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Objective: Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative condition characterized by progressive changes in behavior, cognition, and day-to-day functioning. Progression of the disease usually leads to death 3–5 years after diagnosis. However, there are reports of individuals who are initially diagnosed with bvFTD but fail to progress. These individuals are thought to have what is becoming known as phenocopy bvFTD (phFTD). Methods: This manuscript reviews a single case study of a 68-year-old male Veteran who was diagnosed with bvFTD in 2010, which has not progressed over time. Results: Review of serial neuropsychological evaluations was broadly normal with mild evidence of executive dysfunction with minimal reliable change in his performances from 2015, 2017, and 2022 evaluations. He also has not developed neuroimaging evidence of FTD. Conclusions: This case illustrates the importance of monitoring individuals over time and incorporating neuroimaging data into the diagnosis. We believe this Veteran's presentation is most consistent with what has been described as phFTD. [ABSTRACT FROM AUTHOR]

A 23-year-old man presented with behavioral disinhibition, stereotypies, motor apathy, flattened affect, and inappropriate laughter. CT demonstrated generalized cerebral atrophy. He was admitted with a diagnosis of unspecified psychosis and discharged on antipsychotic medication. He was readmitted 3 months later, was diagnosed with schizophrenia, and antipsychotic medication was continued. Owing to symptom progression and aggressive behavior, he was readmitted 2 months later. CT again demonstrated moderate central and cortical cerebral atrophy. MRI showed severe, stable atrophy with frontotemporal predominance, and he was diagnosed with probable behavioral variant frontotemporal dementia (bvFTD).  Over the next year he rapidly deteriorated, with loss of cognitive abilities. Genetic testing revealed several variants, none of which are clearly disease-causing.

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.

Background: Patients with a frontotemporal lobar degeneration (FTLD) usually manifest with behavioral variant frontotemporal dementia (bvFTD). Alzheimer's disease (AD) may also manifest with a predominant behavioral-dysexecutive syndrome, similar to bvFTD. Cerebrospinal fluid (CSF) biomarkers, such as total tau (τT), phosphorylated tau (τP-181) and amyloid beta with 42 amino-acids (Aβ42), can predict AD pathology in vivo. The aim of this study was to compare the τT/Aβ42 and τP-181/Aβ42 ratios, the BIOMARKAPD/ABSI criteria and the AT(N) classification system in a cohort of bvFTD patients. Methods: A total of 105 bvFTD patients (21 possible bvFTD; 20%) with CSF data, examined from 2008 to 2022, were included. Seventy-eight AD patients and 62 control subjects were included. The CSF biomarkers were measured with Innotest (2008–2017 subcohort) and EUROIMMUN (2017–2022 subcohort) ELISAs. Results: Depending on the classification system, 7.6 to 28.6% of bvFTD had an AD biochemical profile. The τT/Aβ42 and τP-181/Aβ42 ratios classified more patients as AD compared to the BIOMARKAPD/ABSI and AT(N) systems. The patients with possible bvFTD had higher frequencies of AD compared to the probable bvFTD patients. Conclusions: The four classification criteria of CSF AD biomarkers resulted in differences in AD allocation in this bvFTD cohort. A consensus on the optimal classification criteria of CSF AD biomarkers is pivotal. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has multiple clinically and pathologically defined subtypes where the underlying causes of such heterogeneity are not well established. Rare TREM2 variants confer significantly increased risk for clinical AD in addition to other neurodegenerative disease clinical phenotypes. Whether TREM2 variants are associated with atypical clinical or pathologically defined subtypes of AD is not known. We studied here the clinical and pathological features associated with TREM2 risk variants in an autopsy-confirmed cohort. TREM2 variant cases were more frequently associated with non-amnestic clinical syndromes. Pathologically, TREM2 variant cases were associated with an atypical distribution of neurofibrillary tangle density with significantly lower hippocampal NFT burden relative to neocortical NFT accumulation. In addition, NFT density but not amyloid burden was associated with an increase of dystrophic microglia. TREM2 variant cases were not associated with an increased prevalence, extent, or severity of co-pathologies. These clinicopathological features suggest that TREM2 variants contribute to clinical and pathologic AD heterogeneity by altering the distribution of neurofibrillary degeneration and tau-dependent microglial dystrophy, resulting in hippocampal-sparing and non-amnestic AD phenotypes. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer’s disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

