Late-life cognitive disorders may be prevented by influencing age-related conditions such as frailty, characterized by decreased resistance to stressors and increased risk for adverse health ...outcomes. In the present review article, we examined clinical and epidemiological studies investigating the possible role of different frailty models in modulating the risk of Alzheimer's disease (AD), dementia, vascular dementia (VaD), mild cognitive impairment (MCI), and late-life cognitive impairment/decline that have been published over the past 3 years. Both deficit accumulation and physical frailty models were associated with late-life cognitive impairment/decline, incident dementia, AD, MCI, VaD, non-AD dementias, and AD pathology, proposing cognitive frailty as a new clinical construct with coexisting physical frailty and cognitive impairment in nondemented older subjects. Two subtypes of this new clinical condition have been recently proposed: "potentially reversible" cognitive frailty and "reversible" cognitive frailty. The physical factors should be physical prefrailty and frailty, while the cognitive impairment of potentially reversible cognitive frailty should be MCI (Clinical Dementia rating Scale = 0.5), while the cognitive impairment of reversible cognitive frailty should be pre-MCI Subjective Cognitive Decline (SCD), as recently proposed by the SCD Initiative Working Group. The mechanisms underlying the cognitive-frailty link are multifactorial and vascular, inflammatory, nutritional, and metabolic influences may be of major relevance. Considering both physical frailty and cognition as a single complex phenotype may be crucial in the prevention of dementia and its subtypes with secondary preventive trials on cognitive frail older subjects.
In chronic neurological conditions, wearable/portable devices have potential as innovative tools to detect subtle early disease manifestations and disease fluctuations for the purpose of clinical ...diagnosis, care and therapeutic development. Huntington's disease (HD) has a unique combination of motor and non-motor features which, combined with recent and anticipated therapeutic progress, gives great potential for such devices to prove useful. The present work aims to provide a comprehensive account of the use of wearable/portable devices in HD and of what they have contributed so far. We conducted a systematic review searching MEDLINE, Embase, and IEEE Xplore. Thirty references were identified. Our results revealed large variability in the types of sensors used, study design, and the measured outcomes. Digital technologies show considerable promise for therapeutic research and clinical management of HD. However, more studies with standardized devices and harmonized protocols are needed to optimize the potential applicability of wearable/portable devices in HD.
•Wearable/portable sensors have been proposed to detect and quantify manifestations of many neurodegenerative diseases.•No systematic review so far has examined their use in Huntington's disease (HD).•This work draws a broad picture of the digital wearable-based landscape in HD.•The utility of wearables in clinical practice and therapeutic research still needs to be proved.•Collaborative efforts are needed to further investigate their clinical use in HD.
Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its ...cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which leads to death in a median time of 2–3 years. Inflammation has been claimed important to the ALS pathogenesis, but ...its role is still not well-characterized. In the present study, a panel of five cytokines (IL-2, IL-6, IL-10, IFN-gamma, and TNF-alpha) measured in plasma has been investigated in ALS. These biomarkers of inflammation were measured in a population-based cohort of 79 patients with ALS and 79 age- and sex-matched healthy controls using the Bio-Plex technology (Bio-Rad). All the five cytokines were significantly increased in plasma samples of patients compared with controls (
p
< 0.0001), with IL-6 having the highest median concentration (10.11 pg/ml) in the ALS group. Furthermore, IL-6 was the plasma cytokine with the highest discrimination ability between patients and controls according to the receiver operating characteristic analysis (area under the curve = 0.93). At a cut-off point of 5.71 pg/ml, it was able to classify patients and controls with 91% of sensitivity and 87% of specificity. In the ALS group, plasma IL-6 concentration correlated with demographic (age: rs = 0.25,
p
= 0.025) and clinical (revised ALS Functional Rating Scale at evaluation: rs = −0.32,
p
= 0.007; Manual Muscle Testing: rs = −0.33,
p
= 0.004; progression: rs = 0.29,
p
= 0.0395) parameters. In line with previous studies, our results confirm that inflammatory cytokines are elevated in ALS, supporting a possible role of inflammation in disease mechanism and progression. However, the precise role of inflammation in ALS needs to be further investigated on larger samples and with more mechanistic studies.
