Lapid, Maria I.

Abstract People with late-stage Alzheimer’s disease and related dementias (ADRD) who are assumed to have lost coherent cognitive capacity may exhibit unexpected episodes of lucidity (EL). Given the transient nature and lack of scientific explanation of the phenomenon, EL is under-investigated and poorly understood. To better understand this phenomenon, we set out to develop an operational definition of EL. Based on survey data from former and current family caregivers participating in UsAgainstAlzheimer’s A-LIST® (N = 480), we defined four EL typologies. We then interviewed 25 caregiver respondents about their experiences and used analyzed qualitative data to refine the preliminary typologies. Finally, we conducted a Delphi consensus panel with clinicians, researchers, and health care providers with medical, pharmacological, and clinical expertise to describe potential explanations for EL to help further refine the typologies. Next we will test the validity of these typologies in a prospective, demographically diverse sample of current family caregivers.

AbstractBackgroundDelirium and dementia are common causes of cognitive impairment in older adults and frequently co‐exist. Delirium is associated with poor clinical outcomes when comorbid with dementia. Identifying delirium superimposed on dementia (DSD) is clinically challenging given the overlap in symptoms, including inattention, cognitive impairment, and altered level of consciousness, especially in advanced stages of dementia. Recognition of delirium is also critical in ADRD (Alzheimer’s Disease and Related Dementias) clinical trials for both validity and safety reasons. The ECT‐AD study is one such trial investigating the safety and efficacy of electroconvulsive therapy (ECT) for treatment‐refractory agitation and aggression in individuals with advanced ADRD. Herein we review the Confusion Assessment Method (CAM) for identifying delirium in the ECT‐AD study.MethodInclusion criteria for ECT‐AD are hospitalized individuals diagnosed with ADRD (ages 55–89, MMSE ≤ 15) and refractory agitation/aggression, as measured by the Cohen‐Mansfield Agitation Inventory (CMAI). Procedures for detecting baseline and treatment‐emergent delirium involve a 3‐step approach conducted by raters trained in the CAM, which assesses inattention, disorganized thinking, altered levels of consciousness, and fluctuating mental status. Step 1 involves gathering information from nurse informants regarding the patient’s mental status over the past 24 hours. Step 2 involves collecting observational data through informal patient interaction (e.g., brief conversation). Step 3 is an objective assessment of cognitive status using the Severe Impairment Battery – 8 Item (SIB‐8), while also making qualitative observations about delirium features (e.g., level of consciousness). The rater then codes the CAM and determines delirium status based on these 3 steps.ResultOf our 6 consented subjects, 1 experienced delirium detected by the CAM during the Randomization Phase. The subject received three positive CAMs on consecutive treatment days, citing change in mental status, inability to arouse, restlessness, psychomotor agitation, and swearing. ECT/S‐ECT was held each treatment day and the subject was withdrawn from the Randomization Phase.ConclusionIdentifying DSD is challenging due to overlapping symptoms and the fluctuating nature of delirium. The CAM may be useful in this regard by using a multi‐step approach that incorporates observations from reliable informants, direct patient interactions, and structured cognitive assessments.

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

AbstractIntroductionLittle is known about how family caregivers who witness unexpected and spontaneous communication among people in late stages of Alzheimer's disease and related dementias (ADRD) appraise these episodes of lucidity (EL).MethodsIn an electronic, cross‐sectional survey for former and current caregivers who participate in UsAgainstAlzheimer's A‐LIST®, participants who reported witnessing an EL were asked how positive and stressful ELs were, if they made or changed decisions based on an EL, and what resources they sought out to explain ELs.ResultsCaregivers reported 72% of ELs to be quite a bit or very positive, 17% to be stressful, and 10% to be both stressful and positive. Twelve percent of caregivers changed care plans because of ELs and 13% sought out information about ELs.DiscussionThese exploratory data suggest caregiver reactions to EL vary. Caregivers may change or postpone care decisions due to EL, and few resources exist to address caregiver queries about EL.

e24087 Background: Patients with advanced cancer and their caregivers experience a substantial amount of distress. Limited research suggests that mindfulness-based interventions may improve quality of life and reduce anxiety. The virtually delivered Resilient Living program consisted of online modules, a print journal, and a total of 4 virtual training sessions focused on techniques for managing stress and building resilience (mindful presence, uplifting emotions, reframing experiences through principles of gratitude, compassion, acceptance, meaning, and forgiveness). The current pilot study was performed to assess the feasibility of the virtual Resilient Living Program for patients with advanced cancer and their caregivers, as well as preliminary effects on anxiety and related outcomes. Methods: Eligible patients included those age ≥18 years with a diagnosis of advanced cancer with expected prognosis > 6 months. Feasibility was defined as consent of at least 25% of eligible patients and their caregivers. Adherence was defined as 75% of the enrolled participants completing at least 3 of the 4 Resilient Living sessions. The primary outcome measure was anxiety as measured by the GAD-7; others included stress (PSS), quality of life (LASA), sleep (ISI), resiliency (Resiliency Scale), and fatigue (PROMIS-Fatigue SF). Results: Seventy-two eligible patients were referred to the study, of these 33 patients enrolled (46% enrollment), 15 also had a caregiver enroll. Thirty participants completed at least 3 virtual sessions (63% adherence). Data was collected at baseline, week 5 (after 2 session), week 9 (after 4 sessions), and week 12 (1 month after completion) for patients and caregivers. There were statistically significant improvements in anxiety at weeks 5, 9 and 12 (i.e., p < 0.05). Other results are outlined in the table. Conclusions: Virtual participation in the Resilient Living Program is feasible and acceptable for patients with advanced cancer and their caregivers. Data from this pilot study suggest that the program may positivity impact anxiety, stress, sleep, quality of life and resiliency. A larger randomized prospective clinical trial is warranted to confirm these preliminary findings. Clinical trial information: NCT04480008. [Table: see text]

