Feasibility of Telehealth Occupational Therapy for Behavioral Symptoms of Adults With Dementia: Randomized Controlled Trial.

IMPORTANCE: Supporting community residency of adults with Alzheimer's disease (AD) is a critical public health initiative. Occupational therapy can contribute to this goal. OBJECTIVE: To assess the feasibility of a novel telehealth intervention to support occupational engagement in community-residing people with AD. DESIGN: Single-blind, three-arm, parallel, randomized controlled trial. SETTING: Occupational therapy delivered through telehealth in participants' homes. PARTICIPANTS: People with AD who reside in the community with behavioral symptoms and their care partners (dyads). INTERVENTIONS: (1) HARMONY (Helping older Adults cReate & Manage OccupatioNs successfully), a telehealth intervention that applies principles of individualized guided discovery with environmental cueing for caregivers of persons with AD to promote activity participation and manage behavioral symptoms; (2) standardized training regarding the use of a sensory-based approach in dementia care; and (3) a control, including home safety education and weekly monitoring of behaviors. OUTCOMES AND MEASURES: Feasibility was assessed as the primary outcome measured by completion of at least 75% of the telehealth sessions. Secondary outcomes included change in functional activity performance and neuropsychiatric behavioral symptoms. RESULTS: Twenty-eight dyads participated. The intervention was feasible, with high adherence to weekly visits (M number of visits = 5.4 for HARMONY, 4.9 for standardized training, and 4.6 for control), with high participant retention in the intervention arms. HARMONY demonstrated promise in improving patient performance and behavioral symptoms. CONCLUSIONS AND RELEVANCE: HARMONY is feasibly delivered through telehealth service and has a positive effect on occupational performance and behavioral symptoms of AD. Additional studies are needed to explore effectiveness in a broader population. What This Article Adds: Use of HARMONY for community-residing adults with AD is feasible and has promise for improving functional activity performance and behavioral symptoms, as well as caregiver satisfaction.

Acceptability of patient-centered, multi-disciplinary medication therapy management recommendations: results from the INCREASE randomized study.

BACKGROUND: Polypharmacy and inappropriate medications may be a modifiable risk factor for Alzheimer's Disease and Related Dementias (ADRD). Medication therapy management (MTM) interventions may mitigate medication-induced cognitive dysfunction and delay onset of symptomatic impairment. The objective of the current study is to describe an MTM protocol for a patient-centered team intervention (pharmacist and non-pharmacist clinician) in a randomized controlled trial (RCT) directed at delaying the symptomatic onset of ADRD. METHODS: Community dwelling adults 65 + years, non-demented, using ≥ 1 potentially inappropriate medications (PIM) were enrolled in an RCT to evaluate the effect of an MTM intervention on improving medication appropriateness and cognition (NCT02849639). The MTM intervention involved a three-step process: (1) pharmacist identified potential medication-related problems (MRPs) and made initial recommendations for prescribed and over-the-counter medications, vitamins, and supplements; (2) study team reviewed all initial recommendations together with the participants, allowing for revisions prior to the finalized recommendations; (3) participant responses to final recommendations were recorded. Here, we describe initial recommendations, changes during team engagement, and participant responses to final recommendations. RESULTS: Among the 90 participants, a mean 6.7 ± 3.6 MRPs per participant were reported. Of the 259 initial MTM recommendations made for the treatment group participants (N = 46), 40% percent underwent revisions in the second step. Participants reported willingness to adopt 46% of final recommendations and expressed need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications. CONCLUSION: The evaluation of modifications to MTM recommendations demonstrated that pharmacists' initial MTM recommendations often changed following the participation in the multidisciplinary decision-making process that incorporated patient preferences. The team was encouraged to see a correlation between engaging patients and a positive overall response towards participant acceptance of final MTM recommendations. TRIAL REGISTRATION: Study registration number: clinicaltrial.gov NCT02849639 registered on 29/07/2016.

INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer's Symptomatic Expression (INCREASE), a randomized controlled trial: rationale, study design, and protocol.

BACKGROUND: The course of Alzheimer's disease (AD) includes a 10-20-year preclinical period with progressive accumulation of amyloid ß (Aß) plaques and neurofibrillary tangles in the absence of symptomatic cognitive or functional decline. The duration of this preclinical stage in part depends on the rate of pathologic progression, which is offset by compensatory mechanisms, referred to as cognitive reserve (CR). Comorbid medical conditions, psychosocial stressors, and inappropriate medication use may lower CR, hastening the onset of symptomatic AD. Here, we describe a randomized controlled trial (RCT) designed to test the efficacy of a medication therapy management (MTM) intervention to reduce inappropriate medication use, bolster cognitive reserve, and ultimately delay symptomatic AD. METHODS/DESIGN: Our study aims to enroll 90 non-demented community-dwelling adults ≥ 65 years of age. Participants will undergo positron emission tomography (PET) scans, measuring Aß levels using standardized uptake value ratios (SUVr). Participants will be randomly assigned to MTM intervention or control, stratified by Aß levels, and followed for 12 months via in-person and telephone visits. Outcomes of interest include: (1) medication appropriateness (measured with the Medication Appropriateness Index (MAI)); (2) scores from Trail Making Test B (TMTB), Montreal Cognitive Assessment (MoCA), and California Verbal Learning Test (CVLT); (3) perceived health status (measured with the SF-36). We will also evaluate pre- to post-intervention change in: (1) use of inappropriate medications as measured by MAI; 2) CR Change Score (CRCS), defined as the difference in scopolamine-challenged vs unchallenged cognitive scores at baseline and follow-up. Baseline Aß SUVr will be used to examine the relative impact of preclinical AD (pAD) pathology on CRCS, as well as the interplay of amyloid burden with inappropriate medication use. DISCUSSION: This manuscript describes the protocol of INCREASE ("INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer's Symptomatic Expression"): a randomized controlled trial that investigates the impact of deprescribing inappropriate medications and optimizing medication regimens on potentially delaying the onset of symptomatic AD and AD-related dementias. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02849639. Registered on 29 July 2016.

