Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

?It's all communication': Family members' perspectives on the communication needs for themselves and their relatives with primary progressive aphasia.

BACKGROUND: Communication disabilities, such as primary progressive aphasia (PPA), impact family members as well as the individuals with the condition. To provide adequate communication care to people with PPA (PwPPA) and their family members, it is crucial to understand the communication needs from the family members' perspectives. To date, research on the communication needs of people with primary progressive aphasia and their family members from the perspectives of family members has been limited. AIMS: The specific research objectives were to explore (a) the communication needs pertaining to PwPPA in the early, middle and late stages; and (b) the communication needs pertaining to family members of PwPPA in the early, middle and late stages, from the perspectives of family members. METHODS & PROCEDURES: This study employed a qualitative description approach, underpinned by the pragmatic paradigm. Data collection involved semi-structured qualitative interviews with eight family members (relatives of four individuals with the logopenic variant of PPA, of two individuals with the nonfluent variant of PPA, of one individual with the semantic variant of PPA and of one individual with mixed PPA). Qualitative content analysis was used to identify codes and categories in relation to the research objectives. OUTCOMES & RESULTS: Qualitative content analysis revealed eight categories of communication needs pertaining to the PwPPA: person-specific needs; diagnosis and disclosure; general communication difficulties; impact on communication in everyday life; impact on cognition; impact on psychosocial well-being; impact on person's dignity and autonomy; and future planning. Six categories were identified pertaining to the family members: information about and awareness of PPA; impact of communication difficulties on family/others; increased responsibilities for the family in everyday life; impact on psychosocial well-being; and future planning. CONCLUSIONS & IMPLICATIONS: This investigation has expanded our knowledge in the area by providing insights about communication needs which speech-language pathologists and other health professionals should be aware of and take into account when providing communication care to PwPPA and their families. WHAT THIS PAPER ADDS: What is already known on the subject Person- and family-centred communication care is optimally guided by the person's and family's needs and values. Research on communication care for people with primary progressive aphasia has underscored the inclusion of family members. Previous research has investigated the impact and experiences of living with primary progressive aphasia from the family member perspective. What this paper adds to existing knowledge To date, research focusing on identifying the communication needs of people with primary progressive aphasia and their family members from the perspective of family members is limited. This study adds the family members' perspectives on the communication needs pertaining to themselves and their relatives with primary progressive aphasia in the early, middle and late stages of primary progressive aphasia. What are the potential or clinical implications of this work? Several clinical implications have been raised. Family members experience communication needs for themselves and should be included as recipients of communication care. Clinicians supporting people with primary progressive aphasia should be cognizant of the impact of communication fatigue on everyday life and therapy tasks. Communication care for this population should include communication partner training, support for psychosocial well-being and support with communication around future planning.

A Systematic Review of the Genetics and Pathology of Psychosis in Frontotemporal Dementia.

OBJECTIVES: Frontotemporal dementia (FTD) patients frequently present with psychosis, which complicates diagnosis and management. In this study, we aim to examine the relationship between psychosis and the most common genetic mutations predisposing to FTD, and in the different pathological subtypes of FTD. DESIGN: We conducted a systematic review, searching the literature up to December 2022, and reviewed 50 articles that met our inclusion criteria. From the reviewed articles, we extracted and summarized data regarding the frequency of psychosis and patient characteristics in each major genetic and pathological subtype of FTD. RESULTS: Among FTD patients with confirmed genetic mutations or pathological diagnosss, the frequency of psychosis was 24.2%. Among the genetic mutation carriers, C9orf72 mutation carriers had the highest frequency of psychosis (31.4%), whereas GRN (15.0%) and MAPT (9.2%) mutation carriers had lower frequencies of psychosis. MAPT mutation carriers notably developed psychosis at a younger age compared to other genetic groups. The most common psychotic symptoms were delusions among C9orf72 carriers and visual hallucinations among GRN mutation carriers. Among the pathological subtypes, 30% of patients with FUS pathology, 25.3% of patients with TDP-43 pathology, and 16.4% of patients with tau pathology developed psychosis. In the TDP-43 group, subtype B pathology was the most common subtype reported in association with psychosis. CONCLUSION: Our systematic review suggests a high frequency of psychosis in specific subgroups of FTD patients. Further studies are required to understand the structural and biological underpinnings of psychosis in FTD.

