Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia ...(FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.
Abstract Objective To assess the influence of rs5848 polymorphism in serum progranulin (PGRN) level in a cohort of subjects with Alzheimer and related dementias from a tertiary referral clinic. ...Background Mutations in the GRN gene cause autosomal dominant frontotemporal dementia (FTD) with TDP-43 pathology (FTLD-TDP) through haploinsufficiency. It has recently been shown that homozygous carriers of the T allele of rs5848 have an elevated risk of developing FTD, and this polymorphism may play a role in the pathogenesis of other dementia by modifying progranulin level. We hypothesize that genotype of rs5848 may influence serum PGRN level in AD, FTD, and other dementias. Methods Blood samples were obtained from patients with cognitive impairment and dementia referred to a tertiary dementia clinic, as well as samples from a cohort of healthy controls. Serum PGRN level was measured using an ELISA assay, and rs5848 genotype was determined by a TaqMan assay. Results We found that rs5848 SNP significantly influenced serum PGRN level, with TT genotype having the lowest levels, and CC as the highest. This relationship is observed in each of the subgroups. We also confirmed that GRN mutation carriers had significantly lower serum PGRN levels than all other groups. Conclusions The rs5848 polymorphism significantly influences serum PGRN with TT carriers having a lower level of serum PGRN then CT and CC carriers. This is consistent with the finding that miR-659 binding to the high risk T allele of rs5848 may augment translational inhibition of GRN and alter risk of FTD and possibly other dementias.
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.
Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the ...interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.
Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.
Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.
Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.
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).
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, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors.
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 CI1.2, 412.3; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI1.0, 30.4; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI1.2, 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.
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.
Cholesterol in Alzheimer's disease Shobab, Leila A; Hsiung, Ging-Yuek R; Feldman, Howard H
Lancet neurology,
12/2005, Volume:
4, Issue:
12
Journal Article
Peer reviewed
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia and affects up to 15 million people worldwide. Although no single cause of AD has been identified, recent research has ...suggested that several pathogenetic factors influence risk and expression. A growing amount of evidence underscores a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques. Excess brain cholesterol has been associated with increased formation and deposition of amyloid-β peptide from amyloid precursor protein. Cholesterol-lowering statins have become a focus of research in AD. Genetic polymorphisms associated with pivotal points in cholesterol metabolism in brain tissues may contribute to the risk and pathogenesis of AD. In this review, we summarise current knowledge of the role of cholesterol metabolism in the pathogenesis of AD and examine the potential of statins in the prevention and treatment of AD.
This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A ...broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect.
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.
Oligomers of amyloid-β (AβO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer’s disease (AD). However, the heterogeneous and dynamic nature of AβO and inadequate markers for AβO ...subtypes have stymied effective AβO identification and therapeutic targeting in vivo. We identified an AβO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine–asparagine–lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AβOcSNK recognizes ∼50–60 kDa SDS-resistant soluble Aβ assemblages in AD brain and prolongs the lag phase of Aβ aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-AβOcSNK in two AD mouse models reduced soluble brain Aβ aggregates by 20–30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AβOcSNK IgG1 response without epitope spreading to Aβ monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AβOcSNK participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.
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