Background: Patients with a frontotemporal lobar degeneration (FTLD) usually manifest with behavioral variant frontotemporal dementia (bvFTD). Alzheimer’s disease (AD) may also manifest with a predominant behavioral-dysexecutive syndrome, similar to bvFTD. Cerebrospinal fluid (CSF) biomarkers, such as total tau (τT), phosphorylated tau (τP-181) and amyloid beta with 42 amino-acids (Aβ42), can predict AD pathology in vivo. The aim of this study was to compare the τT/Aβ42 and τP-181/Aβ42 ratios, the BIOMARKAPD/ABSI criteria and the AT(N) classification system in a cohort of bvFTD patients. Methods: A total of 105 bvFTD patients (21 possible bvFTD; 20%) with CSF data, examined from 2008 to 2022, were included. Seventy-eight AD patients and 62 control subjects were included. The CSF biomarkers were measured with Innotest (2008–2017 subcohort) and EUROIMMUN (2017–2022 subcohort) ELISAs. Results: Depending on the classification system, 7.6 to 28.6% of bvFTD had an AD biochemical profile. The τT/Aβ42 and τP-181/Aβ42 ratios classified more patients as AD compared to the BIOMARKAPD/ABSI and AT(N) systems. The patients with possible bvFTD had higher frequencies of AD compared to the probable bvFTD patients. Conclusions: The four classification criteria of CSF AD biomarkers resulted in differences in AD allocation in this bvFTD cohort. A consensus on the optimal classification criteria of CSF AD biomarkers is pivotal.

Introduction: There is a shortage of validated instruments to estimate disease progression in frontotemporal dementia (FTD). Objectives: To evaluate the ability of the FTD Rating Scale (FTD-FRS) to detect functional and behavioral changes in patients diagnosed with the behavioral variant of FTD (bvFTD), primary progressive aphasia (PPA), and Alzheimer disease (AD) after 12 months of the initial evaluation, compared to the Clinical Dementia Rating scale−frontotemporal lobar degeneration (CDR-FTLD) and the original Clinical Dementia Rating scale (CDR). Methods: The sample consisted of 70 individuals, aged 40+ years, with at least 2 years of schooling, 31 with the diagnosis of bvFTD, 12 with PPA (8 with semantic variant and 4 with non-fluent variant), and 27 with AD. The FTD-FRS, the CDR, and the 2 additional CDR-FTLD items were completed by a clinician, based on the information provided by the caregiver with frequent contact with the patient. The Addenbrooke Cognitive Examination-Revised was completed by patients. After 12 months, the same protocol was applied. Results: The FTD-FRS, CDR-FTLD, and CDR detected significant decline after 12 months in the 3 clinical groups (exception: FTD-FRS for PPA). The CDR was less sensitive to severe disease stages. Conclusions: The FTD-FRS and the CDR-FTLD are especially useful tools for dementia staging in AD and in the FTD spectrum. [ABSTRACT FROM AUTHOR]

The differential diagnosis among the behavioral variant of frontotemporal dementia FTD (bvFTD) and the linguist one primary progressive aphasia (PPA) is challenging. Presentations of dementia type or variants dominated by personality change or aphasia are frequently misinterpreted as psychiatric illness, stroke, or other conditions. Therefore, it is important to identify cognitive tests that can distinguish the distinct FTD variants to reduce misdiagnosis and best tailor interventions. We aim to examine the discriminative capacity of the most frequently used cognitive tests in their Spanish version for the context of dementia evaluation as well as the qualitative aspects of the neuropsychological performance such as the frequency and type of errors, perseverations, and false positives that can best discriminate between bvFTD and PPA. We also described mood and behavioral profiles of participants with mild to moderate probable bvFTD and PPA. A total of 55 subjects were included in this cross-sectional study: 20 with PPA and 35 with bvFTD. All participants underwent standard dementia screening that included a medical history and physical examination, brain MRI, a semistructured caregiver interview, and neuropsychological testing. We found that bvFTD patients had worse performance in executive function tests, and the PPA presented with the lower performance in language tests and the global score of Mini-Mental State Examination (MMSE). After running the linear discriminant model, we found three functions of cognitive test and subtests combination and three functions made by the Montreal Cognitive Assessment (MoCA) language subtest and performance errors that predicted group belonging. Those functions were more capable to classify bvFTD cases rather than PPA. In conclusion, our study supports that the combination of an individual test of executive function and language, MoCA's subtest, and performance errors as well have good accuracy to discriminate between bvFTD and PPA.

