report a novel clinical phenotype of early-onset ALS and FTD with a previously reported <i>SNCB</i> (β synuclein) mutation with Lewi body dementia. 45-year-old woman presented to our department complaining of progressive quadriparesis and dysphagia, which had started with right hemiparesis 4 months ago. She had a history of hypothyroidism but denied neurological family history. Neurologic examination revealed Hoffmann sign positive bilaterally and hyperreflexia of both knees. Nerve conduction study and electromyography showed low complex motor action potentials and widespread denervation in four limbs and thoracic paraspinal muscles without abnormal sensory nerve action potentials. CSF study was unremarkable. Diagnosis of probable ALS was established and riluzole 100mg daily was administered. Three months later, she reported a cognitive decline. In the neuropsychologic assessment battery, her language, memory, and frontal/executive function were below the first percentile for her age with relatively intact attention and visuospatial function. Brain MRI showed bilateral temporal atrophy, especially in the left anterior temporal area. SPECT revealed hypoperfusion in both frontal, temporal, and parietal cortices. Targeted next generation sequencing was conducted for ALS and FTD, and we found heterozygous c.208G>A mutation in <i>SNCB</i>. Despite tremendous research elucidating ALS-FTD, early onset case is rare. With this case, we report a new clinical phenotype of ALS-FTD with <i>SNCB</i> mutation, which has been only reported in few cases of Lewy body dementia and is being investigated recently. This case implies <i>SNCB,</i> which is assumed to contribute to neurodegeneration, can be a new candidate of ALS-FTD, especially in young age.

Blocking Site-Specific Cleavage of Human Tau Delays Progression of Disease-Related Phenotypes in Genetically Matched Tau-Transgenic Mice Modeling Frontotemporal Dementia.

Studies have recently demonstrated that a caspase-2-mediated cleavage of human tau (htau) at asparate-314 (D314) is responsible for cognitive deficits and neurodegeneration in mice modeling frontotemporal dementia (FTD). However, these animal studies may be confounded by flaws in their model systems, such as endogenous functional gene disruption and inequivalent transgene expression. To avoid these weaknesses, we examined the pathogenic role of this site-specific htau cleavage in FTD using genetically matched htau targeted-insertion mouse lines: rT2 and rT3. Both male and female mice were included in this study. rT2 mice contain a single copy of the FTD-linked htau proline-to-leucine mutation at amino acid 301 (htau P301L), inserted into a neutral site to avoid dysregulation of host gene expression. The similarly constructed rT3 mice harbor an additional D314-to-glutamate (D314E) mutation that blocks htau cleavage. We demonstrate that htau transgene expression occurs primarily in the forebrain at similar levels in rT2 and rT3 mice. Importantly, expression of the cleavage-resistant D314E mutant delays transgene-induced tau accumulation in the postsynaptic density, brain atrophy, hippocampal neurodegeneration, and spatial memory impairment, without altering age-related progression of pathologic tau conformation and phosphorylation. Our comprehensive investigation of age-dependent disease phenotypes associated with the htau P301L variant in precisely engineered FTD-modeling mice unveils a transiently protective effect of blocking htau cleavage at D314. Findings of this study advance our understanding of the contribution of this tau cleavage to the pathogenesis of FTD, and aid the development of effective dementia-targeting therapies.SIGNIFICANCE STATEMENT A site-specific and caspase-2-mediated cleavage of human tau plays a pathologic role in dementia. In this study, we investigate the contribution of this cleavage to the pathogenesis of frontotemporal dementia (FTD) using two genetically matched, tau-transgene targeted-insertion mouse lines that differ only by a cleavage-resistant mutation. The use of these mice avoids confounding effects associated with the random integration of tau transgenes to the mouse genome and allows us to comprehensively evaluate the impact of the tau cleavage on FTD phenotypes. Our data reveal that blocking this tau cleavage delays memory impairment and neurodegeneration of FTD-modeling mice. These findings improve our understanding of the pathogenic mechanisms underlying FTD and will facilitate the development of effective therapeutics.

Frontotemporal dementia: clinical features, diagnosis, and treatment

Frontotemporal dementia (FTD) is the second most common cause of neurodegenerative dementia affecting patients before 65. The classic clinical phenotypes of the disease include the behavioral variant of FTD and variants with a predominant speech disorder - primary progressive aphasia (agrammatic, semantic and logopenic variants). Often, classic FTD phenotypes can be associated with atypical parkinsonism such as corticobasal syndrome and progressive supranuclear palsy, and motor neuron disease. The disease is also heterogeneous from a pathophysiological point of view. It may be based on one of three pathological processes, while up to 40% of cases have a hereditary burden. Currently there have been described mutations in about 20 genes associated with FTD. Given the wide variety of clinical presentation, FTD may be a phenocopy of other diseases, which makes it difficult to diagnose, complicates the differential diagnosis and delays the correct diagnosis for several years. Poor awareness of the disease and its clinical features among clinicians is one of the reasons for the lack of data on the prevalence of the disease in the Russian Federation. In addition, the identification of families with genetic forms of the disease and asymptomatic carriers is an important step in the formation of a strategy for helping this category of patients when approaches to pathogenetic therapy appear. This review of the literature presents modern ideas about the clinical picture, features of diagnosis and differential diagnosis of various clinical variants of FTD. The current understanding of approaches to pharmacological and non-pharmacological therapy is also presented.

Focal thalamus pathology in frontotemporal dementia: Phenotype-associated thalamic profiles

BackgroundThe clinical phenotypes of frontotemporal dementia (FTD) are defined by distinctive clinical features and associated with unique cortical atrophy patterns. Clinical manifestations in FTD however are not solely driven by cortical pathology, but stem from the selective dysfunction of corticobasal circuits, the majority of which are relayed through thalamic nuclei. The objective of this study is the systematic radiological characterisation of thalamic pathology across the clinical spectrum of FTD to describe phenotype-associated thalamic signatures. Methods170 participants were included in a multimodal, prospective neuroimaging study to evaluate thalamic degeneration at a nuclear, vertex, and morphometric level using a uniform imaging protocol and a multimodal analysis approach. ResultsPatients with behavioural variant FTD (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA) and amyotrophic lateral sclerosis-FTD (ALS-FTD) exhibit distinctive thalamic disease-burden profiles with the preferential degeneration of specific thalamic nuclei. While vertex analyses reveal largely overlapping thalamic atrophy patterns, morphometric analyses successfully capture focal intra-thalamic degeneration. ConclusionsMirroring selective cortical vulnerability, focal rather than global thalamic atrophy characterises the clinical subtypes of FTD. Thalamic degeneration is a likely contributor to the heterogeneity of clinical manifestations observed in FTD. As thalamic imaging techniques capture different facets of pathological change and differ in their sensitivity to detect distinguishing features, future studies should implement a multimodal approach with complementary MRI techniques.