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The differentiation of semantic variant primary progressive aphasia from dementia and Alzheimer’s disease can be difficult, particularly when the semantic anomia is pronounced. This report describes a patient who presented with complaints of memory loss and proved to have prominent semantic loss of all types of nouns, common and proper, concrete and abstract, yet continued to live independently and maintain his activities of daily living. The evaluation was consistent for semantic variant primary progressive aphasia with degradation of semantic knowledge and focal anterior temporal atrophy and hypometabolism. This report summarizes the literature and discusses the differential diagnosis of this disorder from Alzheimer’s disease and related dementias.

This report describes a neurologist who, at age 55, developed an irrepressible urge to rhyme after a series of strokes and seizures. His strokes included a right posterior cerebellar infarction and a right thalamic lacune. His subsequent seizures were focal-onset with and without impaired awareness or secondary generalization, which emanated from the left frontotemporal region. On recovery and control of his seizures, he described the emergence of an irresistible urge to rhyme, even in thought and daily speech. His focus on rhyming first manifest as a new affinity for poetry and grew and mutated to a focus on rap music. By age 63 his interest in rap had led him to participate in freestyle rap at an inner-city center for rap improvisation and performance. The potential source for his acquired rhyming and rapping are discussed in terms of his unique insights as a neurologist and the current literature on the brain and rhyme. This patient’s rhyming and rapping may have been initially facilitated by epileptiform activation of word sound associations in the left frontotemporal language areas and possibly perpetuated interictally as a compensation for impaired cerebellar effects on timed anticipation.

High educational attainment may protect individuals, particularly middle-aged and older adults, against a wide range of health risks, including memory decline with age; however, this protection is less clear in patients with Alzheimer's disease (AD). In addition, this effect may differ across racial groups. According to the Marginalized-Related Diminished Return (MDR) theory, for example, the protective effect of high educational attainment on mental and physical health shows a weaker protective effect for racial minority groups, particularly Black people compared to White individuals.This longitudinal study used data of middle-aged and older adults with AD with two aims: first, to test the association between educational attainment and memory, and second, to explore racial differences in this association in the USA.Data came from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The total sample was 1673 American middle-aged and older adults. The independent variable was educational attainment measured as years of education. The main outcome was memory operationalized as Rey Auditory Verbal Learning Test (RAVLT) Verbal Forgetting percentage (VF%). Age, gender, and follow-up duration were covariates. Race was the effect modifier. Linear regression model was utilized to analyze the data.Of all participants, 68 (4.1%) were Black, and the remaining were White, with a mean age of 75 years old. In the pooled sample, educational attainment did not show a significant association with memory, independent of confounders. Educational attainment showed a significant interaction with race on memory, with higher educational attainment having a different effect on memory in White patients compared to Black patients.The effect of higher educational attainment on memory differs for Black patients with AD compared to White patients. To prevent cognitive disparities by race, we need to go beyond racial inequality in access to resources (e.g., education) and minimize diminished returns of educational attainment for racial minorities. To tackle health inequalities, social policies should not be limited to equalizing socioeconomic status but also help minority groups leverage their available resources, such as educational attainment, and secure tangible outcomes.

Background: D. Frank Benson and colleagues first described the clinical and neuropathological features of posterior cortical atrophy (PCA) from patients in the UCLA Neurobehavior Program. Objective: We reviewed the Program’s subsequent clinical experience with PCA, and its potential for clarifying this relatively rare syndrome in comparison to the accumulated literature on PCA. Methods: Using the original criteria derived from this clinic, 65 patients with neuroimaging-supported PCA were diagnosed between 1995 and 2020. Results: On presentation, most had visual localization complaints and related visuospatial symptoms, but nearly half had memory complaints followed by symptoms of depression. Neurobehavioral testing showed predominant difficulty with visuospatial constructions, Gerstmann’s syndrome, and Balint’s syndrome, but also impaired memory and naming. On retrospective application of the current Consensus Criteria for PCA, 59 (91%) met PCA criteria with a modification allowing for “significantly greater visuospatial over memory and naming deficits.” There were 37 deaths (56.9%) with the median overall survival of 10.3 years (95% CI: 9.6–13.6 years), consistent with a slow neurodegenerative disorder in most patients. Conclusion: Together, these findings recommend modifying the PCA criteria for “relatively spared” memory, language, and behavior to include secondary memory and naming difficulty and depression, with increased emphasis on the presence of Gerstmann’s and Balint’s syndromes.

