Early Childhood Adversity Predicts Risk of Family Caregiver Suicidal Ideation:Roles of Neuroticism and Self-Compassion.

Background: Despite high rates of family caregiver suicidal ideation (SI), little is known about its relationship with childhood adversity. Those with a history of adverse childhood experiences (ACEs) have been shown to have higher neuroticism, lower self-compassion, and higher rates of late life mental health disorders. Caregiving for a family member with dementia may pose a particular challenge for those with ACEs. Methods: In a secondary analysis of 81 family caregivers of people living with dementia enrolled in clinical trials, we undertook a cross-sectional baseline analysis of the association between childhood adversity, measured with the ACE questionnaire, and self-reported suicidal ideation (SI). We further assessed whether the relationship between ACE and SI was mediated by neuroticism and self-compassion. Results: 18 caregivers self-reported SI (22%). 89% of caregivers with SI reported childhood adversity (ACE > 0), versus 63% of those without SI (p=.04). The relative risk of SI was 3.6x higher in those with childhood adversity than in those without (p=.04), and for those with a specific history childhood abuse, the relative risk of SI was 3.4x higher (p=.005). Neuroticism and self-compassion mediated the relationship between ACE and SI (p<.05), with neuroticism strengthening the association and self-compassion weakening it. Conclusions: The association of SI with history of childhood adversity is high in family caregivers. Whereas elevated neuroticism might be one mechanism linking ACEs and SI, training self-compassion is a promising target for reducing SI. The phenotypic relationship between childhood adversity and SI in family caregivers should be further explored in larger samples, and could represent a new treatment target to improve the efficacy of therapies on caregiver emotional symptoms.

Physical Activity and Neurocognitive Symptoms in Older Adults During COVID-19 Pandemic.

Objectives: Examine whether physical activity (PA) changes during the COVID-19 pandemic were related to subjective cognitive decline (SCD), depression, and anxiety in older adults and whether these varied by sociodemographic variables. Methods: 301 older adults completed an online survey between May and October 2020 and 3 months later, including self-report questionnaires of SCD, depression, and anxiety. PA changes were determined with a question. Results: 60% of participants reported decreased PA. Those who reduced their PA were more likely to be from low to middle income and younger. PA increase was related to less SCD and depressive symptoms compared to those who decreased it. Participants who maintained their PA had fewer SCD concerns, depressive, and anxiety symptoms than those who decreased it. Discussion: Reducing PA was associated with worse neuropsychiatric and cognitive symptoms. Encouraging older adults to increase PA may help mitigate some of the pandemic's adverse effects on psychological well-being.

APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Family dementia caregivers with suicidal ideation improve with mentalizing imagery therapy: Results from a pilot study.

Background: Family caregivers of persons living with dementia often experience increased depression and suicidal ideation (SI). However, the feasibility and impact of therapies on caregiver SI has remained largely unexplored. Mentalizing imagery therapy (MIT) helps reduce psychological symptoms through mindfulness and guided imagery. This pilot study examined the feasibility of participation by caregivers with SI in a randomized controlled trial (RCT) of MIT versus a psychosocial support group (SG), and the respective impact of group on SI, depression, and secondary outcomes. Methods: A secondary analysis of data from an RCT of 4-week MIT or SG for caregivers (n = 46) was performed, identifying SI (n = 23) and non-SI (n = 23) cohorts. Group attendance and home practice were compared between cohorts. In the SI cohort (total n = 23, MIT n = 11, SG n = 12), group differences in SI, depression, and secondary outcomes were evaluated post-group and at 4-month follow-up. Results: Attendance in both groups and home practice in MIT were similar between SI and non-SI cohorts. In the SI cohort, MIT evinced greater improvements relative to SG in SI (p=.02) and depression (p=.02) post-group, and other secondary outcomes at follow-up. Limitations: Limitations include small sample size and single-item assessments of SI from validated depression rating scales. Conclusions: Participation in an RCT was feasible for caregivers with SI. MIT resulted in important benefits for SI and depression, while SG showed no acute SI benefit. The role of MIT in improving SI should be confirmed with adequately powered trials, as effective therapies to address caregiver SI are critical.

Telemedicine-Based Cognitive Examinations During COVID-19 and Beyond: Perspective of the Massachusetts General Hospital Behavioral Neurology & Neuropsychiatry Group.