Deficiency of XLF and PAXX prevents DNA double-strand break repair by non-homologous end joining in lymphocytes.

Non-homologous end joining (NHEJ) is a major DNA double-strand break (DSB) repair pathway that functions in all phases of the cell cycle. NHEJ repairs genotoxic and physiological DSBs, such as those generated by ionizing radiation and during V(D)J recombination at antigen receptor loci, respectively. DNA end joining by NHEJ relies on the core factors Ku70, Ku80, XRCC4, and DNA Ligase IV. Additional proteins also play important roles in NHEJ. The XRCC4-like factor (XLF) participates in NHEJ through its interaction with XRCC4, and XLF deficiency in humans leads to immunodeficiency and increased sensitivity to ionizing radiation. However, XLF is dispensable for NHEJ-mediated DSB repair during V(D)J recombination in murine lymphocytes, where it may have redundant functions with other DSB repair factors. Paralog of XRCC4 and XLF (PAXX) is a recently identified NHEJ factor that has structural similarity to XRCC4 and XLF. Here we show that PAXX is also dispensable for NHEJ during V(D)J recombination and during the repair of genotoxic DSBs in lymphocytes. However, a combined deficiency of PAXX and XLF blocks NHEJ with a severity comparable to that observed in DNA Ligase IV-deficient cells. Similar to XLF, PAXX interacts with Ku through its C-terminal region, and mutations that disrupt Ku binding prevent PAXX from promoting NHEJ in XLF-deficient lymphocytes. Our findings suggest that the PAXX and XLF proteins may have redundant functions during NHEJ.

HCoDES reveals chromosomal DNA end structures with single-nucleotide resolution.

The structure of broken DNA ends is a critical determinant of the pathway used for DNA double-strand break (DSB) repair. Here, we develop an approach involving the hairpin capture of DNA end structures (HCoDES), which elucidates chromosomal DNA end structures at single-nucleotide resolution. HCoDES defines structures of physiologic DSBs generated by the RAG endonuclease, as well as those generated by nucleases widely used for genome editing. Analysis of G1 phase cells deficient in H2AX or 53BP1 reveals DNA ends that are frequently resected to form long single-stranded overhangs that can be repaired by mutagenic pathways. In addition to 3' overhangs, many of these DNA ends unexpectedly form long 5' single-stranded overhangs. The divergence in DNA end structures resolved by HCoDES suggests that H2AX and 53BP1 may have distinct activities in end protection. Thus, the high-resolution end structures obtained by HCoDES identify features of DNA end processing during DSB repair.

KAP-1 promotes resection of broken DNA ends not protected by γ-H2AX and 53BP1 in G1-phase lymphocytes.

The resection of broken DNA ends is required for DNA double-strand break (DSB) repair by homologous recombination (HR) but can inhibit normal repair by nonhomologous end joining (NHEJ), the main DSB repair pathway in G1-phase cells. Antigen receptor gene assembly proceeds through DNA DSB intermediates generated in G1-phase lymphocytes by the RAG endonuclease. These DSBs activate ATM, which phosphorylates H2AX, forming γ-H2AX in flanking chromatin. γ-H2AX prevents CtIP from initiating resection of RAG DSBs. Whether there are additional proteins required to promote resection of these DNA ends is not known. KRAB-associated protein 1 (KAP-1) (TRIM28) is a transcriptional repressor that modulates chromatin structure and has been implicated in the repair of DNA DSBs in heterochromatin. Here, we show that in murine G1-phase lymphocytes, KAP-1 promotes resection of DSBs that are not protected by H2AX and its downstream effector 53BP1. In these murine cells, KAP-1 activity in DNA end resection is attenuated by a single-amino-acid change that reflects a KAP-1 polymorphism between primates and other mammalian species. These findings establish KAP-1 as a component of the machinery that can resect DNA ends in G1-phase cells and suggest that there may be species-specific features to this activity.

Functional intersection of ATM and DNA-dependent protein kinase catalytic subunit in coding end joining during V(D)J recombination.

V(D)J recombination is initiated by the RAG endonuclease, which introduces DNA double-strand breaks (DSBs) at the border between two recombining gene segments, generating two hairpin-sealed coding ends and two blunt signal ends. ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are serine-threonine kinases that orchestrate the cellular responses to DNA DSBs. During V(D)J recombination, ATM and DNA-PKcs have unique functions in the repair of coding DNA ends. ATM deficiency leads to instability of postcleavage complexes and the loss of coding ends from these complexes. DNA-PKcs deficiency leads to a nearly complete block in coding join formation, as DNA-PKcs is required to activate Artemis, the endonuclease that opens hairpin-sealed coding ends. In contrast to loss of DNA-PKcs protein, here we show that inhibition of DNA-PKcs kinase activity has no effect on coding join formation when ATM is present and its kinase activity is intact. The ability of ATM to compensate for DNA-PKcs kinase activity depends on the integrity of three threonines in DNA-PKcs that are phosphorylation targets of ATM, suggesting that ATM can modulate DNA-PKcs activity through direct phosphorylation of DNA-PKcs. Mutation of these threonine residues to alanine (DNA-PKcs(3A)) renders DNA-PKcs dependent on its intrinsic kinase activity during coding end joining, at a step downstream of opening hairpin-sealed coding ends. Thus, DNA-PKcs has critical functions in coding end joining beyond promoting Artemis endonuclease activity, and these functions can be regulated redundantly by the kinase activity of either ATM or DNA-PKcs.