The Delphi Delirium Management Algorithms. A practical tool for clinicians, the result of a modified Delphi expert consensus approach.

Delirium is common in hospitalised patients, and there is currently no specific treatment. Identifying and treating underlying somatic causes of delirium is the first priority once delirium is diagnosed. Several international guidelines provide clinicians with an evidence-based approach to screening, diagnosis and symptomatic treatment. However, current guidelines do not offer a structured approach to identification of underlying causes. A panel of 37 internationally recognised delirium experts from diverse medical backgrounds worked together in a modified Delphi approach via an online platform. Consensus was reached after five voting rounds. The final product of this project is a set of three delirium management algorithms (the Delirium Delphi Algorithms), one for ward patients, one for patients after cardiac surgery and one for patients in the intensive care unit.

A pragmatic tool to screen for pre-transplant cognitive impairment among potential candidates for liver transplant.

INTRODUCTION: Cognitive impairment (CI) among liver transplant (LT) candidates is associated with increased risk of waitlist mortality and inferior outcomes. While formal neurocognitive evaluation is the gold standard for CI diagnosis, the Montreal Cognitive Assessment (MoCA) is often used for first-line cognitive screening. However, MoCA requires specialized training and may be too lengthy for a busy evaluation appointment. An alternate approach may be the Quick Dementia Rating System (QDRS), which is patient- and informant-based and can be administered quickly. We compared potential LT candidates identified by MoCA and QDRS as potentially benefiting from further formal cognitive evaluation. METHODS: We identified 46 potential LT candidates enrolled at a single center of a prospective, observational cohort study who were administered MoCA and QDRS during transplant evaluation (12/2021-12/2022). Scores were dichotomized as (1) normal versus abnormal and (2) normal/mild impairment versus more-than-mild impairment. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of QDRS compared to MoCA. RESULTS: By MoCA, this population had a prevalence of 48% normal cognition, 48% mild, 4% moderate, and 0% severe impairment. This was categorized as 96% normal/mild and 4% more-than-mild impairment. When comparing to MoCA cognitive screening, QDRS had a sensitivity of 61%, specificity of 56%, NPV of 56%, and PPV of 61%. When identifying more-than-mild impairment, QDRS had a sensitivity of 100%, specificity of 73%, NPV of 100%, and PPV of 10%. CONCLUSION: The high sensitivity and NPV of QDRS in identifying more-than-mild impairment suggests it could identify potential LT candidates who would benefit from further formal cognitive evaluation. The ability to administer QDRS quickly and remotely makes it a pragmatic option for pre-transplant screening.

A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.

Automating the analysis of eye movement for different neurodegenerative disorders.

The clinical observation and assessment of extra-ocular movements is common practice in assessing neurodegenerative disorders but remains observer-dependent. In the present study, we propose an algorithm that can automatically identify saccades, fixation, smooth pursuit, and blinks using a non-invasive eye tracker. Subsequently, response-to-stimuli-derived interpretable features were elicited that objectively and quantitatively assess patient behaviors. The cohort analysis encompasses persons with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), Parkinson's disease mimics (PDM), and controls (CTRL). Overall, results suggested that the AD/MCI and PD groups had significantly different saccade and pursuit characteristics compared to CTRL when the target moved faster or covered a larger visual angle during smooth pursuit. These two groups also displayed more omitted antisaccades and longer average antisaccade latency than CTRL. When reading a text passage silently, people with AD/MCI had more fixations. During visual exploration, people with PD demonstrated a more variable saccade duration than other groups. In the prosaccade task, the PD group showed a significantly smaller average hypometria gain and accuracy, with the most statistical significance and highest AUC scores of features studied. The minimum saccade gain was a PD-specific feature different from CTRL and PDM. These features, as oculographic biomarkers, can be potentially leveraged in distinguishing different types of NDs, yielding more objective and precise protocols to diagnose and monitor disease progression.

Advancing specificity in delirium: The delirium subtyping initiative.

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Optimizing delirium care in the era of Age-Friendly Health System.