Health System Change for Alzheimer's Disease-Modifying Therapies in Canada: Beginning the Discussion.

Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for 60%-70% of patients with dementia, and it is estimated that over one million Canadians will be living with dementia by 2030. Disease-modifying therapies (DMTs) targeting the underlying pathophysiology of AD are currently in development. Several models have demonstrated that the potential arrival of Alzheimer's DMTs will most likely overwhelm the already-constrained Canadian healthcare system. Canada does not have a strategy to address the extensive requirements of using DMTs, including providing an early diagnosis of AD, confirming DMT eligibility via amyloid biomarkers, and conducting ongoing treatment monitoring. Thus, a multidisciplinary group of experts involved in AD care in Canada gathered to review (1) the current barriers to diagnosis and management of AD; (2) how existing clinic models, including those used in multiple sclerosis (MS), could be applied to address key barriers in AD; and (3) how to design and implement optimal care pathways in the future. The actions outlined in this review will help clinicians and healthcare systems improve readiness to integrate the use of disease-modifying therapies in Alzheimer's disease, if such therapies are approved in Canada.

Brain Imaging Abnormalities in Mixed Alzheimer's and Subcortical Vascular Dementia.

BACKGROUND: A large proportion of Alzheimer's disease (AD) patients have coexisting subcortical vascular dementia (SVaD), a condition referred to as mixed dementia (MixD). Brain imaging features of MixD presumably include those of cerebrovascular disease and AD pathology, but are difficult to characterize due to their heterogeneity. OBJECTIVE: To perform an exploratory analysis of conventional and non-conventional structural magnetic resonance imaging (MRI) abnormalities in MixD and to compare them to those observed in AD and SVaD. METHODS: We conducted a cross-sectional, region-of-interest-based analysis of 1) hyperintense white-matter signal abnormalities (WMSA) on T2-FLAIR and hypointense WMSA on T1-weighted MRI; 2) diffusion tensor imaging; 3) quantitative susceptibility mapping; and 4) effective transverse relaxation rate (R2*) in N = 17 participants (AD:5, SVaD:5, MixD:7). General linear model was used to explore group differences in these brain imaging measures. RESULTS: Model findings suggested imaging characteristics specific to our MixD group, including 1) higher burden of WMSAs on T1-weighted MRI (versus both AD and SVaD); 2) frontal lobar preponderance of WMSAs on both T2-FLAIR and T1-weighted MRI; 3) higher fractional anisotropy values within normal-appear white-matter tissues (versus SVaD, but not AD); and 4) lower R2* values within the T2-FLAIR WMSA areas (versus both AD and SVaD). CONCLUSION: These findings suggest a preliminary picture of the location and type of brain imaging characteristics associated with MixD. Future imaging studies may employ region-specific hypotheses to distinguish MixD more rigorously from AD or SVaD.

Expert elicitation of risk factors for progression to dementia in individuals with mild cognitive impairment.

INTRODUCTION: This study assesses experts' beliefs about important predictors of developing dementia in persons with mild cognitive impairment (MCI). METHODS: Structured expert elicitation, a methodology to quantify expert knowledge, was used to elicit the most important risk factors for developing dementia. We recruited 11 experts (6 neurologists, 3 geriatricians, and 2 psychiatrists). Ten experts fully participated in introductory meetings, two rounds of surveys, and discussion meetings. The data from these ten experts were utilized for this study. RESULTS: The expert elicitation identified age, CSF analysis, fluorodeoxyglucose-positron emission tomography (FDG-PET) findings, hippocampal atrophy, MoCA (or MMSE) score, parkinsonism, apathy, psychosis, informant report of cognitive symptoms, and global atrophy as the ten most important predictors of progressing to dementia in persons with MCI. DISCUSSION: Several dementia predictors are not routinely collected in existing registries, observational studies, or usual care. This might partially explain the low uptake of existing published dementia risk scores in clinical practice.

The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology.

INTRODUCTION: It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase. METHODS: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72. RESULTS: We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol. DISCUSSION: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

The role of exercise in mitigating subcortical ischemic vascular cognitive impairment.