Introduction Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders. Methods In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease. Results Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia. Discussion Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

Although Alzheimer’s disease (AD) is primarily a neurocognitive disorder, it also results in prominent neuropsychiatric symptoms (NPS). Much literature has investigated the NPS of apathy and depression in association with AD, but relatively less is known regarding anxiety, the third most common NPS in this disorder. The prevalence of anxiety symptoms in AD is about 40%, and it can be a prelude of AD. Anxiety can be especially present among patients with mild cognitive impairment, mild dementia, or early-onset forms of the disease, and can promote progression or conversion to Alzheimer’s clinical syndrome. A number of studies have established that anxiety is associated with positive amyloid scans, mesial temporal changes with atrophy and hypometabolism in the entorhinal region, and neurofibrillary tangles present on pathological examination of this region. In addition to psychosocial factors, proposed neurobiological mechanisms for increased anxiety in AD include decreased sensorimotor gating, relatively increased activation of amygdalae or the Salience Network, and the presence of comorbid pathology, particularly Lewy bodies. Having management strategies for anxiety in patients with AD is important as anxiety can worsen cognitive deficits. Interventions involve psychological support, behavioral management, and the judicious use of the psychiatric armamentarium of medications.

Cotard syndrome is a clinical condition defined by the presence of nihilistic delusions. We report two patients with Cotard syndrome in whom anti-NMDAR encephalitis (ANMDARE) was confirmed. Both cases showed features of affective psychosis, developed catatonic syndrome, and worsened after the use of antipsychotics. 18F-FDG PET brain studies showed a bilateral hemispheric pattern of hypometabolism in posterior regions, mainly in the cingulate cortex and in the medial aspects of parietal and occipital lobes. A more severe hypometabolism was observed in the right hemisphere of both patients. Both cases remitted with the use of specific immunotherapy for ANMDARE.

BackgroundMeasuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD).MethodsWe measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal (‘asymptomatic non-converters’) and those who became symptomatic (‘asymptomatic converters’) using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL).ResultsWe studied 394 participants (non-carriers=143,C9orf72=117,GRN=62,MAPT=72). InMAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. InC9orf72,higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=−0.16 (−0.22, −0.10), p2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007).ConclusionsSystemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Previous studies have documented manic and hypomanic symptoms in behavioral variant frontotemporal dementia (bvFTD), suggesting a relationship between bipolar disorder and bvFTD.The investigators conducted a literature review as well as a review of the psychiatric histories of 137 patients with bvFTD, and patients with a prior diagnosis of bipolar disorder were identified. The clinical characteristics of patients' bipolar disorder diagnosis, family history, features of bvFTD, and results from fluorodeoxyglucose positron emission tomography (FDG-PET), as well as autopsy findings, were evaluated.Among the 137 patients, 14 (10.2%) had a psychiatric diagnosis of bipolar disorder, eight of whom met criteria for bipolar disorder (type I, N=6; type II, N=2) 6-12 years preceding onset of classic symptoms of progressive bvFTD. Seven of the eight patients with bipolar disorder had a family history of mood disorders, four had bitemporal predominant hypometabolism on FDG-PET, and two had a tauopathy involving temporal lobes on autopsy. Three additional patients with late-onset bipolar I disorder proved to have a nonprogressive disorder mimicking bvFTD. The remaining three patients with bvFTD had prior psychiatric symptoms that did not meet criteria for a diagnosis of bipolar disorder. The literature review and the findings for one patient further suggested a shared genetic mutation in some patients.Manic or hypomanic episodes years before other symptoms of bvFTD may be a prodrome of this dementia, possibly indicating anterior temporal involvement in bvFTD. Other patients with late-onset bipolar disorder exhibit the nonprogressive frontotemporal dementia phenocopy syndrome. Finally, a few patients with bvFTD have a genetic predisposition for both disorders.

Behavioral variant frontotemporal dementia (bvFTD) is associated with social and criminal transgressions; studies from countries around the world have documented such behavior in persons with this condition. An overview and analysis of social and criminal transgressions in bvFTD and their potential neurobiological mechanisms can provide a window for understanding the relationship of antisocial behavior and the brain.This review evaluated the literature on the frequency of social and criminal transgressions in bvFTD and the neurobiological disturbances that underlie them.There is a high frequency of transgressions among patients with bvFTD due to impairments in neurocognition, such as social perception, behavioral regulation, and theory of mind, and impairments in social emotions, such as self-conscious emotions and empathy. Additionally, there is significant evidence for a specific impairment in an innate sense of morality. Alterations in these neurobiological processes result from predominantly right-hemisphere pathology in frontal (ventromedial, orbitofrontal, inferolateral frontal), anterior temporal (amygdala, temporal pole), limbic (anterior cingulate, amygdala), and insular regions.Overlapping disturbances in neurocognition, social emotions, and moral reasoning result from disease in the mostly mesial and right-sided frontotemporal network necessary for responding emotionally to others and for behavioral control. With increased sophistication in neurobiological interventions, future goals may be the routine evaluation of these processes among individuals with bvFTD who engage in social and criminal transgressions and the targeting of these neurobiological mechanisms with behavioral, pharmacological, and other interventions.