Delirium is a significant geriatric condition associated with adverse clinical and economic outcomes. The cause of delirium is usually multifactorial, and person-centered multicomponent approaches for proper delirium management are required. In 2017, the John A. Hartford Foundation and the Institute for Healthcare Improvement (IHI) launched a national initiative, Age-Friendly Health System (AFHS), promoting the use of a framework called 4Ms (what matters, medication, mentation, and mobility). The 4Ms framework's primary goal is to provide comprehensive and practical person-centered care for older adults and it aligns with the core concepts of optimal delirium management. In this special article, we demonstrate how a traditional delirium prevention and management model can be assessed from the perspective of AFHS. An example is the crosswalk with the Hospital Elder Life Program (HELP) Core Interventions and the 4MS, which demonstrates alignment in delirium management. We also introduce useful tools to create an AFHS environment in delirium management. Although much has been written about delirium management, there is a need to identify the critical steps in advancing the overall delirium care in the context of the AFHS. In this article, we suggest future directions, including the need for more prospective and comprehensive research to assess the impact of AFHS on delirium care, the need for more innovative and sustainable education platforms, fundamental changes in the healthcare payment system for proper adoption of AFHS in any healthcare setting, and application of AFHS in the community for continuity of care for older adults with delirium.

Hearing Loss, Hearing Aids, and Satisfaction With Health Care in the National Health Interview Survey.

OBJECTIVE: Hearing loss may negatively impact satisfaction with health care via patient-provider communication barriers and may be amenable to hearing care treatment. STUDY DESIGN: Cross-sectional. SETTING: National Health Interview Survey, a nationally representative survey of noninstitutionalized US residents, 2013 to 2018 pooled cycles. METHODS: Participants described satisfaction with health care in the past year, categorized as optimal (very satisfied) versus suboptimal (satisfied, dissatisfied, very dissatisfied) satisfaction. Self-report hearing without hearing aids (excellent, good, a little trouble, moderate trouble, a lot of trouble) and hearing aid use (yes, no) were collected. Weighted Poisson regression models adjusted for sociodemographic and health covariates were used to estimate prevalence rate ratios (PRRs) of satisfaction with care by hearing loss and hearing aid use. RESULTS: Among 137,216 participants (mean age 50.9 years, 56% female, 12% black), representing 77.2 million Americans in the weighted model, 19% reported trouble hearing. Those with good (PRR = 1.20, 95% confidence interval [CI]: 1.18-1.23), a little trouble (PRR = 1.27, 95% CI, 1.23-1.31), moderate trouble (PRR = 1.29, 95% CI, 1.24-1.35), and a lot of trouble hearing (PRR = 1.26, 95% CI, 1.18-1.33) had a higher prevalence rate of suboptimal satisfaction with care relative to those with excellent hearing. Among all participants with trouble hearing, hearing aid users had a 17% decrease in the prevalence rate of suboptimal satisfaction with care (PRR = 0.83, 95% CI, 0.78-0.88) compared to nonusers. CONCLUSION: Hearing loss decreases patient satisfaction with health care, which is tied to Medicare hospital reimbursement models. Hearing aid use may improve patient-provider communication and patient satisfaction, although prospective studies are warranted to truly establish their protective effect.

ACR Appropriateness Criteria® Tinnitus: 2023 Update.

Tinnitus is abnormal perception of sound and has many subtypes. Clinical evaluation, audiometry, and otoscopy should be performed before ordering any imaging, as the choice of imaging will depend on various factors. Type of tinnitus (pulsatile or nonpulsatile) and otoscopy findings of a vascular retrotympanic lesion are key determinants to guide the choice of imaging studies. High-resolution CT temporal bone is an excellent tool to detect glomus tumors, abnormal course of vessels, and some other abnormalities when a vascular retrotympanic lesion is seen on otoscopy. CTA or a combination of MR and MRA/MRV are used to evaluate arterial or venous abnormalities like dural arteriovenous fistula, arteriovenous malformation, carotid stenosis, dural sinus stenosis, and bony abnormalities like sigmoid sinus wall abnormalities in cases of pulsatile tinnitus without a vascular retrotympanic lesion. MR of the brain is excellent in detecting mass lesions such as vestibular schwannomas in cases of unilateral nonpulsatile tinnitus. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

The association of hearing loss with frailty among community-dwelling older adults: findings from the National Health and Aging Trends Study.