Subcortical ischemic vascular cognitive impairment (SIVCI) is the most preventable form of cognitive dysfunction. There is converging evidence from animal and human studies that indicate vascular injury as the primary cause of SIVCI. Currently, there are no curative pharmaceutical treatments for vascular dementia; however, exercise may be a promising strategy to combat SIVCI. This review will focus on the role of exercise as a strategy to prevent or slow the progression of SIVCI, with particular emphasis on the mechanisms by which exercise may improve cerebrovascular function. We propose that exercise may be an effective strategy to combat SIVCI by improving cognitive function, increasing the bioavailability of neurotrophins, stimulating endothelial function, and controlling vascular risk factors. This article is part of the Special Issue "Vascular Dementia".

Associations between cerebral amyloid and changes in cognitive function and falls risk in subcortical ischemic vascular cognitive impairment.

BACKGROUND: To determine the association between amyloid-beta (Aß) plaque deposition and changes in global cognition, executive functions, information processing speed, and falls risk over a 12-month period in older adults with a primary clinical diagnosis of subcortical ischemic vascular cognitive impairment (SIVCI). METHODS: This is a secondary analysis of data acquired from a subset of participants (N = 22) who were enrolled in a randomized controlled trial of aerobic exercise (NCT01027858). The subset of individuals completed an 11C Pittsburgh compound B (PIB) scan. Cognitive function and falls risk were assessed at baseline, 6-months, and 12-months. Global cognition, executive functions, and information processing speed were measured using: 1) ADAS-Cog; 2) Trail Making Test; 3) Digit Span Test; 4) Stroop Test, and 5) Digit Symbol Substitution Test. Falls risk was measured using the Physiological Profile Assessment. Hierarchical multiple linear regression analyses determined the unique contribution of Aß on changes in cognitive function and falls risk at 12-months after controlling for experimental group (i.e. aerobic exercise training or usual care control) and baseline performance. To correct for multiple comparisons, we applied the Benjamini-Hochberg procedure to obtain a false discovery rate corrected threshold using alpha = 0.05. RESULTS: Higher PIB retention was significantly associated with greater decrements in set shifting (Trail Making Test, adjusted R2 = 35.3%, p = 0.002), attention and conflict resolution (Stroop Test, adjusted R2 = 33.4%, p = 0.01), and information processing speed (Digit Symbol Substitution Test, adjusted R2 = 24.4%, p = 0.001) over a 12-month period. Additionally, higher PIB retention was significantly associated with increased falls risk (Physiological Profile Assessment, adjusted R2 = 49.1%, p = 0.04). PIB retention was not significantly associated with change in ADAS-Cog and Verbal Digit Span Test (p > 0.05). CONCLUSIONS: Symptoms associated with SIVCI may be amplified by secondary Aß pathology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01027858 , December 7, 2009.

The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis.

BACKGROUND: Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. METHODS: PubMed, EMBASE and PsychINFO were queried for 'depression' and/or 'depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. RESULTS: We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. CONCLUSIONS: Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.

Exploring the effects of coexisting amyloid in subcortical vascular cognitive impairment.

BACKGROUND: Mixed pathology, particularly Alzheimer's disease with cerebrovascular lesions, is reported as the second most common cause of dementia. Research on mixed dementia typically includes people with a primary AD diagnosis and hence, little is known about the effects of co-existing amyloid pathology in people with vascular cognitive impairment (VCI). The purpose of this study was to understand whether individual differences in amyloid pathology might explain variations in cognitive impairment among individuals with clinical subcortical VCI (SVCI). METHODS: Twenty-two participants with SVCI completed an (11)C Pittsburgh compound B (PIB) position emission tomography (PET) scan to quantify global amyloid deposition. Cognitive function was measured using: 1) MOCA; 2) ADAS-Cog; 3) EXIT-25; and 4) specific executive processes including a) Digits Forward and Backwards Test, b) Stroop-Colour Word Test, and c) Trail Making Test. To assess the effect of amyloid deposition on cognitive function we conducted Pearson bivariate correlations to determine which cognitive measures to include in our regression models. Cognitive variables that were significantly correlated with PIB retention values were entered in a hierarchical multiple linear regression analysis to determine the unique effect of amyloid on cognitive function. We controlled for age, education, and ApoE ε4 status. RESULTS: Bivariate correlation results showed that PIB binding was significantly correlated with ADAS-Cog (p < 0.01) and MOCA (p < 0.01); increased PIB binding was associated with worse cognitive function on both cognitive measures. PIB binding was not significantly correlated with the EXIT-25 or with specific executive processes (p > 0.05). Regression analyses controlling for age, education, and ApoE ε4 status indicated an independent association between PIB retention and the ADAS-Cog (adjusted R-square change of 15.0%, Sig F Change = 0.03). PIB retention was also independently associated with MOCA scores (adjusted R-Square Change of 27.0%, Sig F Change = 0.02). CONCLUSION: We found that increased global amyloid deposition was significantly associated with greater memory and executive dysfunctions as measured by the ADAS-Cog and MOCA. Our findings point to the important role of co-existing amyloid deposition for cognitive function in those with a primary SVCI diagnosis. As such, therapeutic approaches targeting SVCI must consider the potential role of amyloid for the optimal care of those with mixed dementia. TRIAL REGISTRATION: NCT01027858.

Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Effect of white matter hyperintensity on medial temporal lobe atrophy in Alzheimer's disease.

BACKGROUND: Medial temporal atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), and white matter hyperintensities (WMH) are frequently observed on MRI of AD. The purpose of this study was to understand the role of WMH in MTA. METHODS: Subjects were 94 probable AD patients and 51 cognitively normal subjects. WMH was assessed based on the severity of deep WMH (DWMH) and periventricular WMH (PWMH). Each structural volume was evaluated using the Individual Brain Atlases from the Statistical Parametric Mapping Toolbox. RESULTS: There were no significant differences between subjects with and without WMH in terms of general cognitive function scales. Subjects with AD with WMH had decreased volume in the bilateral orbital frontal gyrus, frontal rectus gyrus, and olfactory gyrus, but not in the medial temporal lobes. After correcting for differences in DWMH, age and Clinical Dementia Rating Scale (CDR), AD with PWMH showed decreased volumes in the bilateral hippocampi. AD with PWMH showed worse scores on the Clinical Dementia Rating-Sum of Boxes and Barthel-ADL, and some frontal executive function tests. Those with DWMH did not show any reductions in the medial temporal lobes. CONCLUSION: WMH in AD is not associated with medial temporal lobe atrophy, but PWMH is independently correlated with hippocampal volume reduction.

White-matter abnormalities in presymptomatic GRN and C9orf72 mutation carriers.

A large proportion of familial frontotemporal dementia is caused by TAR DNA-binding protein 43 (transactive response DNA-binding protein 43 kDa) proteinopathies. Accordingly, carriers of autosomal dominant mutations in the genes associated with TAR DNA-binding protein 43 aggregation, such as Chromosome 9 open reading frame 72 (C9orf72) or progranulin (GRN), are at risk of later developing frontotemporal dementia. Brain imaging abnormalities that develop before dementia onset in mutation carriers may serve as proxies for the presymptomatic stages of familial frontotemporal dementia due to a genetic cause. Our study objective was to investigate brain MRI-based white-matter changes in predementia participants carrying mutations in C9orf72 or GRN genes. We analysed mutation carriers and their family member controls (noncarriers) from the University of British Columbia familial frontotemporal dementia study. First, a total of 42 participants (8 GRN carriers; 11 C9orf72 carriers; 23 noncarriers) had longitudinal T1-weighted MRI over ∼2 years. White-matter signal hypointensities were segmented and volumes were calculated for each participant. General linear models were applied to compare the baseline burden and the annualized rate of accumulation of signal abnormalities among mutation carriers and noncarriers. Second, a total of 60 participants (9 GRN carriers; 17 C9orf72 carriers; 34 noncarriers) had cross-sectional diffusion tensor MRI available. For each participant, we calculated the average fractional anisotropy and mean, radial and axial diffusivity parameter values within the normal-appearing white-matter tissues. General linear models were applied to compare whether mutation carriers and noncarriers had different trends in diffusion tensor imaging parameter values as they neared the expected age of onset. Baseline volumes of white-matter signal abnormalities were not significantly different among mutation carriers and noncarriers. Longitudinally, GRN carriers had significantly higher annualized rates of accumulation (estimated mean: 15.87%/year) compared with C9orf72 carriers (3.69%/year) or noncarriers (2.64%/year). A significant relationship between diffusion tensor imaging parameter values and increasing expected age of onset was found in the periventricular normal-appearing white-matter region. Specifically, GRN carriers had a tendency of a faster increase of mean and radial diffusivity values and C9orf72 carriers had a tendency of a faster decline of fractional anisotropy values as they reached closer to the expected age of dementia onset. These findings suggest that white-matter changes may represent early markers of familial frontotemporal dementia due to genetic causes. However, GRN and C9orf72 mutation carriers may have different mechanisms leading to tissue abnormalities.