Telehealth and telemedicine have encountered explosive growth since the beginning of the COVID-19 pandemic, resulting in increased access to care for patients located far from medical centers and clinics. Subspecialty clinicians in behavioral neurology & neuropsychiatry (BNNP) have implemented the use of telemedicine platforms to perform cognitive examinations that were previously office based. In this perspective article, BNNP clinicians at Massachusetts General Hospital (MGH) describe their experience performing cognitive examinations via telemedicine. The article reviews the goals, prerequisites, advantages, and potential limitations of performing a video- or telephone-based telemedicine cognitive examination. The article shares the approaches used by MGH BNNP clinicians to examine cognitive and behavioral areas, such as orientation, attention and executive functions, language, verbal learning and memory, visual learning and memory, visuospatial function, praxis, and abstract abilities, as well as to survey for neuropsychiatric symptoms and assess activities of daily living. Limitations of telemedicine-based cognitive examinations include limited access to and familiarity with telecommunication technologies on the patient side, limitations of the technology itself on the clinician side, and the limited psychometric validation of virtual assessments. Therefore, an in-person examination with a BNNP clinician or a formal in-person neuropsychological examination with a neuropsychologist may be recommended. Overall, this article emphasizes the use of standardized cognitive and behavioral assessment instruments that are either in the public domain or, if copyrighted, are nonproprietary and do not require a fee to be used by the practicing BNNP clinician.

Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease.

INTRODUCTION: Plasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD. METHODS: We examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers. RESULTS: As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. DISCUSSION: Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. HIGHLIGHTS: We examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers. Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

Virtual mentalizing imagery therapy for Spanish language Latino family dementia caregivers: A feasibility and acceptability study.

Spanish speaking family caregivers of people living with dementia have limited supportive resources in Spanish. There are few validated, culturally acceptable virtual interventions for reducing these caregivers' psychological distress. We investigated the feasibility of a Spanish language adaptation of a virtual Mentalizing Imagery Therapy (MIT) program, which provides guided imagery and mindfulness training to reduce depression, increase mentalizing, and promote well-being. 12 Spanish-speaking family dementia caregivers received a 4-week virtual MIT program. Follow-up was obtained post group and at 4 months post baseline assessment. Feasibility, acceptability, and satisfaction with MIT were assessed. The primary psychological outcome was depressive symptoms; secondary outcomes included caregiver burden, dispositional mindfulness, perceived stress, well-being, interpersonal support, and neurological quality of life. Statistical analysis was performed with mixed linear models. Caregivers were 52 ± 8 (mean ± SD) years of age. 60% had a high school education or less. Participation in weekly group meetings was 100%. Home practice was performed on average 4 ± 1 times per week [range 2-5]. Satisfaction with MIT reached 19 ± 2 of a possible 20 points. Reduction in depression from baseline was observed by week three (p = 0.01) and maintained at 4 month follow-up (p = 0.05). There were significant improvements in mindfulness post-group, and in caregiver burden and well-being at 4 months. MIT was successfully adapted for Latino Spanish language family dementia caregivers within a virtual group environment. MIT is feasible and acceptable and may help reduce depressive symptoms and improve subjective well-being. Larger, randomized controlled trials of MIT should determine durability of effects and validate efficacy in this population.

Associations Among Loneliness, Purpose in Life and Subjective Cognitive Decline in Ethnoracially Diverse Older Adults Living in the United States.

Subjective cognitive decline (SCD), which precedes Mild Cognitive Impairment and dementia, may be affected by purpose in life (PiL) and loneliness in older adults. We investigated associations among PiL, loneliness, and SCD in US Latino (n = 126), Black (n = 74), Asian (n = 33), and White (n = 637) adults. Higher PiL predicted lower SCD in all groups (p-values < .012), except Black participants. Lower loneliness predicted lower SCD in Latino and White groups (p-values < .05), and PiL moderated this association in White adults. PiL and loneliness may play important roles in cognitive decline. Differential predictors of SCD suggest differential targets for preventing cognitive decline and dementia across ethnoracial groups.

Waning locus coeruleus integrity precedes cortical tau accrual in preclinical autosomal dominant Alzheimer's disease.