BACKGROUND: The identification of modifiable risk factors is crucial for the prevention and/or reversal of frailty, which is associated with significant morbidity and mortality. Hearing loss affects two-thirds of older adults in the United States (U.S.) and is associated with physical and cognitive decline which may increase frailty risk. We investigated the association of hearing loss and hearing aid use with frailty and pre-frailty in a nationally representative sample of older adults in the U.S. METHODS: Cross-sectional analysis of the National Health and Aging Trends Study (2021 round). The better-hearing ear pure-tone average (BPTA) at speech-frequencies (0.5-4 kHz) was modeled continuously (per 10 dB) and categorically (no ≤ 25 dB, mild 26-40 dB, moderate or greater > 40 dB hearing loss). Hearing aid use was self-reported. The physical frailty phenotype (frail, pre-frail, robust) was determined based on Fried criteria: unintentional weight loss, exhaustion, low physical activity, weakness, slow walking speed. We used multinomial multivariable regression adjusted for sociodemographic and health characteristics (odds ratios [95% Confidence Intervals]). RESULTS: Among 2,361 participants (mean age = 81 years, 56% female, 19% Black), 860 (36%) had mild and 864 (37%) had moderate or greater hearing loss. Worse hearing was associated with greater odds of being frail versus robust (OR = 1.20 [1.05-1.38] per 10 dB difference). Categorically, moderate or greater hearing loss was associated with greater odds of being frail (OR = 1.84 [1.01-3.08]) and pre-frail (OR = 1.46 [1.01-2.10]) versus robust. Among 1,724 participants with hearing loss, compared to hearing aid users (N = 522), nonusers had greater odds of being frail (OR = 2.54 [1.54-4.18]) and pre-frail (OR = 1.51 [1.05-2.17]) versus robust, and frail versus pre-frail (OR = 1.68 [1.04-2.72]). CONCLUSIONS: In a nationally representative sample of older adults in the U.S., using gold-standard hearing measures and a validated frailty phenotype, hearing loss and lack of hearing aid use was cross-sectionally associated with frailty and pre-frailty. Future longitudinal studies are needed to establish if hearing loss is a risk factor for frailty, which may have significant clinical importance.

Endogenous and Exogenous Thyrotoxicosis and Risk of Incident Cognitive Disorders in Older Adults.

Importance: Thyroid hormone is among the most common prescriptions in the US and up to 20% may be overtreated. Endogenous hyperthyroidism may be a risk factor for dementia, but data are limited for iatrogenic thyrotoxicosis. Objective: To determine whether thyrotoxicosis, both endogenous and exogenous, is associated with increased risk of cognitive disorders. Design, Setting, and Participants: This cohort study performed a longitudinal time-varying analysis of electronic health records for patients receiving primary care in the Johns Hopkins Community Physicians Network between January 1, 2014, and May 6, 2023. Patients 65 years and older with at least 2 visits 30 days apart to their primary care physicians were eligible. None of the 65 931 included patients had a history of low thyrotropin (TSH) level or cognitive disorder diagnoses within 6 months of their first visit. Data analysis was performed from January 1 through August 5, 2023. Exposure: The exposure variable was a low TSH level, characterized based on the clinical context as due to endogenous thyrotoxicosis, exogenous thyrotoxicosis, or unknown cause, excluding those attributable to acute illness or other medical factors such as medications. Main Outcomes and Measures: The outcome measure was cognitive disorders, including mild cognitive impairment and all-cause dementia, to improve sensitivity and account for the underdiagnosis of dementia in primary care. Results: A total of 65 931 patients were included in the analysis (median [IQR] age at first visit, 68.0 [65.0-74.0] years; 37 208 [56%] were female; 46 106 [69.9%] were White). Patients exposed to thyrotoxicosis had cognitive disorder incidence of 11.0% (95% CI, 8.4%-14.2%) by age 75 years vs 6.4% (95% CI, 6.0%-6.8%) for those not exposed. After adjustment, all-cause thyrotoxicosis was significantly associated with risk of cognitive disorder diagnosis (adjusted hazard ratio, 1.39; 95% CI, 1.18-1.64; P < .001) across age groups. When stratified by cause and severity, exogenous thyrotoxicosis remained a significant risk factor (adjusted hazard ratio, 1.34; 95% CI, 1.10-1.63; P = .003) with point estimates suggestive of a dose response. Conclusions and Relevance: In this cohort study among patients 65 years and older, a low TSH level from either endogenous or exogenous thyrotoxicosis was associated with higher risk of incident cognitive disorder. Iatrogenic thyrotoxicosis is a common result of thyroid hormone therapy. With thyroid hormone among the most common prescriptions in the US, understanding the negative effects of overtreatment is critical to help guide prescribing practice.

