Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Feasibility, Acceptability, and Impact of a self-guided e-learning Memory and Brain Health Promotion Program for Healthy Older Adults.

OBJECTIVES: To examine the feasibility (e.g., completion rate), acceptability (e.g., satisfaction), and participant-reported impact (e.g., memory concerns, behavior change, goal attainment) of a self-guided, e-learning adaptation of a validated, facilitator-guided, in-person memory intervention for older adults. METHODS: Participants were 139 healthy older adults (mean age: 73 ± 7, 73% women). Participation tracking and pre/post questionnaires embedded within the e-learning program were used to assess feasibility, acceptability, and impact. RESULTS: Sixty-eight percent of participants completed the program. Anonymous feedback data indicated a high level of satisfaction with the program, the pace and clarity of the learning modules, and the user interface. Suggested improvements included offering more interaction with others and addressing minor platform glitches. There was a 41% decrease in the prevalence of concern about memory changes from baseline to posttest. The majority of participants reported an increase in use of memory strategies and uptake of health-promoting lifestyle behaviors. All participants reported moderate-to-high satisfaction with personal goal attainment. CONCLUSIONS: The program demonstrated good feasibility, acceptability, and lead to reduction in age-related memory concerns. CLINICAL IMPLICATIONS: Self-guided, e-learning programming shows promise for fostering positive adaptation to age-related memory changes and improving the uptake of evidence-based strategies to promote brain health among older adults.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

BACKGROUND AND PURPOSE: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. METHODS: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. RESULTS: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. CONCLUSION: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

Neurocognitive Outcome Following Recovery from Severe Acute Respiratory Syndrome - Coronavirus-1 (SARS-CoV-1).

OBJECTIVE: Severe acute respiratory syndrome (SARS) is a highly contagious viral respiratory illness associated with hypoxia and dyspnea. Many of those who contracted and recovered from SARS during the 2002-2003 outbreak reported persistent physical, psychological, and cognitive difficulties. Here, we investigated the residual influences of SARS on cognition for a subset of healthcare professionals who recovered and were referred for neuropsychological evaluation through their workplace insurance. METHOD: Twenty-eight healthcare professionals were evaluated on neuropsychological and mood functioning approximately 1.5 years post-recovery from a severe respiratory illness. Test scores were compared with age-matched normative data, and correlations were examined between mood, self-report memory scales, subjective complaints (e.g., poor concentration, pain, fatigue), illness severity (i.e., length of hospitalization, oxygen use during hospital stay), and cognitive performance. RESULTS: Participants performed within age expectations on the majority of cognitive measures including overall memory ability. Although processing speed was generally within normal limits, 43% showed significant speed-accuracy trade-offs favoring accuracy over maintaining speed. Deficits were observed on measures of complex attention, such as working memory and the ability to sustain attention under conditions of distraction. Participants endorsed poorer memory ability than same-age peers on a meta-memory measure and mild to moderate depression and anxiety symptoms. Objective test performance was largely uncorrelated with self-reports, mood, or illness severity, except for moderate correlations between complex attention and participants' subjective ratings of Everyday Task-Oriented Memory. CONCLUSIONS: These findings demonstrate specific long-term cognitive deficits associated with SARS and provide further evidence of the cognitive effects of hypoxic illnesses.

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative.

OBJECTIVES: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders? METHODS/DESIGN: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. RESULTS: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. CONCLUSIONS: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions.

Initiation and maintenance of behaviour change to support memory and brain health in older adults: A randomized controlled trial.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02087137.

An evaluation of memory and attention in BRCA mutation carriers using an online cognitive assessment tool.