INTRODUCTION: Autopsy studies recognize the locus coeruleus (LC) as one of the first sites accumulating tau in Alzheimer's disease (AD). Recent AD work related in vivo LC magnetic resonance imaging (MRI) integrity to tau and cognitive decline; however, relationships of LC integrity to age, tau, and cognition in autosomal dominant AD (ADAD) remain unexplored. METHODS: We associated LC integrity (3T-MRI) with estimated years of onset, cortical amyloid beta, regional tau (positron emission tomography [PET]) and memory (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word-List-Learning) among 27 carriers and 27 non-carriers of the presenilin-1 (PSEN1) E280A mutation. Longitudinal changes between LC integrity and tau were evaluated in 10 carriers. RESULTS: LC integrity started to decline at age 32 in carriers, 12 years before clinical onset, and 20 years earlier than in sporadic AD. LC integrity was negatively associated with cortical tau, independent of amyloid beta, and predicted precuneus tau increases. LC integrity was positively associated with memory. DISCUSSION: These findings support LC integrity as marker of disease progression in preclinical ADAD.

Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia.

We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer's disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer's symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.

Olfactory Function and Markers of Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Olfactory dysfunction is one of the earliest signs of Alzheimer's disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia. OBJECTIVE: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members. METHODS: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. RESULTS: Worse olfactory identification performance was associated with greater age in mutation carriers (r = -0.52 p = 0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r = 0.55, p = 0.024) and CERAD delayed recall (r = 0.63, p = 0.007) and greater cortical amyloid-ß (r = -0.53, p = 0.042) and tau pathology burden (entorhinal: r = -0.59, p = 0.016; inferior temporal: r = -0.52, p = 0.038). CONCLUSION: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.

Mentalizing imagery therapy to augment skills training for dementia caregivers: Protocol for a randomized, controlled trial of a mobile application and digital phenotyping.

More than 50 million people worldwide live with a dementia, and most are cared for by family members. Family caregivers often experience chronic stress and insomnia, resulting in decreased mental and physical health. Accessibility of in-person stress reduction therapy is limited due to caregiver time constraints and distance from therapy sites. Mentalizing imagery therapy (MIT) provides mindfulness and guided imagery tools to reduce stress, promote self and other understanding, and increase feelings of interconnectedness. Combining MIT with caregiver skills training might enable caregivers to both reduce stress and better utilize newly learned caregiving skills, but this has never been studied. Delivering MIT through a smartphone application (App) has the potential to overcome difficulties with scalability and dissemination and offers caregivers an easy-to-use format. Harnessing passive smartphone data provides an important opportunity to study behavioral changes continuously and with higher granularity than routine clinical assessments. This protocol describes a randomized, controlled, superiority trial in which 120 family dementia caregivers, aged 60 years or older, will be assigned to smartphone App delivery of caregiver skills with MIT (experimental condition) or without MIT (control condition). The primary objectives of the trial are to assess whether the experimental condition is superior to control on reducing family caregiver stress, insomnia and related outcomes and to demonstrate the feasibility of developing behavioral markers from passive smartphone data that predict health outcomes in older adults. Trial outcomes may inform the suitability of our intervention for caregivers and provide new methods for assessment of older adults.

Four-Week Mentalizing Imagery Therapy for Family Dementia Caregivers: A Randomized Controlled Trial with Neural Circuit Changes.

INTRODUCTION: Family caregivers of patients with dementia suffer a high burden of depression and reduced positive emotions. Mentalizing imagery therapy (MIT) provides mindfulness and guided imagery skills training to improve balanced mentalizing and emotion regulation. OBJECTIVE: Our aims were to test the hypotheses that MIT for family caregivers would reduce depression symptoms and improve positive psychological traits more than a support group (SG), and would increase dorsolateral prefrontal cortex (DLPFC) connectivity and reduce subgenual anterior cingulate cortex (sgACC) connectivity. METHODS: Forty-six caregivers participated in a randomized controlled trial comparing a 4-week MIT group (n = 24) versus an SG (n = 22). Resting state neuroimaging was obtained at baseline and post-group in 28 caregivers, and questionnaires completed by all participants. The primary outcome was change in depression; secondary measures included anxiety, mindfulness, self-compassion, and well-being. Brain networks with participation of DLPFC and sgACC were identified. Connectivity strengths of DLPFC and sgACC with respective networks were determined with dual regression. DLPFC connectivity was correlated with mindfulness and depression outcomes. RESULTS: MIT significantly outperformed SG in improving depression, anxiety, mindfulness, self-compassion, and well-being, with moderate to large effect sizes. Relative to SG, participants in MIT showed significant increases in DLPFC connectivity - exactly replicating pilot study results - but no change in sgACC. DLPFC connectivity change correlated positively with mindfulness and negatively with depression change. CONCLUSIONS: In this trial, MIT was superior to SG for reducing depression and anxiety symptoms and improving positive psychological traits. Neuroimaging results suggested that strengthening DLPFC connectivity with an emotion regulation network might be mechanistically related to MIT effects.

