Alzheimer's disease (AD) is a neurodegenerative disease characterized by extracellular amyloid-β (Aβ) peptide aggregates, forming amyloid plaques, and intracellular deposits of phosphorylated tau. ...Neuroinflammation is now considered as the third hallmark of AD. The majority of clinical trials tested pharmacological strategies targeting amyloid, tau, and neuroinflammation, with disappointing results overall. In parallel, innovative strategies exploring other pathways and approaches are being tested. In this article, we focus on the rationale and preliminary preclinical evidence for a novel application to AD of a widely used therapeutic strategy for oncological and benign conditions: low-dose radiation therapy (LD-RT). LD-RT has shown to be effective against systemic amyloid deposits, as well as against chronic inflammatory diseases, and could thus be able to modulate amyloid load and neuroinflammation in AD. The anti-amyloid effect could be possibly mediated by the LD-RT action on the β-sheet structure of amyloid fibrils, by breaking H-bonds, and depolymerize glucoaminoglycans which are highly radiation-sensitive molecules associated with amyloid fibrils. The anti-inflammatory effect could be linked to the decrease of leukocytes-endothelial cells interactions and to the stimulation of the release of anti-inflammatory molecules. One preclinical study has observed a dramatic reduction of amyloid plaques 4 weeks post-RT, more important with fractionated protocols at low doses than hypofractionated single dose treatments, associated with modulation of inflammatory and anti-inflammatory cytokines and cognitive improvement. Ongoing Phase I clinical trials will test the ability of LD-RT to hold these promises.
The guidelines on hypertension recently published by the European Societies of Hypertension and Cardiology, have acknowledged cognitive function (and its decline) as a hypertension-mediated organ ...damage. In fact, brain damage can be the only hypertension-mediated organ damage in more than 30% of hypertensive patients, evolving undetected for several years if not appropriately screened; as long as undetected it cannot provide either corrective measures, nor adequate risk stratification of the hypertensive patient.The medical community dealing with older hypertensive patients should have a simple and pragmatic approach to early identify and precisely treat these patients. Both hypertension and cognitive decline are undeniably growing pandemics in developed or epidemiologically transitioning societies. Furthermore, there is a clear-cut connection between exposure to the increased blood pressure and development of cognitive decline.Therefore, a group of experts in the field from the European Society of Hypertension and from the European Geriatric Medicine Society gathered together to answer practical clinical questions that often face the physician when dealing with their hypertensive patients in a routine clinical practice. They elaborated a decision-making approach to help standardize such clinical evaluation.
Abstract We investigated volume and shape changes in the striatum (caudate, putamen, and nucleus accumbens) of 18 early-onset (EOAD) and 18 late-onset (LOAD) Alzheimer's Disease patients compared ...with 2 control groups age- and sex-matched to each patient group, and explored the relationship between striatal atrophy and apolipoprotein E ( APOE ) genotype. EOAD patients showed significant shape changes in the left and right ventral putamen ( p < 0.05, corrected for multiple comparison with permutation tests). LOAD patients showed significant reductions in the left and right nucleus accumbens volumes ( p < 0.05; Mann–Whitney test) and shape ( p < 0.05; permutation test). Caudate abnormalities were detected in EOAD and LOAD patients in terms of local enlargements and reductions ( p < 0.05 for the left and right, permutation test). When APOE was considered, significant differences were detected between LOAD ϵ4 carriers and noncarriers in the left and right caudate ( p < 0.05, permutation test). These results suggest distinct patterns of striatal pathology in EOAD and LOAD patients, the dorsal striatum being involved in EOAD and the ventral striatum in LOAD.
Behavioural and psychological symptoms of dementia (BPSD) are a clinical challenge for the lack of a sound taxonomy, frequent presentation with comorbid BPSD, lack of specific pharmacologic ...interventions, poor base of methodologically sound evidence with randomized clinical trials, contamination from the treatment of behavioural disturbances of young and adult psychiatric conditions, and small efficacy window of psychotropic drugs. We present here a treatment workflow based on a concept‐driven literature review based on the notions that (i) the aetiology of BPSD can be mainly neurobiological (so‐called ‘primary’ symptoms) or mainly environmental and functional (‘secondary’ symptoms) and that this drives treatment; (ii) the clinical efficacy of psychotropic drugs is driven by their specific profile of receptor affinity; (iii) drug treatment should follow the rules of ‘start low–go slow, prescribe and revise’. This article argues in support of the distinction between primary and secondary BPSD, as well as their characteristics, which until now have been just sketchily described in the literature. It also offers comprehensive and pragmatic clinician‐oriented recommendations for the treatment of BPSD.
