Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Demographics, Symptoms, Psychotropic Use, and Caregiver Distress in Patients With Early vs Late Onset Dementia.

BACKGROUND: Understanding experiences and challenges faced by persons living with Early-Onset Dementia (EOD) compared to individuals diagnosed with Late-Onset Dementia (LOD) is important for the development of targeted interventions. OBJECTIVE: Describe differences in sociodemographic, neuropsychiatric behavioral symptoms, caregiver characteristics, and psychotropic use. DESIGN, SETTING, PARTICIPANTS: Cross-sectional, retrospective study including 908 UCLA Alzheimer's Dementia Care Program participants (177 with EOD and 731 with LOD). MEASUREMENTS: Onset of dementia was determined using age at program enrollment, with EOD defined as age <65 years and LOD defined as age >80 years. Sociodemographic and clinical characteristics were measured once at enrollment. Behavioral symptoms were measured using the Neuropsychiatric Inventory Questionnaire (NPI-Q) severity score and caregiver distress was measured using the NPI-Q distress score. Medications included antipsychotic, antidepressant, benzodiazepines and other hypnotics, antiepileptics, and dementia medications. RESULTS: EOD compared to LOD participants were more likely men, college graduates, married, live alone, and have fewer comorbidities. EOD caregivers were more often spouses (56% vs 26%, p <0.01), whereas LOD caregivers were more often children (57% vs 10%, p <0.01). EOD was associated with lower odds of being above the median (worse) NPI-Q severity (adjusted odds ratio [aOR], 0.58; 95% CI 0.35-0.96) and NPI-Q distress scores (aOR, 0.53; 95% CI 0.31-0.88). Psychotropic use did not differ between groups though symptoms were greater for LOD compared to EOD. CONCLUSION: Persons with EOD compared to LOD had sociodemographic differences, less health conditions, and fewer neuropsychiatric symptoms. Future policies could prioritize counseling for EOD patients and families, along with programs to support spousal caregivers of persons with EOD.

Diagnostic utility of brain MRI volumetry in comparing traumatic brain injury, Alzheimer disease and behavioral variant frontotemporal dementia.

BACKGROUND: Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments. OBJECTIVE: To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD). METHOD: We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups. RESULT: LOAD was the oldest compared to other groups (F = 27.5, p < .001). There were no statistically significant differences in sex (p = .58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p = .04 for EOAD and p = .01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p < .001), low white matter volume in TBI (F = 5.9, p < .001), lower left parietal lobe volume in EOAD (F = 9.4, p < .001), and lower total gray matter volume in bvFTD (F = 32.8, p < .001) and caudate atrophy (F = 1737.5, p < .001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes. CONCLUSION: We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders.

Socioemotional Dysfunction From Temporal Lobe Involvement in Frontotemporal Dementia: A Preliminary Report.

OBJECTIVE: Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD). METHODS: This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images. RESULTS: As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex. CONCLUSIONS: This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD.

Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers.

INTRODUCTION: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing. RESULTS: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories. DISCUSSION: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD. HIGHLIGHTS: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring 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). METHODS: We 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). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, 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), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=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). CONCLUSIONS: Systemic 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.

Proposed research criteria for prodromal behavioural variant frontotemporal dementia.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

The Implications of Moral Neuroscience for Brain Disease: Review and Update.

The last 2 decades have seen an explosion of neuroscience research on morality, with significant implications for brain disease. Many studies have proposed a neuromorality based on intuitive sentiments or emotions aimed at maintaining collaborative social groups. These moral emotions are normative, deontological, and action based, with a rapid evaluation of intentionality. The neuromoral circuitry interacts with the basic mechanisms of socioemotional cognition, including social perception, behavioral control, theory of mind, and social emotions such as empathy. Moral transgressions may result from primary disorders of moral intuitions, or they may be secondary moral impairments from disturbances in these other socioemotional cognitive mechanisms. The proposed neuromoral system for moral intuitions has its major hub in the ventromedial prefrontal cortex and engages other frontal regions as well as the anterior insulae, anterior temporal lobe structures, and right temporoparietal junction and adjacent posterior superior temporal sulcus. Brain diseases that affect these regions, such as behavioral variant frontotemporal dementia, may result in primary disturbances of moral behavior, including criminal behavior. Individuals with focal brain tumors and other lesions in the right temporal and medial frontal regions have committed moral violations. These transgressions can have social and legal consequences for the individuals and require increased awareness of neuromoral disturbances among such individuals with brain diseases.

A Functional and Neuroanatomical Model of Dehumanization.

The dehumanization of others is a major scourge of mankind; however, despite its significance, physicians have little understanding of the neurobiological mechanisms for this behavior. We can learn much about dehumanization from its brain-behavior localization and its manifestations in people with brain disorders. Dehumanization as an act of denying to others human qualities includes two major forms. Animalistic dehumanization (also called infrahumanization) results from increased inhibition of prepotent tendencies for emotional feelings and empathy for others. The mechanism may be increased activity in the inferior frontal gyrus. In contrast, mechanistic dehumanization results from a loss of perception of basic human nature and decreased mind-attribution. The mechanism may be hypofunction of a mentalization network centered in the ventromedial prefrontal cortex and adjacent subgenual anterior cingulate cortex. Whereas developmental factors may promote animalistic dehumanization, brain disorders, such as frontotemporal dementia, primarily promote mechanistic dehumanization. The consideration of these two processes as distinct, with different neurobiological origins, could help guide efforts to mitigate expression of this behavior.

Learning slopes in early-onset Alzheimer's disease.

OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without ß-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. HIGHLIGHTS: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort.

INTRODUCTION: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). METHODS: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). RESULTS: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. DISCUSSION: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease.

INTRODUCTION: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). METHODS: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. RESULTS: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers. DISCUSSION: The effects of sex and APOE ε4 must be considered when studying these populations. HIGHLIGHTS: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE Îµ4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

White matter hyperintensities are higher among early-onset Alzheimer's disease participants than their cognitively normal and early-onset nonAD peers: Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. METHODS: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. HIGHLIGHTS: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Profiling baseline performance on the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort near the midpoint of data collection.

OBJECTIVE: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. METHODS: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]). RESULTS: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. CONCLUSIONS: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

Behavioral Variant Frontotemporal Dementia and Social and Criminal Transgressions.

OBJECTIVE: 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. METHODS: This review evaluated the literature on the frequency of social and criminal transgressions in bvFTD and the neurobiological disturbances that underlie them. RESULTS: 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. CONCLUSIONS: 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.

Empathy and Impaired Socioemotional Self-Perception in Frontotemporal Dementia.

OBJECTIVE: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

The neurologist who could not stop rhyming and rapping.

.A neurologist, at age 55, developed an irrepressible urge to rhyme after a series of strokes and seizures. His strokes included right posterior cerebellar and right thalamic infarctions, and his subsequent focal-onset seizures emanated from the left frontotemporal region. On recovery, he described the emergence of an irresistible urge to rhyme, even in thought and daily speech. His pronounced focus on rhyming led him to actively participate in freestyle rap and improvisation. This patient's rhyming and rapping may have been initially facilitated by epileptiform activation of word sound associations but perpetuated as compensation for impaired cerebellar effects on timed anticipation.

Clinical Screening for Posterior Cortical Atrophy.

BACKGROUND: 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. OBJECTIVE: To identify neurobehavioral screening tasks for PCA-beyond simple visual constructions-that can be administered in clinic or at bedside. METHOD: 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. RESULTS: 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. CONCLUSION: 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.