Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. ...Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10−6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.
•Mutations affecting the low-complexity domain of TIA1 cause ALS and ALS-FTD•ALS-linked TIA1 mutations share a neuropathological TDP-43 signature•TIA1 mutations promote phase separation and impair stress granule dynamics•TDP-43 recruited to poorly dynamic stress granules becomes immobile and insoluble
Mackenzie et al. report the identification of mutations in TIA1 as a novel cause of ALS and ALS-FTD. ALS-linked mutations perturb phase transitions of TIA1, which impair the dynamics of stress granules and indirectly promote TDP-43 insolubility.
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.
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.
Apathy is highly prevalent in Alzheimer's disease (AD), but whether pharmacotherapy is effective in managing apathy is unclear.
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.
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.
The lack of an effect could be explained by methodological limitations, publication bias, and heterogeneity.
Abstract We performed case-control studies using 2 Canadian cohorts to examine the role of 10 promising Alzheimer's disease (AD) loci identified in recent genomewide association studies. Patients age ...65 years and older diagnosed with AD at baseline (prevalent cases) or who developed AD during follow-up assessments (incident cases) were compared with control subjects with no cognitive impairment. Our prevalent case study comparing prevalent AD cases (n = 428) with participants with no cognitive impairment (n = 524) revealed a significant association of rs6656401 and rs3818361 ( CR1 ), rs2075650 ( TOMM40 ), rs7561528 ( BIN1 ), and rs3865444 ( CD33 ) with late-onset AD that were robust to adjustment with age and apolipoprotein E ε4 genotype. The incident case study comparing patients who developed AD during longitudinal observation (n = 152) with participants with no cognitive impairment found that rs2075650 ( TOMM40 ) and rs3865444 ( CD33 ) influence the risk of developing AD in this population. In addition, pooled analysis of our AD patients confirmed that CR1 , TOMM40 , BIN1 , and CD33 contribute to late-onset AD susceptibility, in addition to apolipoprotein E.
Clinical value of Alzheimer's disease biomarker testing Patel, Khushbu J.; Yang, David; Best, John R. ...
Alzheimer's & dementia : translational research & clinical interventions,
April‐June 2024, Volume:
10, Issue:
2
Journal Article
Peer reviewed
Open access
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.
Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its ...efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT.
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‐β 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‐β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid‐β 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‐β 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‐β biomarkers in PPA patients. Ann Neurol 2018;84:737–748
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.
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.
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.
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.
•FDG-PET can detect cerebral glucose hypometabolism in presymptomatic C9orf72 carriers.•Metabolic changes are seen in cingulate gyrus, frontal and temporal cortices and thalami.•Glucose metabolic ...changes are detectable up to 10 years prior to symptom onset.•Glucose metabolic changes are detectable prior to changes in gray matter volume.
Our aim is to investigate patterns of brain glucose metabolism using fluorodeoxyglucose positron emission tomography (FDG-PET) in presymptomatic carriers of the C9orf72 repeat expansion to better understand the early preclinical stages of frontotemporal dementia (FTD).
Structural MRI and FDG-PET were performed on clinically asymptomatic members of families with FTD caused by the C9orf72 repeat expansion (15 presymptomatic mutation carriers, C9orf72+; 20 non-carriers, C9orf72-). Regional glucose metabolism in cerebral and cerebellar gray matter was compared between groups.
The mean age of the C9orf72+ and C9orf72- groups were 45.3 ± 10.6 and 56.0 ± 11.0 years respectively, and the mean age of FTD onset in their families was 56 ± 7 years. Compared to non-carrier controls, the C9orf72+ group exhibited regional hypometabolism, primarily involving the cingulate gyrus, frontal and temporal neocortices (left > right) and bilateral thalami.
The C9orf72 repeat expansion is associated with changes in brain glucose metabolism that are demonstrable up to 10 years prior to symptom onset and before changes in gray matter volume become significant. These findings indicate that FDG-PET may be a particularly sensitive and useful method for investigating and monitoring the earliest stages of FTD in individuals with this underlying genetic basis.
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