Background: The differentiation of behavioral variant frontotemporal dementia (bvFTD) from early-onset Alzheimer’s disease (EOAD) by clinical criteria can be inaccurate. The volumetric quantification of clinically available magnetic resonance (MR) brain scans may facilitate early diagnosis of these neurodegenerative dementias. Objective: To determine if volumetric quantification of brain MR imaging can identify persons with bvFTD from EOAD. Methods: 3D T1 MR brain scans of 20 persons with bvFTD and 45 with EOAD were compared using Neuroreader to measure subcortical, and lobar volumes, and Volbrain for hippocampal subfields. Analyses included: 1) discriminant analysis with leave one out cross-validation; 2) input of predicted probabilities from this process into a receiver operator characteristic (ROC) analysis; and 3) Automated linear regression to identify predictive regions. Results: Both groups were comparable in age and sex with no statistically significant differences in symptom duration. bvFTD had lower volume percentiles in frontal lobes, thalamus, and putamen. EOAD had lower parietal lobe volumes. ROC analyses showed 99.3% accuracy with Neuroreader percentiles and 80.2% with subfields. The parietal lobe was the most predictive percentile. Although there were differences in hippocampal (particularly left CA2-CA3) subfields, it did not add to the discriminant analysis. Conclusion: Percentiles from an MR based volumetric quantification can help differentiate between bvFTD from EOAD in routine clinical care. Use of hippocampal subfield volumes does not enhance the diagnostic separation of these two early-onset dementias.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Author(s): Casaletto, KB; Staffaroni, AM; Wolf, A; Appleby, B; Brushaber, D; Coppola, G; Dickerson, B; Domoto-Reilly, K; Elahi, FM; Fields, J; Fong, JC; Forsberg, L; Ghoshal, N; Graff-Radford, N; Grossman, M; Heuer, HW; Hsiung, G-Y; Huey, ED; Irwin, D; Kantarci, K; Kaufer, D; Kerwin, D; Knopman, D; Kornak, J; Kramer, JH; Litvan, I; Mackenzie, IR; Mendez, M; Miller, B; Rademakers, R; Ramos, EM; Rascovsky, K; Roberson, ED; Syrjanen, JA; Tartaglia, MC; Weintraub, S; Boeve, B; Boxer, AL; Rosen, H; Yaffe, K; ARTFL/LEFFTDS Study | Abstract: IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated g55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated gtwo-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

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.

Impaired empathy is a core feature of behavioral variant frontotemporal dementia (bvFTD). Patients with bvFTD are also prominently impaired in experiencing self-conscious emotions. The investigators explored whether impaired empathy in bvFTD, such as self-conscious emotions, may result from impaired self-consciousness in social situations (socioemotional self-perception).This pilot study evaluated 25 patients with bvFTD and compared them with 25 patients with Alzheimer's disease who had comparable dementia severity. Their caregivers completed the Social Dysfunction Scale (SDS), which quantifies empathy, and an extensive intake interview that included questions regarding self-consciousness and insight. The patients completed two measures of self-perception in social situations, the Schutte Self-Report Emotional Intelligence Test (SSEIT) scale and the Embarrassability Scale (EMB).Caregivers of patients with bvFTD, but not of patients with Alzheimer's disease, reported a high correlation between significantly decreased empathy (SDS) and decreased self-consciousness (intake interview questions). Consistent with lack of insight, the patients with bvFTD, unlike the patients with Alzheimer's disease, did not report decreases on the SSEIT and EMB measures.These preliminary findings suggest that impaired socioemotional self-perception plays a role in the loss of empathy among patients with bvFTD. A lack of self-consciousness in social situations may contribute to a loss of empathy resulting from an inability to co-represent another's emotion in relation to oneself.