BACKGROUND: The objective of this study was to evaluate the impact of various surgical, hormonal, and lifestyle factors on memory and attention in women with a BRCA1 or BRCA2 mutation. METHODS: BRCA mutation carriers enrolled in a longitudinal study were invited to complete an online brain health assessment tool designed to screen for cognitive deficits. Four measures of memory and executive attention were assessed individually, and an overall score was compiled adjusting for age. Exposures, including preventive surgery, hormone use, and lifestyle factors, were captured by questionnaire. Performance on each of the 5 subtasks was analyzed according to various exposures. Analysis of covariance was used to compare overall scores. RESULTS: In total, 880 women completed the online cognitive assessment. The average age of the participants was 54 years (range, 23-86 years). The mean overall test score was 54.4 (range, 0-93). The individual subtask scores declined with age at test completion (P < .0001) and increased with level of education (P ≤ .01). Women who underwent a preventive oophorectomy had a significantly higher overall score compared with women who did not undergo this surgery (55.5 vs 50.5; P = .01). Reconstructive breast surgery was also associated with a higher overall score (56.5 vs 52.3; P = .005). Chemotherapy and hormone-replacement therapy were not predictive of the overall score. CONCLUSIONS: These findings are reassuring to high-risk women who undergo early surgical menopause for their cancer predisposition. Further studies are needed to evaluate cognitive function over time when memory deficits become more prevalent.

The Impact of Memory Change on Everyday Life Among Older Adults: Association with Cognition and Self-Reported Memory.

OBJECTIVES: Many older adults experience memory changes that can have a meaningful impact on their everyday lives, such as restrictions to lifestyle activities and negative emotions. Older adults also report a variety of positive coping responses that help them manage these changes. The purpose of this study was to determine how objective cognitive performance and self-reported memory are related to the everyday impact of memory change. METHODS: We examined these associations in a sample of 94 older adults (age 60-89, 52% female) along a cognitive ability continuum from normal cognition to mild cognitive impairment. RESULTS: Correlational analyses revealed that greater restrictions to lifestyle activities (|rs| = .36-.66), more negative emotion associated with memory change (|rs| = .27-.76), and an overall greater burden of memory change on everyday living (|rs| = .28-.61) were associated with poorer objective memory performance and lower self-reported memory ability and satisfaction. Performance on objective measures of executive attention was unrelated to the impact of memory change. Self-reported strategy use was positively related to positive coping with memory change (|r| = .26), but self-reported strategy use was associated with more negative emotions regarding memory change (|r| = .23). CONCLUSIONS: Given the prevalence of memory complaints among older adults, it is important to understand the experience of memory change and its impact on everyday functioning in order to develop services that target the specific needs of this population.

Examining the factor structure of the Multifactorial Memory Questionnaire.

Many adults report memory changes as they age. The Multifactorial Memory Questionnaire (MMQ) measures different aspects of self-reported memory, including satisfaction with one's memory, self-appraisal of memory ability, and compensatory strategy use. This questionnaire has been extensively used for clinical and research purposes, with studies reporting differences in the factor structure (three or four factors) underlying this measure. The current study evaluates previously reported factor configurations of the MMQ using best measurement practices. Confirmatory factor analyses were conducted on data from 560 cognitively - normal adults, ranging in age from 50 to 90 years old. Our results demonstrate support for both 3-factor model (with Satisfaction, Ability and Strategy scales) and 4-factor model structure (with Satisfaction, Ability, Internal Strategy and External Strategy scales) of this instrument. These results harmonise the existing literature which, in separate studies using exploratory analyses, supports the validity of one model or the other. The confirmation of multiple Strategy scales will provide clinicians and researchers with additional relevant information about how older adults compensate for their memory changes, enabling a broader understanding of the experience of age-related memory change. We contextualise these results within existing research identifying conceptual differences between internal and external strategy implementation.

Assessing one's sense of normalcy: psychometric properties of the subjective normalcy inventory.