Background: Informal support of a bereaved parent is common after the loss of a child (stillborn, young or adult child); however, it is not clear which aspects of informal support were perceived to be helpful by the bereaved parent. The aim of this scoping review is to clarify from the standpoint of bereaved parents what are considered helpful and unhelpful characteristics of informal support given by the support network of bereaved parents. Methods: A comprehensive search of databases from 2000 to April 20, 2020 was conducted for clinical studies published in English on informal bereavement support of adult bereaved parents of stillborn to adult children; 52 articles met criteria for the scoping review. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Ovid PsycINFO, and Scopus. Results: Specific supportive strategies reported by parents as helpful more frequently included talking with other supportive persons felt to be supportive, meeting another person with a similar type of loss, and a loss-specific peer support group. Other support included peer support groups in general, tangible aid, talking with the spouse about the child who died and/or accepting each other's different grieving styles, and remembrance gestures. Specific supportive strategies reported by parents as unhelpful more frequently included feeling of stigma or blame due to type of death or feeling that the type of death was not considered equal to other deaths and platitudes & insensitive comments. Other unhelpful support included talking with others felt to be unsupportive about discussing the loss, others stating a time limit to grief, others actively avoiding or stopping all communication with the bereaved parent, and one spouse not accepting the grieving style of the other or the spouse not willing to discuss the loss. Conclusion: Support focused on supportive verbal and nonverbal communication towards the bereaved parent and tangible aid were noted to be helpful informal support. Feeling stigma for or judged by others due to the type of death or the death not being considered equal (such as in deaths due to suicide and stillborn deaths) to other types of deaths as well as informational support (utilization of clichés/platitudes, advice giving, statements about the process and end point of grieving) were noted to be unhelpful informal support.

Key points Persons with severe and persistent mental illness (SPMI) experience disparities in accessing and initiating cancer treatment The assertive community treatment (ACT) model promotes the integration of physical and mental health care and improves the quality of life for a patient diagnosed with cancer The ACT model is essential in promoting decisional capacity of those with SPMI and cancer diagnoses The ability to access 24‐h support from the ACT model provides psychological support to patients dealing with chronic physical health diagnoses Collaboration between cancer treatment teams and the multidisciplinary ACT team can improve treatment engagement and enhance a patient's natural support system

AbstractBackgroundFrontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.MethodPlasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.ResultThe sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p < 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.ConclusionWhen FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.

AbstractBackgroundBlood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored.MethodFLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9orf72, 16 GRN, 34 MAPT, 34 mutation non‐carriers) and prospectively evaluated for 3 years. Baseline CSF was analyzed for NfL, phosphorylated neurofilament heavy chain (p‐NfH), tau, phosphorylated tau181 (p‐tau) and neurogranin using fit‐for‐purpose immunoassays. Mixed effect linear models, with random slopes, corrected for age, sex, genotype and total intracranial volume related CSF biomarkers to longitudinal clinical variables.ResultNfL (β = 0.64, p < 0.001), p‐NfH (β = 0.68, p < 0.001) and tau (β = 0.46, p < 0.001) correlated with age. There were no differences in biomarker concentrations by phenotype or severity, except for higher NfL and p‐NfH in full phenotype, compared to prodromal disease and asymptomatic carriers. Low neurogranin (β = ‐0.39, p < 0.001), low p‐tau (β = ‐0.33, p < 0.001) and high NfL (β = 0.42, p < 0.001) correlated with worse baseline disease severity measured by the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module sum of boxes (CDR®+NACC‐FTLDsb), and with other measures of global cognition, instrumental and daily function, and frontal and temporal brain volumes. Regardless of genotype, the predicted annualized rate of CDR®+NACC‐FTLDsb score worsenings per higher baseline CSF biomarker Log pg/mL were tau: 3.0 ± 0.2, NfL: 2.8 ± 0.2 and p‐NfH: 2.8 ± 0.2. High tau, NfL and p‐NfH also predicted worsening in other measures of global cognition and instrumental and daily function. Neurogranin and p‐tau did not predict clinical decline.ConclusionCSF tau, p‐tau, neurogranin, NfL and p‐NfH reflect important aspects of disease severity in fFTLD. In contrast to Alzheimer’s disease, low p‐tau and neurogranin are inversely related to clinical severity, which suggests a distinctive pathophysiological process and has implications for therapeutic development. CSF NfL, p‐NfH and tau have strong prognostic value in fFTLD.