Elicited clinician knowledge did not improve dementia risk prediction in individuals with mild cognitive impairment.

OBJECTIVES: This study aims to develop and validate a Bayesian risk prediction model that combines research cohort data with elicited expert knowledge to predict dementia progression in people with mild cognitive impairment (MCI). STUDY DESIGN AND SETTING: This is a prognostic risk prediction modeling study based on cohort data (Alzheimer's disease neuroimaging initiative [ADNI]; n = 365) of research participants with MCI and elicited expert data. Bayesian Cox models were used to combine expert knowledge and ADNI data to predict dementia progression in people with MCI. Posterior distributions were obtained based on Gibbs sampler and the predictive performance was evaluated using ten-fold cross-validation via c-index, integrated calibration index (ICI), and integrated brier score (IBS). RESULTS: 365 people with MCI were included, mean age was 73 years (SD = 7.5), and 39% developed dementia within 3 years. When expert knowledge was incorporated, the c-index, ICI, and IBS values were 0.74 (95% CI 0.70-0.79), 0.06 (95% CI 0.05-0.08), and 0.17 (95% CI 0.14-0.19), respectively. These were similar to the model without expert knowledge data. CONCLUSION: The addition of expert knowledge did not improve model accuracy in this ADNI sample to predict dementia progression in individuals with MCI.

Economic Evaluation of Exercise or Cognitive and Social Enrichment Activities for Improved Cognition After Stroke.

Importance: Cognitive impairment is prevalent in survivors of stroke, affecting approximately 30% of individuals. Physical exercise and cognitive and social enrichment activities can enhance cognitive function in patients with chronic stroke, but their cost-effectiveness compared with a balance and tone program is uncertain. Objective: To conduct a cost-effectiveness and cost-utility analysis of multicomponent exercise or cognitive and social enrichment activities compared with a balance and tone program. Design, Setting, and Participants: This economic evaluation used a Canadian health care systems perspective and the Vitality study, a randomized clinical trial aimed at improving cognition after stroke with a 6-month intervention and a subsequent 6-month follow-up (ie, 12 months). The economic evaluation covered the duration of the Vitality trial, between June 6, 2014, and February 26, 2019. Participants were community-dwelling adults aged 55 years and older who experienced a stroke at least 12 months prior to study enrollment in the Vancouver metropolitan area, British Columbia, Canada. Data were analyzed from June 1, 2022, to March 31, 2023. Interventions: Participants were randomly assigned to twice-weekly classes for 1 of the 3 groups: multicomponent exercise program, cognitive and social enrichment activities program, or a balance and tone program (control). Main Outcomes and Measures: The primary measures for the economic evaluation included cost-effectiveness (incremental costs per mean change in cognitive function, evaluated using the Alzheimer Disease Assessment Scale-Cognitive-Plus), cost-utility (incremental cost per quality-adjusted life-year gained), intervention costs, and health care costs. Since cognitive benefits 6 months after intervention cessation were not observed in the primary randomized clinical trial, an economic evaluation at 12 months was not performed. Results: Among 120 participants (mean [SD] age, 71 [9] years; 74 [62%] male), 34 were randomized to the multicomponent exercise program, 34 were randomized to the social and cognitive enrichment activities program, and 52 were randomized to the balance and tone control program. At the end of the 6-month intervention, the cost per mean change in Alzheimer Disease Assessment Scale-Cognitive-Plus score demonstrated that exercise was more effective and costlier compared with the control group in terms of cognitive improvement with an incremental cost-effectiveness ratio of CAD -$8823. The cost per quality-adjusted life-year gained for both interventions was negligible, with exercise less costly (mean [SD] incremental cost, CAD -$32 [$258]) and cognitive and social enrichment more costly than the control group (mean [SD] incremental cost, CAD $1018 [$378]). The balance and tone program had the lowest delivery cost (CAD $777), and the exercise group had the lowest health care resource utilization (mean [SD] $1261 [$1188]) per person. Conclusions and Relevance: The findings of this economic evaluation suggest that exercise demonstrated potential for cost-effectiveness to improve cognitive function in older adults with chronic stroke during a 6-month intervention.