The differential diagnosis among the behavioral variant of frontotemporal dementia FTD (bvFTD) and the linguist one primary progressive aphasia (PPA) is challenging. Presentations of dementia type or variants dominated by personality change or aphasia are frequently misinterpreted as psychiatric illness, stroke, or other conditions. Therefore, it is important to identify cognitive tests that can distinguish the distinct FTD variants to reduce misdiagnosis and best tailor interventions. We aim to examine the discriminative capacity of the most frequently used cognitive tests in their Spanish version for the context of dementia evaluation as well as the qualitative aspects of the neuropsychological performance such as the frequency and type of errors, perseverations, and false positives that can best discriminate between bvFTD and PPA. We also described mood and behavioral profiles of participants with mild to moderate probable bvFTD and PPA. A total of 55 subjects were included in this cross-sectional study: 20 with PPA and 35 with bvFTD. All participants underwent standard dementia screening that included a medical history and physical examination, brain MRI, a semistructured caregiver interview, and neuropsychological testing. We found that bvFTD patients had worse performance in executive function tests, and the PPA presented with the lower performance in language tests and the global score of Mini-Mental State Examination (MMSE). After running the linear discriminant model, we found three functions of cognitive test and subtests combination and three functions made by the Montreal Cognitive Assessment (MoCA) language subtest and performance errors that predicted group belonging. Those functions were more capable to classify bvFTD cases rather than PPA. In conclusion, our study supports that the combination of an individual test of executive function and language, MoCA's subtest, and performance errors as well have good accuracy to discriminate between bvFTD and PPA. [ABSTRACT FROM AUTHOR]

Abstract Introduction Frontotemporal dementia (FTD) is a neurodegenerative disorder for which there is no effective pharmacological treatment. Recently, interneuron activity responsible for fast oscillatory brain activity has been found to be impaired in a mouse model of FTD with consequent cognitive and behavioral alterations. In this study, we aim to investigate the safety, tolerability, and efficacy of a novel promising therapeutic intervention for FTD based on 40 Hz transcranial alternating current stimulation (tACS), a form of non‐invasive brain stimulation thought to engage neural activity in a frequency‐specific manner and thus suited to restore altered brain oscillatory patterns. Methods This is a multi‐site, randomized, double‐blind, placebo‐controlled trial on 50 patients with a diagnosis of behavioral variant FTD (bvFTD). Participants will be randomized to undergo either 30 days of 1‐hour daily tACS or Sham (placebo) tACS. The outcomes will be assessed at baseline, right after the intervention and at a 3‐ to 6‐months follow‐up. The primary outcome measures are represented by the safety and feasibility of tACS administration, which will be assessed considering the nature, frequency, and severity of adverse events as well as attrition rate, respectively. To assess secondary outcomes, participants will undergo extensive neuropsychological and behavioral assessments and fluorodeoxyglucose (FDG)–positron emission tomography (PET) scans to evaluate changes in brain metabolism, functional and structural magnetic resonance imaging (MRI), resting and evoked electroencephalography, as well as blood biomarkers to measure changes in neurodegenerative and neuroinflammatory markers. Results The trial started in October 2020 and will end in October 2023. Study protocols have been approved by the local institutional review board (IRB) at each data‐collection site. Discussion This study will evaluate the safety and tolerability of 40 Hz tACS in bvFTD patients and its efficacy on gamma oscillatory activity, cognitive function, and brain glucose hypometabolism.

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]

Introduction: Frontotemporal dementia (FTD) is a neurodegenerative disorder for which there is no effective pharmacological treatment. Recently, interneuron activity responsible for fast oscillatory brain activity has been found to be impaired in a mouse model of FTD with consequent cognitive and behavioral alterations. In this study, we aim to investigate the safety, tolerability, and efficacy of a novel promising therapeutic intervention for FTD based on 40 Hz transcranial alternating current stimulation (tACS), a form of non‐invasive brain stimulation thought to engage neural activity in a frequency‐specific manner and thus suited to restore altered brain oscillatory patterns. Methods: This is a multi‐site, randomized, double‐blind, placebo‐controlled trial on 50 patients with a diagnosis of behavioral variant FTD (bvFTD). Participants will be randomized to undergo either 30 days of 1‐hour daily tACS or Sham (placebo) tACS. The outcomes will be assessed at baseline, right after the intervention and at a 3‐ to 6‐months follow‐up. The primary outcome measures are represented by the safety and feasibility of tACS administration, which will be assessed considering the nature, frequency, and severity of adverse events as well as attrition rate, respectively. To assess secondary outcomes, participants will undergo extensive neuropsychological and behavioral assessments and fluorodeoxyglucose (FDG)–positron emission tomography (PET) scans to evaluate changes in brain metabolism, functional and structural magnetic resonance imaging (MRI), resting and evoked electroencephalography, as well as blood biomarkers to measure changes in neurodegenerative and neuroinflammatory markers. Results: The trial started in October 2020 and will end in October 2023. Study protocols have been approved by the local institutional review board (IRB) at each data‐collection site. Discussion: This study will evaluate the safety and tolerability of 40 Hz tACS in bvFTD patients and its efficacy on gamma oscillatory activity, cognitive function, and brain glucose hypometabolism. [ABSTRACT FROM AUTHOR]