Investigators report greater parietal tau deposition and alternate frontoparietal network involvement in early onset Alzheimer’s Disease (EOAD) with onset

Understanding how psychopathy compares with brain disease can help clarify its underlying mechanisms. This literature review is a broad overview of the neurobiology of psychopathic traits in comparison to behavioral variant frontotemporal dementia (bvFTD), a disorder uniquely associated with criminal behavior. In addition to violation of social norms, both psychopathy and bvFTD result in impaired socioemotional perception and empathy, impulsivity, and altered moral judgment. Despite wide areas of decreased function in psychopathy, structural changes are primarily evident in amygdala and, to a lesser extent, anterior insula, whereas in bvFTD neuropathology involves a wider paralimbic region. In psychopathy, relatively intact medial prefrontal and anterior cingulate cortices facilitate theory of mind and psychopathic traits such as deceitfulness and manipulation, bold fearlessness, and risk-taking behavior. In conclusion, many frontotemporal areas are hypoactive in psychopathy and bvFTD, but differences in dysfunctional connectivity in psychopathy vs. direct involvement in bvFTD potentially explain similarities and differences between these two conditions.

Background and ObjectivesFamilial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.MethodsWe screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy–Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.ResultsWe identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.DiscussionWe present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.Trial Registration InformationNCT02365922, NCT02372773, and NCT04363684.

Degenerative dementias such as Alzheimer's disease and frontotemporal dementia result in distinct alterations in emotional processing, emotional experiences, and mood. The neuropathology of these dementias extends to structures involved in emotional processing, including the basolateral limbic network (orbitofrontal cortex, anterior temporal lobe, amygdala, and thalamus), the insula, and ventromedial frontal lobe. Depression is the most common emotion and mood disorder affecting patients with Alzheimer's disease. The onset of depression can be a prodromal sign of this dementia. Anxiety can also be present early in the course of Alzheimer's disease and especially among patients with early-onset forms of the disease. In contrast, patients with behavioral variant frontotemporal dementia demonstrate hypoemotionality, deficits in the recognition of emotion, and decreased psychophysiological reactivity to emotional stimuli. They typically have a disproportionate impairment in emotional and cognitive empathy. One other unique feature of behavioral variant frontotemporal dementia is the frequent occurrence of bipolar disorder. The management strategies for these alterations of emotion and mood in degenerative dementias primarily involve the judicious use of the psychiatric armamentarium of medications.

Background Posterior cortical atrophy (PCA) is a neurocognitive disorder characterized by difficulty localizing in space. Recognizing PCA is important because it is usually missed early in its course and may result from a number of neurological disorders other than Alzheimer's disease (AD). Objective This study aimed to clarify whether impaired visual search tasks of spatial localization distinguished patients with PCA from those with other more typical dementias as well as from healthy control (HC) subjects. Methods Twelve patients meeting neuroimaging-supported Consensus Criteria for PCA, 12 comparably advanced patients with amnestic-predominant typical AD (tAD), and 24 HC participants were compared on tests of untimed and timed visual search, spatial neglect, mental rotation, environmental orientation, visuospatial construction, and face recognition. Results Only abnormalities in untimed and timed visual search and environmental orientation distinguished the PCA patients from both the tAD group and the HC group without also distinguishing the tAD patients from HC's. The PCA patients also had a tendency to greater difficulty scanning left hemispace compared to HC's. Visuospatial constructions, although worse in PCA, and face recognition were impaired in both dementia groups. Conclusions These findings support the concept of PCA as a disorder of spatial processing and localization, indicating that visual search tasks are particularly sensitive and specific for detecting PCA and distinguishing it from more typical dementia syndromes.

Posterior cortical atrophy (PCA) is a progressive neurologic syndrome that presents with complex visual deficits. Although PCA is most commonly a form of Alzheimer disease (AD), its early diagnosis is usually delayed due to a lack of understanding for how best to clinically screen for the syndrome.To identify neurobehavioral screening tasks for PCA-beyond simple visual constructions-that can be administered in clinic or at bedside.We compared the performance of 12 individuals who met neuroimaging-supported consensus criteria for PCA with that of 12 matched individuals with typical AD (tAD) and 24 healthy controls (HC) on clinic/bedside tasks measuring (a) complex figure copying, (b) Balint syndrome, (c) visual object agnosia, (d) color identification, (e) figure-ground discrimination, (f) global-local processing, (g) dressing apraxia, (h) ideomotor apraxia, and (i) Gerstmann syndrome.All of the individuals with PCA were impaired on the figure-ground discrimination task compared with half of the tAD group and no HC. Approximately half of the PCA group had Balint syndrome, dressing apraxia, and ideomotor apraxia compared with none in the tAD group. Difficulty copying a complex figure, global-local processing impairment, and Gerstmann syndrome did not distinguish between the two dementia groups.The figure-ground discrimination task can be used successfully as an overall screening measure for PCA, followed by specific tasks for Balint syndrome and dressing and limb apraxia. Findings reinforce PCA as a predominant occipitoparietal disorder with dorsal visual stream involvement and parietal signs with spatiomotor impairments.