Effect of Exercise Training or Complex Mental and Social Activities on Cognitive Function in Adults With Chronic Stroke: A Randomized Clinical Trial.

Importance: A stroke doubles one's risk for dementia. How to promote cognitive function among persons with chronic stroke is unclear. Objective: To evaluate the effect of exercise (EX) or cognitive and social enrichment activities (ENRICH) on cognitive function in adults with chronic stroke. Design, Setting, and Participants: This was a 3-group parallel, single-blinded, single-site, proof-of-concept randomized clinical trial at a research center in Vancouver, British Columbia, Canada. Participants included community-dwelling adults with chronic stroke, aged 55 years and older, able to walk 6 meters, and without dementia. The trial included a 6-month intervention and a 6-month follow-up. Randomization occurred from June 6, 2014, to February 26, 2019. Measurement occurred at baseline, 6 months, and 12 months. Data were analyzed from January to November 2021. Interventions: Participants were randomly allocated to twice-weekly supervised classes of: (1) EX, a multicomponent exercise program; (2) ENRICH, a program of cognitive and social enrichment activities; or (3) balance and tone (BAT), a control group that included stretches and light-intensity exercises. Main Outcomes and Measures: The primary outcome was the Alzheimer Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus), which included the 13-item ADAS-Cog, Trail Making Test Parts A and B, Digit Span Forward and Backward, Animal Fluency, and Vegetable Fluency. Results: One-hundred and twenty participants, with a mean (range) of 1.2 (1-4) strokes, a mean (SD) of 66.5 (53.8) months since the most recent stroke, mean (SD) baseline age of 70 (8) years, mean (SD) baseline ADAS-Cog-Plus of 0.22 (0.81), and 74 (62%) male participants, were randomized to EX (34 participants), ENRICH (34 participants), or BAT (52 participants). Seventeen withdrew during the 6-month intervention and another 7 during the 6-month follow-up. Including all 120 participants, at the end of the 6-month intervention, EX significantly improved ADAS-Cog-Plus performance compared with BAT (estimated mean difference: -0.24; 95% CI, -0.43 to -0.04; P = .02). This difference did not persist at the 6-month follow-up (estimated mean difference: -0.08; 95% CI, -0.29 to 0.12; P = .43). For the 13-item ADAS-Cog, the EX group improved by 5.65 points over the 6-month intervention (95% CI, 2.74 to 8.57 points; P < .001), exceeding the minimally clinical difference of 3.0 points. Conclusions and Relevance: These findings suggest that exercise can induce clinically important improvements in cognitive function in adults with chronic stroke. Future studies need to replicate current findings and to understand training parameters, moderators, and mediators to maximize benefits. Trial Registration: ClinicalTrials.gov identifier: NCT01916486.

Müller cell degeneration and microglial dysfunction in the Alzheimer's retina.

Amyloid beta (Aß) deposits in the retina of the Alzheimer's disease (AD) eye may provide a useful diagnostic biomarker for AD. This study focused on the relationship of Aß with macroglia and microglia, as these glial cells are hypothesized to play important roles in homeostasis and clearance of Aß in the AD retina. Significantly higher Aß load was found in AD compared to controls, and specifically in the mid-peripheral region. AD retina showed significantly less immunoreactivity against glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) compared to control eyes. Immunoreactivity against ionized calcium binding adapter molecule-1 (IBA-1), a microglial marker, demonstrated a higher level of microgliosis in AD compared to control retina. Within AD retina, more IBA-1 immunoreactivity was present in the mid-peripheral retina, which contained more Aß than the central AD retina. GFAP co-localized rarely with Aß, while IBA-1 co-localized with Aß in more layers of control than AD donor retina. These results suggest that dysfunction of the Müller and microglial cells may be key features of the AD retina.

Reshaping the path of mild cognitive impairment by refining exercise prescription: a study protocol of a randomized controlled trial to understand the "what," "for whom," and "how" of exercise to promote cognitive function.

BACKGROUND: Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. METHODS: Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). DISCUSSION: Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as "medicine" to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.