Abstract This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) ...amyloid-β1–42 , tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.
•SimulAD is a disease progression model previously developed on the ADNI cohort.•Generalization of SimulAD is tested on a cohort from the Geneva University Hospitals.•SimulAD allows to identify ...subjects at risk of cognitive decline.•SimulAD could be used to monitor the efficacy of drug intervention.•SimulAD simulates the personalized evolution of patients.
SimulAD is a computational disease progression model (DPM) originally developed on the ADNI database to simulate the evolution of clinical and imaging markers characteristic of AD, and to quantify the disease severity (DS) of a subject. In this work, we assessed the validity of this estimated DS, as well as the generalization of the DPM., by applying SimulAD on a new cohort from the Geneva Memory Center (GMC). The differences between the estimated DS of healthy, mild cognitive impairment and AD dementia groups were statistically significant (p-values < 0.05; d ≥ 0.8). DS correlated with MMSE (ρ = -0.55), hippocampal atrophy (ρ = -0.62), glucose hypometabolism (ρ = -0.67), amyloid burden (ρ = 0.31) and tau deposition (ρ = 0.62) (p-values < 0.01). Based on the dynamics estimated on the ADNI cohort, we simulated a DPM for the subjects of the GMC cohort. The difference between the temporal evolution of similar biomarkers simulated on the ADNI and GMC cohorts remained below 10%. This study illustrates the robustness and good generalization of SimulAD, highlighting its potential for clinical and pharmaceutical studies.
Background and objective
Phosphorylated tau (
p
-tau) 217 has recently received attention because it seems more reliable than other
p
-tau variants for identifying Alzheimer’s disease (AD) pathology. ...Thus, we aimed to compare the diagnostic accuracy of plasma and CSF
p
-tau217 with
p
-tau181 and
p
-tau231 in a memory clinic cohort.
Methods
The study included 114 participants (CU = 33; MCI = 67; Dementia = 14). The
p
-tau variants were correlated versus continuous measures of amyloid (A) and tau (T)-PET. The
p
-tau phospho-epitopes were assessed through: (i) effect sizes (
δ
) between diagnostic and A ± and T ± groups; (ii) receiver operating characteristic (ROC) analyses in A-PET and T-PET.
Results
The correlations between both plasma and CSF
p
-tau217 with A-PET and T-PET (
r
range 0.64–0.83) were stronger than those of
p
-tau181 (
r
range 0.44–0.79) and
p
-tau231 (
r
range 0.46–0.76). Plasma
p
-tau217 showed significantly higher diagnostic accuracy than
p
-tau181 and
p
-tau231 in (i) differences between diagnostic and biomarker groups (
δ
range
:
p
-tau217 = 0.55–0.96;
p
-tau181 = 0.51–0.67;
p
-tau231 = 0.53–0.71); (ii) ROC curves to identify A-PET and T-PET positivity (AUC
average
:
p
-tau217 = 0.96;
p
-tau181 = 0.76;
p
-tau231 = 0.79). On the other hand, CSF
p
-tau217 (AUC
average
= 0.95) did not reveal significant differences in A-PET and T-PET AUC than
p
-tau181 (AUC
average
= 0.88) and
p
-tau231 (AUC
average
= 0.89).
Discussion
Plasma
p
-tau217 demonstrated better performance in the identification of AD pathology and clinical phenotypes in comparison with other variants of
p
-tau in a memory clinic cohort. Furthermore,
p
-tau217 had comparable performance in plasma and CSF. Our findings suggest the potential of plasma
p
-tau217 in the diagnosis and screening for AD, which could allow for a decreased use of invasive biomarkers in the future.
...the findings add further substance to the amyloid cascade hypothesis of Alzheimer's disease, which is presently the rationale of most drug treatments in development, and for which the many critics ...have so far few more persuasive alternatives to propose.10 As is often the case, the road to reconciliation does not run smoothly.
Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual's prevention potential for dementia.
We investigated the predictive validity of the LIBRA index for ...incident dementia in midlife, late life, and the oldest-old.
9,387 non-demented individuals were recruited from the European population-based DESCRIPA study. An individual's LIBRA index was calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, range 1-16).
In midlife (55-69 y, n = 3,256) and late life (70-79 y, n = 4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80-97 y, n = 1,811), higher LIBRA scores did not increase the risk for dementia.
LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.
This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) ...amyloid-β1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.
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