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]

Frontotemporal dementia is a neurodegenerative disease characterized by atrophy of the frontal and temporal lobes of the brain, and it is believed to primarily develop based on genetic factors. Its initial symptoms can appear relatively early, even between the ages of 40-50, affecting approximately 15-22 individuals out of 100,000 annually. The disease manifests in various forms, categorized into behavioral, aphasic, and motor variants due to its diverse presentations. The behavioral variant, constituting about half of the cases, is the most common type. It involves personality changes, behavioral problems, and cognitive decline, with patients surviving an average of 8.5 years from the onset of symptoms. Currently, there is no curative therapy available, and only symptomatic treatment can be administered to improve the quality of life. In the case we presented, the symptoms of the behavioral variant of frontotemporal dementia appeared atypically, accompanied by perceptual disturbances and a paranoid attitude, further complicating the definitive diagnosis.

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is a common cause of early-onset dementia characterized by behavioral and personality changes, as well as, altered eating habits. FTD is associated with complex changes in neural networks of gustatory processing which may be responsible for eating abnormalities. Here, we present a 66-years-old lady suffered from behavioral variant of FTD with an interesting symptom of food aversion, typically sour foods. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) is responsible for as many as every fifth case of early-onset dementia. Very few epidemiological studies of FTLD have been conducted; there are no published epidemiological data of FTLD from Finland or the other Nordic countries. The C9ORF72 expansion-associated FTLD is common in Finland; thus, the prevalence of FTLD is expected to be high in this population. Methods: We retrospectively evaluated the incidence and prevalence of FTLD in university hospital settings in Northern Finland. Results: The mean 1-year incidence of FTLD was 5.54/100,000 (range 1.9-11.3/100,000) in the population aged 45-65 years. The prevalence of FTLD in the same age group was 20.5/100,000. Conclusion: The incidence and prevalence of FTLD in Finland seem to be the highest in Europe. However, studies from different countries may not be directly mutually comparable due to methodological issues.

Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer's disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-β (Aβ)42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with definite and/or probable frontotemporal lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP. [ABSTRACT FROM AUTHOR]

Behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome characterized mainly by behavioral symptoms due to frontal dysfunction. Major neurodegenerative bases of bvFTD include Pick's disease, frontotemporal lobar degeneration with trans-activation response DNA protein 43-positive inclusions, corticobasal degeneration, and progressive supranuclear palsy. Early disinhibition characterized by socially inappropriate behaviors, loss of manners, and impulsive, rash and careless actions is the most important clinical feature of bvFTD. On the other hand, it was reported that clinical presentations of some Alzheimer's disease cases and patients with psychiatric disorders (e.g., addictive disorders, gambling disorder and kleptomania) often resemble that of bvFTD. Although clinical differentiation of 'true' bvFTD cases with frontotemporal lobar degeneration (FTLD) pathology from mimicking cases without it is not always easy, evaluation of the following features, which were noted in autopsy-confirmed FTLD cases and/or clinical bvFTD cases with circumscribed lobar atrophy, may often provide clues for the diagnosis. (i) The initial symptoms frequently develop at 65 years or younger, and (ii) 'socially inappropriate behaviors' can be frequently interpreted as contextually inappropriate behaviors prompted by environmental visual and auditory stimuli. Taking a detailed history usually reveals various kinds of such behaviors in various situations in everyday life rather than the repetition of a single kind of behavior (e.g., repeated shoplifting). (iii) A correlation between the distribution of cerebral atrophy and neurological and behavioral symptoms is usually observed, and the proportion of FTLD cases with right side-predominant cerebral atrophy may be higher in a psychiatric setting than a neurological setting. Finally, (iv) whether the previous course and the combination of symptoms observed at the first medical visit can be explained by major evolution patterns of clinical syndromes in pathologically confirmed FTLD cases should be considered. These views may provide clues to differentiate FTLD from Alzheimer's disease and to predict a subsequent clinical course and therapeutic interventions needed in the future. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) was one of the lesser known dementias until the recent advancements revealing its genetic and pathological foundation. This common neurodegenerative disorder has three clinical subtypes- behavioral, semantic and progressive non fluent aphasia. The behavioral variant mostly exhibits personality changes, while the other two encompass various language deficits. This review discusses the basic pathology, genetics, clinical and histological presentation and the diagnosis of the 3 subtypes. It also deliberates the different therapeutic modalities currently available for frontotemporal dementia and the challenges faced by the caregivers. Lastly it explores the scope of further research into the diagnosis and management of FTD. [ABSTRACT FROM AUTHOR]