Comparative assessment of Alzheimer's disease-related biomarkers in plasma and neuron-derived extracellular vesicles: a nested case-control study.

Introduction: Alzheimer's disease (AD) is currently defined according to biomarkers reflecting the core underlying neuropathological processes: Aß deposition, Tau, and neurodegeneration (ATN). The soluble phase of plasma and plasma neuron-derived extracellular vesicles (NDEVs) are increasingly being investigated as sources of biomarkers. The aim of this study was to examine the comparative biomarker potential of these two biofluids, as well as the association between respective biomarkers. Methods: We retrospectively identified three distinct diagnostic groups of 44 individuals who provided samples at baseline and at a mean of 3.1 years later; 14 were cognitively unimpaired at baseline and remained so (NRM-NRM), 13 had amnestic MCI that progressed to AD dementia (MCI-DEM) and 17 had AD dementia at both timepoints (DEM-DEM). Plasma NDEVs were isolated by immunoaffinity capture targeting the neuronal markers L1CAM, GAP43, and NLGN3. In both plasma and NDEVs, we assessed ATN biomarkers (Aß42, Aß40, total Tau, P181-Tau) alongside several other exploratory markers. Results: The Aß42/Aß40 ratio in plasma and NDEVs was lower in MCI-DEM than NRM-NRM at baseline and its levels in NDEVs decreased over time in all three groups. Similarly, plasma and NDEV-associated Aß42 was lower in MCI-DEM compared to NRM-NRM at baseline and its levels in plasma decreased over time in DEM-DEM. For NDEV-associated proBDNF, compared to NRM-NRM, its levels were lower in MCI-DEM and DEM-DEM at baseline, and they decreased over time in the latter group. No group differences were found for other exploratory markers. NDEV-associated Aß42/Aß40 ratio and proBDNF achieved the highest areas under the curve (AUCs) for discriminating between diagnostic groups, while proBDNF was positively associated with Mini-Mental State Examination (MMSE) score. No associations were found between the two biofluids for any assessed marker. Discussion: The soluble phase of plasma and plasma NDEVs demonstrate distinct biomarker profiles both at a single time point and longitudinally. The lack of association between plasma and NDEV measures indicates that the two types of biofluids demonstrate distinct biomarker signatures that may be attributable to being derived through different biological processes. NDEV-associated proBDNF may be a useful biomarker for AD diagnosis and monitoring.

Precision Medicine for Preventing Alzheimer's Disease: Analysis of the ADAPT Study.

BACKGROUND: The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was the first-ever large-scale anti-inflammatory prevention trial targeting Alzheimer's disease. OBJECTIVE: The overall goal of this study was to evaluate predictive blood biomarker profiles that identified individuals most likely to be responders on NSAID treatment or placebo at 12 and 24 months. METHODS: Baseline (n = 193) and 12-month (n = 562) plasma samples were assayed. The predictive biomarker profile was generated using SVM analyses with response on treatment (yes/no) as the outcome variable. RESULTS: Baseline (AUC = 0.99) and 12-month (AUC = 0.99) predictive biomarker profiles were highly accurate in predicting response on Celecoxib arm at 12 and 24 months. The baseline (AUC = 0.95) and 12-month (AUC = 0.9) predictive biomarker profile predicting response on Naproxen were also highly accurate at 12 and 24 months. The baseline (AUC = 0.93) and 12-month (AUC = 0.99) predictive biomarker profile was also highly accurate in predicting response on placebo. As with our prior work, the profiles varied by treatment arm. CONCLUSIONS: The current results provide additional support for a precision medicine model for treating and preventing Alzheimer's disease.

Excitatory Neurons Derived from Human-Induced Pluripotent Stem Cells Show Transcriptomic Differences in Alzheimer's Patients from Controls.

The recent advances in creating pluripotent stem cells from somatic cells and differentiating them into a variety of cell types is allowing us to study them without the caveats associated with disease-related changes. We generated induced Pluripotent Stem Cells (iPSCs) from eight Alzheimer's disease (AD) patients and six controls and used lentiviral delivery to differentiate them into excitatory glutamatergic neurons. We then performed RNA sequencing on these neurons and compared the Alzheimer's and control transcriptomes. We found that 621 genes show differences in expression levels at adjusted p < 0.05 between the case and control derived neurons. These genes show significant overlap and directional concordance with genes reported from a single-cell transcriptome study of AD patients; they include five genes implicated in AD from genome-wide association studies and they appear to be part of a larger functional network as indicated by an excess of interactions between them observed in the protein-protein interaction database STRING. Exploratory analysis with Uniform Manifold Approximation and Projection (UMAP) suggests distinct clusters of patients, based on gene expression, who may be clinically different. Our research outcomes will enable the precise identification of distinct biological subtypes among individuals with Alzheimer's disease, facilitating the implementation of tailored precision medicine strategies.