OBJECTIVES: Individuals facing a personal challenge, such as age-related memory changes, may feel that their experiences are abnormal or pathological. Previous qualitative research on a group intervention that focuses on memory changes in older adulthood revealed that one of the greatest benefits derived by participants was the realization that their experience with memory changes was normal. In order to quantify this experience, we developed and validated a new measure, the 26-item Subjective Normalcy Inventory (SNI). METHOD: Reliability and validity were assessed with a sample of 167 community-dwelling adults between the ages of 55 and 90. Questionnaire responsiveness was assessed with an additional sample of 29 older adults who completed a 5-session memory intervention program known to cultivate normalization. RESULTS: The SNI exhibited a two-factor structure, excellent test-retest reliability, ICC = .79, excellent internal consistency, Cronbach's α = .91, and good convergent, |rs| = .46-.58, and discriminant, rs = .02-.06, validity. The measure was also responsive to change, as participants who completed the memory intervention program reported a greater sense of normalcy relative to nonintervention controls, η2p = 0.17. CONCLUSION: The SNI has the potential to provide novel and useful outcome information for interventions designed to improve one's sense of normalcy and may be applied in both clinical and research settings. The SNI can also be modified, validated, and used to assess subjective normalcy with respect to other personal challenges outside of memory and attention changes.

Episodic memory decline is associated with deficits in coherence of discourse.

This study investigates coherence of discourse in the production of autobiographical narratives by individuals with aMCI. Autobiographical interviews were analyzed to determine whether reduced episodic recall was related to deficits in discourse coherence. A coherence rating scale was used to evaluate relatedness of the autobiographical details produced by participants to the topic of discourse. Interviews were transcribed, segmented into details, and divided into sets of episodic, semantic, or supplementary information, which were subsequently analysed with the coherence rating scale. We predicted that the known episodic deficits observed in aMCI could also affect the retrieval of coherent episodic information. The results revealed deficits in coherence could be found in both episodic and semantic information in the aMCI group. These results suggest that the cognitive deficits experienced by individuals with aMCI may go beyond their known difficulty in recalling episodic details, as they also affect the controlled retrieval of both episodic and semantic information.

Methods for Improving Screening for Vascular Cognitive Impairment Using the Montreal Cognitive Assessment.

BACKGROUND: Vascular cognitive impairment (VCI) post-stroke is frequent but may go undetected, which highlights the need to better screen cognitive functioning following a stroke. AIM: We examined the clinical utility of the Montreal Cognitive Assessment (MoCA) in detecting cognitive impairment against a gold-standard neuropsychological battery. METHODS: We assessed cognitive status with a comprehensive battery of neuropsychological tests in 161 individuals who were at least 3-months post-stroke. We used receiver operating characteristic (ROC) curves to identify two cut points for the MoCA to maximize sensitivity and specificity at a minimum 90% threshold. We examined the utility of the Symbol Digit Modalities Test, a processing speed measure, to determine whether this additional metric would improve classification relative to the MoCA total score alone. RESULTS: Using two cut points, 27% of participants scored ≤ 23 and were classified as high probability of cognitive impairment (sensitivity 92%), and 24% of participants scored ≥ 28 and were classified as low probability of cognitive impairment (specificity 91%). The remaining 48% of participants scored from 24 to 27 and were classified as indeterminate probability of cognitive impairment. The addition of a processing speed measure improved classification for the indeterminate group by correctly identifying 65% of these individuals, for an overall classification accuracy of 79%. CONCLUSIONS: The utility of the MoCA in detecting cognitive impairment post-stroke is improved when using a three-category approach. The addition of a processing speed measure provides a practical and efficient method to increase confidence in the determined outcome while minimally extending the screening routine for VCI.

The measurement of participant-reported memory across diverse populations and settings: a systematic review and meta-analysis of the Multifactorial Memory Questionnaire.

The Multifactorial Memory Questionnaire (MMQ) is a participant-reported measure of memory satisfaction, ability, and strategy use. Initially validated with healthy older adults, it has since been used in many different populations and settings for a variety of purposes. We conducted a systematic review and meta-analysis of the measurement properties of the MMQ across multiple, diverse studies. METHODS: The study was designed using the Consensus-Based Standards for the Selection of Health Measurement Instruments and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We calculated aggregate statistics and evaluated the methodological quality of 29 studies retrieved from PsycINFO, MEDLINE, EMBASE, and Web of Science. RESULTS: Analyses revealed high-quality evidence for internal consistency, stability, measurement error, convergent validity, and known-groups validity of the three MMQ scales. There was moderate-quality evidence for responsiveness and structural validity, with some studies identifying separate factors for internal and external memory strategy use. Measurement properties were similar across languages, participant samples, and study designs. CONCLUSIONS: The MMQ is a valid, reliable, and responsive measure across diverse settings and populations. Future research is needed to determine whether more detailed information can be obtained from the scales, specifically, internal versus external strategy use.