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Greater neuroticism has been associated with higher risk for Alzheimer's disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology. OBJECTIVE: To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers. METHODS: A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27-46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging. RESULTS: Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels. CONCLUSION: The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

Associations between subregional thalamic volume and brain pathology in autosomal dominant Alzheimer's disease.

Histopathological reports suggest that subregions of the thalamus, which regulates multiple physiological and cognitive processes, are not uniformly affected by Alzheimer's disease. Despite this, structural neuroimaging studies often consider the thalamus as a single region. Identification of in vivo Alzheimer's-dependent volumetric changes in thalamic subregions may aid the characterization of early nuclei-specific neurodegeneration in Alzheimer's disease. Here, we leveraged access to the largest single-mutation cohort of autosomal-dominant Alzheimer's disease to test whether cross-sectional abnormalities in subregional thalamic volumes are evident in non-demented mutation carriers (n = 31), compared to non-carriers (n = 36), and whether subregional thalamic volume is associated with age, markers of brain pathology and cognitive performance. Using automatic parcellation we examined the thalamus in six subregions (anterior, lateral, ventral, intralaminar, medial, and posterior) and their relation to age and brain pathology (amyloid and tau), as measured by PET imaging. No between-group differences were observed in the volume of the thalamic subregions. In carriers, lower volume in the medial subregion was related to increased cortical amyloid and entorhinal tau burden. These findings suggest that thalamic Alzheimer's-related volumetric reductions are not uniform even in preclinical and prodromal stages of autosomal-dominant Alzheimer's disease and therefore, this structure should not be considered as a single, unitary structure in Alzheimer's disease research.

The impact of COVID-19 on the well-being and cognition of older adults living in the United States and Latin America.

BACKGROUND: In the COVID-19 pandemic, older adults from vulnerable ethnoracial groups are at high risk of infection, hospitalization, and death. We aimed to explore the pandemic's impact on the well-being and cognition of older adults living in the United States (US), Argentina, Chile, Mexico, and Peru. METHODS: 1,608 (646 White, 852 Latino, 77 Black, 33 Asian; 72% female) individuals from the US and four Latin American countries aged ≥ 55 years completed an online survey regarding well-being and cognition during the pandemic between May and September 2020. Outcome variables (pandemic impact, discrimination, loneliness, purpose of life, subjective cognitive concerns) were compared across four US ethnoracial groups and older adults living in Argentina, Chile, Mexico, and Peru. FINDINGS: Mean age for all participants was 66.7 (SD = 7.7) years and mean education was 15.4 (SD = 2.7) years. Compared to Whites, Latinos living in the US reported greater economic impact (p < .001, ηp 2  = 0.031); while Blacks reported experiencing discrimination more often (p < .001, ηp 2  = 0.050). Blacks and Latinos reported more positive coping (p < .001, ηp 2  = 0.040). Compared to Latinos living in the US, Latinos in Chile, Mexico, and Peru reported greater pandemic impact, Latinos in Mexico and Peru reported more positive coping, Latinos in Argentina, Mexico, and Peru had greater economic impact, and Latinos in Argentina, Chile, and Peru reported less discrimination. INTERPRETATION: The COVID-19 pandemic has differentially impacted the well-being of older ethnically diverse individuals in the US and Latin America. Future studies should examine how mediators like income and coping skills modify the pandemic's impact. FUNDING: Massachusetts General Hospital Department of Psychiatry.

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study.

BACKGROUND: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-ß (Aß) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD. METHODS: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aß (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers. RESULTS: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aß accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers. CONCLUSIONS: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aß burden and neocortical tau accumulation in ADAD.

Seizure-related 6 homolog like 2 autoimmunity: Neurologic syndrome and antibody effects.

OBJECTIVE: To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures. METHODS: SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons. RESULTS: In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54-69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons. CONCLUSIONS: SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.