Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.

AIMS: Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations. METHODS: The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life. RESULTS: We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis. CONCLUSIONS: This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.

Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

INTRODUCTION: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes. DISCUSSION: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

Prevalence of amyloid-ß pathology in distinct variants of primary progressive aphasia.

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

Prevalence of delusions in drug-naïve Alzheimer disease patients: A meta-analysis.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are common at all stages of Alzheimer disease (AD). Delusions in AD are associated with negative clinical consequences and may signal rapid disease progression. Hence, we sought to determine the prevalence of delusions in drug-naïve (no cholinesterase inhibitor or neuroleptic medications) AD patients. METHODS: In this meta-analysis, a search of the EMBASE, MEDLINE, and PsycINFO databases was performed. We selected studies reporting delusion prevalence measured by the Neuropsychiatric Inventory (NPI) in drug-naïve AD patients. An aggregate delusion event rate with 95% confidence interval (CI) was calculated. The I2 statistic was used to assess the magnitude of between-study heterogeneity. Single variable meta-regressions allowed examination of the effect of moderating factors and heterogeneity. Quantitative measures were used to appraise for publication bias. RESULTS: We identified 6 studies with 591 participants allowing calculation of the aggregate delusional prevalence rate. Irrespective of dementia severity, the aggregate event rate for delusions was 29.1% (95% CI: 20-41%; I2  = 84.59). No publication bias was observed. CONCLUSION: This meta-analysis calculates a 29.1% prevalence rate of delusions in AD patients. There is a trend towards increasing delusion prevalence in concordance with increasing severity of dementia. Given delusions are associated with poorer outcomes, the obtained prevalence should motivate clinicians to screen carefully for delusions. Current literature limitations warrant future studies, with sub-analyses on dementia severity, and other neurobiological factors known to influence the presence of delusions.

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study.

BACKGROUND: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams. METHODS: The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here. RESULTS: The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020. CONCLUSION: Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.

Évaluation complète d'une étude de cohorte canadienne portant sur la démence et la neuro-dégénérescence. Contexte : L'évaluation globale de la neuro-dégénérescence et de la démence (COMPASS-ND), étude de cohorte du Consortium canadien en neuro-dégénérescence associée au vieillissement (CCNV), représente une initiative nationale visant à promouvoir la recherche portant sur la démence et à soutenir les programmes de recherche des équipes du CCNV. Totalisant 2310 sujets recrutés partout au pays, cette cohorte longitudinale regroupe des individus fortement « phénotypés ¼ qui présentent diverses formes de démence et de pertes de mémoire légères. En plus de sujets âgés dont les fonctions cognitives sont intactes, ces 2310 sujets ont permis de valider les hypothèses formulées par les équipes du CCNV. Méthodes : Nous avons utilisé de nombreux documents pour décrire cette étude : le protocole de la COMPASS-ND ; la demande initiale de subvention ; le cinquième rapport d'étape semi-annuel du CCNV soumis aux Instituts de recherche en santé du Canada (IRSC) en décembre 2017 ; ainsi que d'autres documents produits à la suite de modifications consécutives à la mise en œuvre de ce projet. Résultats: L'étude de cohorte COMPASS-ND du CCNV inclut des participants de partout au Canada dont les divers états cognitifs sont associés à des maladies neurodégénératives ou au risque d'en souffrir. Ils feront l'objet d'un large éventail d'examens expérimentaux, cliniques, génétiques et d'imagerie afin d'aborder de manière spécifique les causes, le diagnostic, le traitement et la prévention de ces états cognitifs chez les personnes âgées. Les données obtenues à la suite d'évaluations cliniques et cognitives, ainsi que celles issues d'échantillons biologiques, d'imagerie cérébrale, de tests génétiques et de dons de cerveaux, seront utilisées pour tester les hypothèses générées par les équipes de recherche du CCNV et d'autres chercheurs canadiens. Cette étude constitue donc à ce jour l'étude canadienne la plus complète et la plus ambitieuse au sujet de la démence. La présentation des données initiales ayant eu lieu en 2018, la cohorte devrait atteindre sa taille maximale d'ici à 2020.Conclusion : La disponibilité des données de l'étude COMPASS-ND stimulera considérablement la recherche sur la démence au Canada au cours des prochaines années.

16-Year Survival of the Canadian Collaborative Cohort of Related Dementias.