Utility of amyloid PET Imaging in a Memory Clinic.

There is greater interest in amyloid biomarker for the diagnosis of Alzheimer disease (AD) with the recent Food and Drug Administration approval of amyloid-targeted therapy. The goal of this study was to assess the clinical utility of amyloid positron emission tomography (PET) in clinically ambiguous cases of cognitive impairment by examining outcomes of patients enrolled in the Imaging Dementia-Evidence of Amyloid Scanning study at 2 academic institutions. Of the 112 patients in the study, 66.1% (n=74) of patients had a positive amyloid PET scan, and 33.96% (n=38) had a negative amyloid PET scan. Lower cognitive test scores were predictive of positive amyloid PET scan ( P =0.001). Eighty-two percent (92/112) of the patients were seen for follow-up. Of the 30 patients with negative amyloid PET scan results, 90% had a diagnosis of non-AD etiology after receiving the negative results, suggesting a negative amyloid scan can be used to rule out AD diagnosis.

Prevalence of Hearing Loss and Hearing Aid Use Among US Medicare Beneficiaries Aged 71 Years and Older.

Importance: National prevalence estimates are needed to guide and benchmark initiatives to address hearing loss. However, current estimates are not based on samples that include representation of the oldest old US individuals (ie, aged ≥80 years), who are most at-risk of having hearing loss. Objective: To estimate the prevalence of hearing loss and hearing aid use by age and demographic covariates in a large, nationally representative sample of adults aged 71 years and older. Design, Setting, and Participants: In this cohort study, prevalence estimates of hearing loss by age, gender, race and ethnicity, education, and income were computed using data from the 2021 National Health Aging and Trends Study. Survey weights were applied to produce nationally representative estimates to the US older population. Data were collected from June to November 2021 and were analyzed from November to December 2022. Main Outcomes and Measures: Criterion-standard audiometric measures of hearing loss and self-reported hearing aid use. Results: In this nationally representative sample of 2803 participants (weighted estimate, 33.1 million individuals) aged 71 years or older, 38.3% (95% CI, 35.5%-41.1%) were aged 71 to 74 years, 36.0% (95% CI, 33.1%-38.8%) were aged 75 to 79 years, 13.8% (95% CI, 12.6%-14.9%) were aged 80 to 84 years, 7.9% (95% CI, 7.2%-8.6%) were aged 85 to 89 years, and 4.0% (95% CI, 3.5%-4.6%) were aged 90 years or older; 53.5% (95% CI, 50.9%-56.1%) were female and 46.5% (95% CI, 43.9%-49.1%) were male; and 7.5% (95% CI, 6.2%-8.7%) were Black, 6.5% (95% CI, 4.4%-8.7%) were Hispanic, and 82.7% (95% CI, 79.7%-85.6%) were White. An estimated 65.3% of adults 71 years and older (weighted estimate, 21.5 million individuals) had at least some degree of hearing loss (mild, 37.0% [95% CI, 34.7%-39.4%]; moderate, 24.1% [95% CI, 21.9%-26.4%]; and severe, 4.2% [95% CI, 3.3%-5.3%]). The prevalence was higher among White, male, lower-income, and lower education attainment subpopulations and increased with age, such that 96.2% (95% CI, 93.9%-98.6%) of adults aged 90 years and older had hearing loss. Among those with hearing loss, only 29.2% (weighted estimate, 6.4 million individuals) used hearing aids, with lower estimates among Black and Hispanic individuals and low-income individuals. Conclusions and Relevance: These findings suggest that bilateral hearing loss is nearly ubiquitous among older US individuals, prevalence and severity increase with age, and hearing aid use is low. Deeper consideration of discrete severity measures of hearing loss in this population, rather than binary hearing loss terminology, is warranted.

Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults.

BACKGROUND: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. RESULTS: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. CONCLUSION: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.