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer’s disease, while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3,058 patients clinically diagnosed with Alzheimer’s disease, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5,089 control subjects. RESULTS: We observed a significant association between the R47H variant and Alzheimer’s disease, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with Alzheimer’s disease. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

Since the nineteenth century, clinicians and investigators have systematically evaluated the origin of delusions and psychotic thinking. One major clue to understanding the neurobiological underpinnings of delusions is the emergence of false narratives from brain disease. In addition to delusions themselves, there are a range of other false narratives not due to deliberate lying and resulting from neurological disorders, including provoked confabulations, fantastic confabulations, false memories, magical thinking, dream delusions, and “fantastic thinking”. A comparison of their characteristics, similarities, and differences suggest a hypothesis: despite different sources for their false narrative experiences, such as unusual thoughts or perceptions, all false narratives from brain disease involve erroneous or mismatched “affective biases” applied to the experiences. Affective labels usually signal the sense of rightness, sense of familiarity, and the external vs. internal origin of an experience, and they can be altered by limbic neuropathology. The location and involvement of neuropathology that facilitates false narratives involves frontolimbic regions and their connections, particularly on the right. Future investigations can focus on frontolimbic mechanisms involved in the provision of the intrinsically-linked affective biases, which indicate the nature and external/internal origin of experiences.

BACKGROUND The neuropsychological recognition of early-onset Alzheimer's disease (AD) can be difficult because of non-amnestic variants such as logopenic variant primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA). OBJECTIVE This study evaluated the similarities and differences between typical amnestic AD (tAD) and lvPPA and PCA on a screening neuropsychological battery. METHODS We enrolled 51 patients meeting NIA-AA criteria for biomarker-supported AD (amnestic or non-amnestic) and having an age of onset of

Background Repetitive traumatic brain injury (TBI) is associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by Alzheimer-like changes in the brain. CTE has been defined through neuropathological findings among deceased athletes and others exposed to repetitive TBI, but to date there are no definitive clinical criteria for CTE. Objective To evaluate the utility of currently proposed clinical criteria for CTE and suggest improvements. Methods We describe two well-characterized patients referred for evaluation of CTE and apply the four major proposed criteria for CTE. These criteria were further assessed in a cohort of patients referred to a neurobehavior clinic with or without a history of TBI. Results Without a CTE biomarker, the current criteria were of limited utility when applied to the two patient and the Neurobehavior cohort. Six items were extracted as potentially improving the clinical diagnosis of CTE: length of exposure to head impacts, a progressive course, specific psychiatric symptoms, frontal-executive dysfunction, parkinsonism and tremors, and targeted findings on neuroimaging. Conclusions The prevention and neurorehabilitation of CTE depends on clinical diagnosis, but, without a biomarker, the clinical diagnosis of CTE remains difficult. This report suggests that clinical criteria for CTE may be greatly improved with emphasis on several critical historical and clinical correlates of CTE.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Alexithymia is pervasive among psychiatric patients, but its neurobiological mechanism is unclear. Patients with alexithymia cannot "read emotions," a process involving interoception, or the perception of the body's internal state, primarily in the insulae. The frontotemporal dementias are also associated with inability to correctly read emotions; hence, these dementias can provide a window into the mechanism of alexithymia. Patients with behavioral variant frontotemporal dementia (bvFTD) have a weak emotional signal with impaired emotional recognition, hypoemotionality, and decreased physiological arousal. bvFTD affects the insulae, and the weak emotional signal facilitates impaired interoceptive accuracy, resulting in an overreliance on cognitive appraisal rather than on internal sensations. In contrast, patients with semantic dementia, another frontotemporal dementia syndrome, can have intact interoception, but they have disturbed cognitive appraisal of the meaning of their bodily sensations. This "alexisomia" in semantic dementia can lead to misinterpreted somatic symptoms. Together, the findings in alexithymic patients and frontotemporal dementia syndromes support the model of impaired interoceptive accuracy as the mechanism of alexithymia, possibly from dysfunction in the insulae.