Background Survival estimates are integral to care for patients diagnosed with dementia. Few Canadian studies have carried out long-term follow-up of well-described cohorts, analyzing survival related to multiple risk factors. Methods Survival analysis of an inception cohort enrolled at a British Columbia (BC) tertiary dementia referral clinic between 1997 and 1999 was undertaken. Vital status was completed for 168 patients diagnosed with dementia. An evaluation of the effects of demographics, vascular risk factors, cognitive and functional ratings, apolipoprotein 4-status, and cholinesterase use on survival was performed using a log-rank test and time-dependent Cox regression. Survival of this dementia cohort was compared with the age-matched life expectancy of persons in BC. Results In all, 158/168 (94.0%) subjects died over 16.6 years, with a median survival of 7.08 years. Risk factors associated with shorter survival in dementia groups included age of onset ≥80 (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.05-2.32); greater functional disability (Disability Assessment for Dementia<55% [HR 1.47, 95% CI 1.04-2.08]); and cumulative medical illness severity (Cumulative Illness Rating Scale≥7 [HR 1.51, 95% CI 1.08-2.12)]. Compared with the BC population, years of potential life lost for dementia subjects aged <65 was 15.36 years, and for dementia subjects aged ≥80 it was 1.82 years. Conclusions Survival in dementia subjects is shorter than population life expectancies for each age strata, with greatest impact on younger patients. For people diagnosed with dementia, age ≥80 years, cumulative medical illness severity, and functional disabilities are the most significant survival predictors and can be used to guide prognosis.

Pharmacological Therapy for Apathy in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Apathy is highly prevalent in Alzheimer's disease (AD), but whether pharmacotherapy is effective in managing apathy is unclear. METHODS: To assess the efficacy of pharmacotherapy for apathy in AD we searched for randomized controlled trials (RCT) and aggregate data reporting on apathy in several search engines, reference lists of articles, and reviews. Demographic characteristics and relevant data were extracted to assess apathy. RESULTS: Fifteen RCTs' were examined, and 11 were used in aggregate meta-analytic statistics. Drugs included were cholinesterase inhibitors, memantine, and psycho-stimulants. We found no significant treatment effect in favour of any of the drugs, and the effect-size estimates under a random effect model were heterogeneous. Most RCTs had a high attrition rate and used the NPI apathy subscale to measure apathy. CONCLUSION: The lack of an effect could be explained by methodological limitations, publication bias, and heterogeneity.

C-TOC (Cognitive Testing on Computer): investigating the usability and validity of a novel self-administered cognitive assessment tool in aging and early dementia.

INTRODUCTION: Cognitive Testing on Computer (C-TOC) is a novel computer-based test battery developed to improve both usability and validity in the computerized assessment of cognitive function in older adults. METHODS: C-TOC's usability was evaluated concurrently with its iterative development to version 4 in subjects with and without cognitive impairment, and health professional advisors representing different ethnocultural groups. C-TOC version 4 was then validated against neuropsychological tests (NPTs), and by comparing performance scores of subjects with normal cognition, Cognitive Impairment Not Dementia (CIND) and Alzheimer disease. C-TOC's language tests were validated in subjects with aphasic disorders. RESULTS: The most important usability issue that emerged from consultations with 27 older adults and with 8 cultural advisors was the test-takers' understanding of the task, particularly executive function tasks. User interface features did not pose significant problems. C-TOC version 4 tests correlated with comparator NPT (r=0.4 to 0.7). C-TOC test scores were normal (n=16)>CIND (n=16)>Alzheimer disease (n=6). All normal/CIND NPT performance differences were detected on C-TOC. Low computer knowledge adversely affected test performance, particularly in CIND. C-TOC detected impairments in aphasic disorders (n=11). DISCUSSION: In general, C-TOC had good validity in detecting cognitive impairment. Ensuring test-takers' understanding of the tasks, and considering their computer knowledge appear important steps towards C-TOC's implementation.

Challenges with cost-utility analyses of behavioural interventions among older adults at risk for dementia.

BACKGROUND: Cognitive decline is one of the most prominent healthcare issues of the 21st century. Within the context of combating cognitive decline through behavioural interventions, physical activity is a promising approach. There is a dearth of health economic data in the area of behavioural interventions for dementia prevention. Yet, economic evaluations are essential for providing information to policy makers for resource allocation. It is essential we first address population and intervention-specific methodological challenges prior to building a larger evidence base. We use a cost-utility analysis conducted alongside the exercise for cognition and everyday living (EXCEL) study to illustrate methodological challenges specific to assessing the cost-effectiveness of behavioural interventions aimed at older adults at risk of cognitive decline. METHODS: A cost-utility analysis conducted concurrently with a 6-month, three-arm randomised controlled trial (ie, the EXCEL study) was used as an example to identify and discuss methodological challenges. RESULTS: Both the aerobic training and resistance training interventions were less costly than twice weekly balance and tone classes. In critically evaluating the economic evaluation of the EXCEL study we identified four category-specific challenges: (1) analysing costs; (2) assessing quality-adjusted life-years; (3) Incomplete data; and (4) 'Intervention' activities of the control group. CONCLUSIONS: Resistance training and aerobic training resulted in healthcare cost saving and were equally effective to balance and tone classes after only 6 months of intervention. To ensure this population is treated fairly in terms of claims on resources, we first need to identify areas for methodological improvement.

TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia.

Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.

Early neuropsychological characteristics of progranulin mutation carriers.

Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature.

The Effect of Computerized Cognitive Training, with and without Exercise, on Cortical Volume and Thickness and Its Association with Gait Speed in Older Adults: A Secondary Analysis of a Randomized Controlled Trial.