Background: White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Objective: Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting. Methods: We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants. Results: Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group. Conclusions: The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group. [ABSTRACT FROM AUTHOR]

While recent advances in the development of neuroimaging and molecular biomarkers for studying neurodegenerative conditions have revolutionized the field, dementia remains a clinical diagnosis. No component of the diagnostic process is more crucial than obtaining a good history. Getting to know the first manifestations of the disease, tracking their evolution and functional impact, combined with a targeted neurological examination, further guides differential diagnosis. This paper summarizes the key symptoms of the behavioral and language variants of frontotemporal dementia. The behavioral variant of frontotemporal dementia (bvFTD) is characterized by severe changes in behavior and personality such as disinhibition, apathy, loss of empathy, or stereotypic behavior, leading to a loss of social competence. Executive functions are impaired, while memory and visuospatial skills are relatively better preserved. By contrast, the language variants or primary progressive aphasias (PPAs) are marked by prominent language disturbances that can be subclassified into a non-fluent/agrammatic variant (naPPA), a semantic variant (svPPA), and a logopenic variant (lvPPA). Although combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis of such heterogeneous conditions, the author emphasizes the importance of accurate recognition of key symptoms that can lead to better identification of underlying neuropathology and appropriate treatment approaches. [ABSTRACT FROM AUTHOR]

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings., Competing Interests: None

Pathology underlying behavioral variant frontotemporal dementia (bvFTD) is heterogeneous, with the most common pathologies being Pick's disease (PiD), corticobasal degeneration (CBD), and FTLD-TDP type 1. Clinical features are unhelpful in differentiating these pathologies. We aimed to determine whether imaging atrophy patterns differ across these pathologies in bvFTD subjects. We identified 15 bvFTD subjects that had volumetric MRI during life and autopsy: five with PiD, five CBD, and five FTLD-TDP type 1. Voxel-based morphometry was used to assess atrophy patterns in each bvFTD group compared to 20 age- and gender-matched controls. All three pathological groups showed gray matter loss in frontal lobes, although specific patterns of atrophy differed across groups: PiD showed widespread loss in frontal lobes with additional involvement of anterior temporal lobes; CBD showed subtle patterns of loss involving posterior lateral and medial superior frontal lobe; and FTLD-TDP type 1 showed widespread loss in frontal, temporal, and parietal lobes. Greater parietal loss was observed in FTLD-TDP type 1 compared to both other groups, and greater anterior temporal and medial frontal loss was observed in PiD compared to CBD. Imaging patterns of atrophy in bvFTD vary according to pathological diagnosis and may therefore be helpful in predicting these pathologies in bvFTD. [ABSTRACT FROM AUTHOR]

We report the first case of dental flossing behavior by a Japanese macaque. We used cross-sectional data to assess the presence of this novel tool-use behavior at the group-level. Although this behavior was performed frequently by a central middle-ranking middle-aged female during her grooming interactions, and appeared at least four years ago, it remained idiosyncratic to its innovator, and until now has not spread to other group members. We examined the factors that may have favored this innovation, including the environmental context, the individual characteristics of the innovator, and the structural and functional aspects of the behavior. Group size, kinship, and dominance are socio-demographic factors that are likely to limit the opportunities for any group member to observe the innovator, and thus constrain the diffusion of this potential candidate as a new behavioral tradition. This is one of the rare studies to document the spontaneous appearance of tool-use behavior in primates under natural conditions. Identifying the determinants of innovations and the constraints on their diffusion within social groups of non-human primates is of special interest to understanding cultural evolution. [ABSTRACT FROM AUTHOR]