Comparable achievement of client-identified, self-rated goals in intervention and no-intervention groups: reevaluating the use of Goal Attainment Scaling as an outcome measure.

Goal Attainment Scaling (GAS) is widely used as a measure of client-centered outcomes in clinical interventions. There are few well-controlled studies using GAS, however, and this limits the conclusions that can be drawn about the determinants of goal attainment post-intervention. In collaboration with researchers, 67- community-dwelling older adults used GAS to establish individualised goals for lifestyle change and memory strategy use in a randomised controlled trial of a multidimensional memory program (ClinicalTrials.gov: NCT02087137). Participants were allocated to an intervention or no-contact control group. Goal attainment was self-rated by participants at baseline, immediate post-intervention, and six-week follow-up. A mixed-model analysis of variance revealed a main effect of time, but no main effect of group and no interaction between time and group. In both the intervention and control groups, respectively, T-scores increased from baseline (Ms = 37 and 37) to post-intervention (Ms = 52 and 50) and were stable at follow-up (Ms = 52 and 51). Results were similar using ordinal data interpretation. Comparable goal attainment in participants receiving intervention versus no intervention underscores the importance of control groups in evaluation studies utilising GAS as an outcome measure, and supports a possible therapeutic contribution of setting and rating goals with GAS.

'Accepting where I'm at' - a qualitative study of the mechanisms, benefits, and impact of a behavioral memory intervention for community-dwelling older adults.

OBJECTIVE: Gain novel, in-depth insight into therapeutic mechanisms, benefits, and impact of a multi-modal behavioral memory intervention for older adults with concerns about memory. METHODS: Participants were11 community-dwelling older adults (aged 63-88) who completed the Memory and Aging Program, an evidence-based multi-modal group intervention for normal age-related memory change. Semi-structured interviews were administered post-intervention. Responses were analyzed using qualitative content analysis until meaningful themes were agreed upon. RESULTS: Analyses revealed a main theme of normalization as the overarching benefit of participation. The mechanism for this comprised both specific intervention content and the process of participating with others. A positive impact of the intervention was demonstrated at emotional (feelings of reassurance, hope, and confidence) and functional (increasing motivation for lifestyle change) levels; for some, there was a direct link between emotion and function. CONCLUSION: This study highlighted a single, prominent therapeutic benefit of normalization, illustrated a dual mechanism for achieving this, and characterized a nuanced inter-relationship of the emotional and functional impact of the intervention for participants. Results support the notion that group behavioral interventions can educate, empower, and promote psychological well-being in older adults and may be an effective avenue to reduce risk of disease and promote sustained functional independence.

Taoist Tai Chi® and Memory Intervention for Individuals with Mild Cognitive Impairment.

OBJECTIVE: It was hypothesized that a combined Taoist Tai Chi (TTC) and a memory intervention program (MIP) would be superior to a MIP alone in improving everyday memory behaviors in individuals with amnestic mild cognitive impairment (aMCI). A secondary hypothesis was that TTC would improve cognition, self-reported health status, gait, and balance. METHOD: A total of 48 individuals were randomly assigned to take part in MIP + TTC or MIP alone. The TTC intervention consisted of twenty 90 min sessions. Outcome measures were given at baseline, and after 10 and 22 weeks. RESULTS: Both groups significantly increased their memory strategy knowledge and use, ratings of physical health, processing speed, everyday memory, and visual attention. No preferential benefit was found for individuals in the MIP + TTC group on cognition, gait, or balance measures. CONCLUSIONS: Contrary to expectations, TTC exercise did not specifically improve cognition or physical mobility. Explanations for null findings are explored.

Naturalistic Action Performance Distinguishes Amnestic Mild Cognitive Impairment from Healthy Aging.