Background: Slower walking is associated with changes in cortical volume and thickness. Computerized cognitive training (CCT) and exercise improve cortical volume and thickness and thus, may promote gait speed. Slowing of gait is predictive of Alzheimer's disease. Objective: To examine: 1) the effect of CCT, with or without physical exercise, on cortical volume and thickness and; 2) the association of changes in cortical volume and thickness with changes in gait speed. Methods: A subset of 124 adults (n = 53), aged 65-85 years, enrolled in an 8-week randomized controlled trial and completed T1-weighted MRI and 4-meter walk at baseline and 8 weeks. Participants were randomized to: 1) active control (BAT; n = 19); 2) CCT (n = 17); or 3) CCT preceded by exercise (Ex-CCT; n = 17). Change in cortical volume and thickness were assessed and compared across all groups using Freesurfer. RESULTS: BAT versus CCT increased left rostral middle frontal gyrus volume (p  = 0.027) and superior temporal gyrus thickness (p = 0.039). Ex-CCT versus CCT increased left cuneus thickness (p < 0.001) and right post central gyrus thickness (p = 0.005), and volume (p < 0.001). Ex-CCT versus BAT increased left (p = 0.001) and right (p = 0.020) superior parietal gyri thickness. There were no significant between-group differences in gait speed (p > 0.175). Increased left superior parietal volume (p = 0.036, r = 0.340) and thickness (p = 0.002, r = 0.348), right post central volume (p = .017, r = 0.341) and thickness (p = 0.001, r = 0.348), left banks of superior temporal sulcus thickness (p = 0.002, r = 0.356), and left precuneus thickness (p < 0.001, r = 0.346) were associated with increased gait speed. CONCLUSIONS: CCT with physical exercise, but not CCT alone, improves cortical volume and thickness in older adults. These changes may contribute to the maintenance of gait speed in aging.

Clinical value of Alzheimer's disease biomarker testing.

INTRODUCTION: In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. METHODS: The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. RESULTS: Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). DISCUSSION: AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

Personal value of Alzheimer's disease biomarker testing and result disclosure from the patient and care partner perspective.

INTRODUCTION: We described patients' and care partners' experiences with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing and result disclosure in routine care. METHODS: IMPACT-AD BC is an observational study of clinic patients who underwent AD CSF biomarker testing as part of their routine medical care (n = 142). In the personal utility arm of the study, semi-structured phone interviews were conducted with a subset of patients (n = 34), and separately with their care partners (n = 31). Post-disclosure interviews were conducted ∼1 month and ∼6 months after biomarker result disclosure and investigated the patients' decision-making process around testing, impact of receiving results, wellness and lifestyle changes, and future planning. RESULTS: A majority of patients (90%) rated their decision to undergo testing as "easy." Post-disclosure, the majority (82%) reported overall positive feelings from having greater certainty and the ability to plan ahead, and results spurred them to adopt/continue healthy behaviors such as exercise (84%) and cognitive activities (54%). Care partners expressed relief from having more diagnostic certainty, increased appreciation of future caregiving responsibilities, and a desire to connect with support resources. DISCUSSION: Perspectives of persons with lived experience in dementia provide new insight into the value of biomarker testing and should be included as part of evidence-guided considerations for pre-test counseling and result disclosure. Moreover, study findings identify an interval when patients and care partners are highly receptive to positive lifestyle and medical interventions.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia.

Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD-TDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over-expression. However, over-expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk. We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD-TDP in these patients.

Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p.

Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34-74 years) and disease duration (mean = 5.3, range = 1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with M(r) 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.

Prevalence of mild cognitive impairment and its subtypes in the Mexican population.

BACKGROUND/AIM: To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes, taking into account education and health status. METHODS: This is the first report of our Study on Aging and Dementia in Mexico. This study included 2,944 elderly individuals 60 years old or more with in-home assessment for cognitive impairment. The prevalence of MCI was based on Petersen criteria. MCI was classified as amnestic of single domain (a-MCI-s) or multiple domain (a-MCI-md) or nonamnestic of single domain (na-MCI-s) or multiple domain (na-MCI-md). In addition to a battery of neuropsychological measures, a self-report depression measure and a medical history including history of stroke, heart disease and other health conditions were recorded. RESULTS: The global estimated prevalence of MCI in the Mexican population was 6.45%. Of these subjects, 2.41% met criteria for a-MCI-s, 2.56% for a-MCI-md, 1.18% for na-MCI-s and 0.30% for na-MCl-md. Women showed a higher prevalence of MCI than men (63.7 vs. 36.3%, respectively). The analysis showed that heart disease [odds ratio (OR) 1.5], stroke (OR 1.2) and depression (OR 2.1) were associated with an increased risk of MCI. CONCLUSIONS: The prevalence of MCI in Mexico is similar to that in other countries. The results suggest that stroke, heart disease and depression may have an important role in the etiology of MCI.