Introduction: Frontotemporal dementia (FTD) is a neurodegenerative disorder for which there is no effective pharmacological treatment. Recently, interneuron activity responsible for fast oscillatory brain activity has been found to be impaired in a mouse model of FTD with consequent cognitive and behavioral alterations. In this study, we aim to investigate the safety, tolerability, and efficacy of a novel promising therapeutic intervention for FTD based on 40 Hz transcranial alternating current stimulation (tACS), a form of non-invasive brain stimulation thought to engage neural activity in a frequency-specific manner and thus suited to restore altered brain oscillatory patterns., Methods: This is a multi-site, randomized, double-blind, placebo-controlled trial on 50 patients with a diagnosis of behavioral variant FTD (bvFTD). Participants will be randomized to undergo either 30 days of 1-hour daily tACS or Sham (placebo) tACS. The outcomes will be assessed at baseline, right after the intervention and at a 3- to 6-months follow-up. The primary outcome measures are represented by the safety and feasibility of tACS administration, which will be assessed considering the nature, frequency, and severity of adverse events as well as attrition rate, respectively. To assess secondary outcomes, participants will undergo extensive neuropsychological and behavioral assessments and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans to evaluate changes in brain metabolism, functional and structural magnetic resonance imaging (MRI), resting and evoked electroencephalography, as well as blood biomarkers to measure changes in neurodegenerative and neuroinflammatory markers., Results: The trial started in October 2020 and will end in October 2023. Study protocols have been approved by the local institutional review board (IRB) at each data-collection site., Discussion: This study will evaluate the safety and tolerability of 40 Hz tACS in bvFTD patients and its efficacy on gamma oscillatory activity, cognitive function, and brain glucose hypometabolism., Competing Interests: E. Santarnecchi reports that this grant is supported by the Alzheimer's Drug Discovery Foundation (ADDF), the Association for Frontotemporal Dementia (AFTD), and Treat FTD Fund via GA – 201902 – 2017902 (payment to the hospitals); he is supported by the Defense Advanced Research Projects Agency (DARPA) via HR001117S0030, the NIH (P01 AG031720‐06A1, R01 MH117063‐01, R01 AG060981‐01; all payments to the hospital); he received honoraria for an invited meeting/talks with payment to him. D. Press is supported by NIH grants R01 MH117063, R01 AG060987‐01, R01AG060981, 1R01 MH111875‐01; ‐; he is also supported by Industry Sponsored Clinical Trials Aggregated Effort 1.8 CM 221AD301 Biogen ENGAGE and EMBARK Title: A Phase 3 Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study to evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects with Early Alzheimer's Disease. This study is restarting as an open‐label study (EMBARK) and he is the site PI; he is also PI for the JNJ‐63733657 Jansen Phase II trial Title: A Randomized, Double‐blind, Placebo‐controlled, Parallel‐group, Multicenter Study to Assess the Efficacy and Safety of JNJ‐63733657, an Anti‐Tau Monoclonal Antibody, in Participants with Prodromal Alzheimer's disease; he is on a DSMB for research in noninvasive brain stimulation with Timothy Wagner and Felipe Fregni at MGH. B. Dickerson received a grant from NIH and consulting fees from Acadia, Alector, Arkuda, Biogen, Denali, Lilly, Merck, Novartis, Takeda, and Wave Lifesciences. A. Connor received a payment contract from Harvard Medical School with payments made to her institution. B. Wong received payment from NIH grants with payment made to her institution. C. Shen received an NIH grant with payment made to his institution and consulting fees from Indiana University and Cardiovascular System, Inc. G. Ruffini has received grants from the EU (ERC Galvani and FET Proactive Neurotwin), with payments to his institution; his company is the source of support (paying for traveling and lodging). He has a pending patent on brain stimulation in AD and in brain cancer; he holds stock in his company, Neuroelectrics; his company is the source of support (paying for traveling and lodging; he works and he is shareholder of Neuroelectrics, a company in the brain stimulation/neuromodulation business. G. El Fakhri received NIH grants to MGH and he has an unrelated patent for PET imaging of membrane potential. G. Koch received grants from ADDF and he has a patent for rotigotine in AD. M. Assogna, G. Sprugnoli, J. Macone, S. Bonnì, I. Borghi, M. Hoffman, N. Grover, A. Martorana, and M. O'Reilly have nothing to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)