Individuals with amnestic mild cognitive impairment (aMCI) show minor decrements in their instrumental activities of daily living (IADL). Sensitive measures of IADL performance are needed to capture the mild difficulties observed in aMCI groups. Routine naturalistic actions (NAs) are familiar IADL-type activities that require individuals to enact everyday tasks such as preparing coffee. In the current study we examined the extent to which NAs could be used to help facilitate differential diagnosis of aMCI relative to composite measures of episodic memory, semantic knowledge, and executive function. Healthy older adults (n=24) and individuals with aMCI (n=24) enacted two highly familiar NAs and completed tests of episodic memory, semantic knowledge, and executive function. Binary logistic regression was used to predict group membership (aMCI vs. control participants). The regression analyses indicated that NA performance could reliably predict group membership, over and above measures of cognitive functioning. These findings indicated that NA performance can be used to help facilitate differential diagnosis of healthy aging and aMCI and used as an outcome measure in intervention studies.

Evaluating functional abilities within the context of memory assessment: A practice survey of neuropsychologists.

Objective: Functioning in daily life is an important consideration when differentiating between individuals with normal cognition, mild neurocognitive disorder, and major neurocognitive disorder. Despite this, there is no gold standard measurement approach for assessing functional abilities and few guidelines on how to do so. The objective of this study was to examine neuropsychologists' practices regarding the assessment of functional abilities across the spectrum of memory ability. Method: A total of 278 psychologists who routinely conduct neuropsychological assessments completed an online survey (estimated 15% response rate) querying their practices and perspectives with respect to the assessment of functional abilities. Results: Respondents identified that changes to several components of daily functioning, including activities of daily living, were important when evaluating functional abilities. Respondents reported utilizing a variety of instruments to assess functioning, with an overwhelming majority indicating the use of semi-structured interviews. Although most respondents are satisfied with existing tools, a quarter of respondents felt strongly that there was a need for more instruments of everyday functioning. Respondents further indicated that their recommendations to patients, particularly regarding compensatory strategies and follow-up with other professionals, were informed by results of their functional assessment. Conclusions: Overall, our survey results indicate that neuropsychologists perceive multiple factors of daily life to be important considerations when evaluating functioning, use a variety of techniques to assess functioning, and perceive a need for more measures of functional abilities.

Sex Matters: Association with Superager Classification and Risk Factors.

Superagers are 80 to 89-year-olds with average or better cognition and memory equivalent to individuals 20 to 30 years younger. As sex and modifiable lifestyle/health factors influence cognitive aging and dementia risk, we examined their impact on superager status. Data from participants (n = 469; 67% female) aged 80-89 years old were analyzed from an online database that included demographic and dementia risk factors, and performance on tasks assessing working memory, cognitive inhibition, associative memory, and set shifting. Cross-sectional comparisons were made between superagers and those with typical-for-age cognitive abilities (typical-agers) to examine relationships between sex, superager status, and dementia risk factors. Females performed better than age-matched males on the associative memory task in the 50-69 years old group used for normative comparisons, and in the 80-89 years old group (ps < .001). More females than males were classified as superagers using non-sex-stratified normative comparisons (p = .009), and in sex-stratified normative comparisons (p = .022). Total weighted dementia risk reduced odds of superager status (OR = 0.199, 95% CI [0.046, 0.829]). Other lifestyle dementia risk factors were unrelated to superager status or could not be tested due to low endorsement. The findings support observations that superaging is more common in females, even when controlling for sex differences in memory performance. Future studies of superagers should account for sex differences. Results support being ambitious about dementia prevention, as having fewer modifiable dementia risk factors may be positively associated with superager status.

History of traumatic brain injury is associated with increased grey-matter loss in patients with mild cognitive impairment.

OBJECTIVES: To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). METHODS: 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function. RESULTS: At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1-2%, 90%HDI [-0.01%: -0.001%], probability of direction (PD) = 90-99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [-5.17%: 43.2%], PD = 91.7%). CONCLUSIONS: Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI.