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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.

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.

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.

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.

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.

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.