We sought to determine sex differences in outcomes in patients with severe stroke who had been admitted to inpatient rehabilitation.
We studied 1,316 patients aged 18 to 99 (mean 72) classified as ...case-mix groups 0108, 0109, and 0110 of the Medicare case-mix classification system. These groups encompass the most severe strokes. Three outcomes were analyzed: (1) 3-year mortality from admission to rehabilitation; (2) combined outcome of transfer to acute care or death within 90 days from admission to rehabilitation; (3) functional outcome, including proportional recovery in motor functioning and good functional outcome as defined by achievement of a Functional Independence Measure (FIM)-motor score ≥65 points at discharge. Multivariable regression analyses were used to assess sex-difference in each outcome between women and men. The covariates examined included age, marital status, comorbidities, time from stroke onset to rehabilitation admission <30 days, ischemic stroke, dysphagia, neglect, motor FIM score at admission, and cognitive FIM score at admission.
Kaplan-Meier estimated 3-year mortality rate was 20.7% in women and 22.0% in men. The crude hazard ratio (HR) of death for women compared with men was 0.94 (95% CI 0.74-1.20). After adjustment for significant covariates, the HR of 3-year mortality was 0.73 (95% CIs 0.56-0.96;
= 0.025). Comorbidity, including diabetes, anemia, coronary artery disease, atrial fibrillation, and chronic obstructive pulmonary disease, significantly increased mortality risk by 49-88%. The incidence of the combined outcome was 8.3% in women and 8.4% in men. The crude HR of the combined end-point for women compared with men was 1.05 (95% CI 0.72-1.53). After adjustment for significant covariates, the HR was 0.95 (95% CIs 0.65-1.40;
= 0.810). Likewise, no significant difference in proportional recovery or in the rate of achievement of a good functional outcome between women and men was observed.
Among patients admitted to inpatient rehabilitation after severe stroke, women and men had comparable crude mortality rates at 3 years. After multivariable adjustment, however, women had lower mortality risk. No sex-differences in the risk of being transferred to acute care or dying within 90 days from admission to rehabilitation or in responsiveness to rehabilitation were observed.
Cognitive frailty, a condition describing the simultaneous presence of physical frailty and mild cognitive impairment, has been recently defined by an international consensus group. We estimated the ...predictive role of a "reversible" cognitive frailty model on incident dementia, its subtypes, and all-cause mortality in nondemented older individuals. We verified if vascular risk factors or depressive symptoms could modify this predictive role.
Longitudinal population-based study with 3.5- and 7-year of median follow-up.
Eight Italian municipalities included in the Italian Longitudinal Study on Aging.
In 2150 older individuals from the Italian Longitudinal Study on Aging, we operationalized reversible cognitive frailty with the presence of physical frailty and pre-mild cognitive impairment subjective cognitive decline, diagnosed with a self-report measure based on item 14 of the Geriatric Depression Scale.
Incidence of dementia, its subtypes, and all-cause mortality.
Over a 3.5-year follow-up, participants with reversible cognitive frailty showed an increased risk of overall dementia hazard ratio (HR) 2.30, 95% confidence interval (CI) 1.02-5.18, particularly vascular dementia (VaD), and all-cause mortality (HR 1.74, 95% CI 1.07-2.83). Over a 7-year follow-up, participants with reversible cognitive frailty showed an increased risk of overall dementia (HR 2.12, 95% CI 1.12-4.03), particularly VaD, and all-cause mortality (HR 1.39, 95% CI 1.03-2.00). Vascular risk factors and depressive symptoms did not have any effect modifier on the relationship between reversible cognitive frailty and incident dementia and all-cause mortality.
A model of reversible cognitive frailty was a short- and long-term predictor of all-cause mortality and overall dementia, particularly VaD. The absence of vascular risk factors and depressive symptoms did not modify the predictive role of reversible cognitive frailty on these outcomes.
Mounting evidence indicates an increased risk of cognitive impairment in adults with end-stage kidney disease on dialysis, but the extent and pattern of deficits across the spectrum of cognitive ...domains are uncertain.
We conducted a cross-sectional study of 676 adult hemodialysis patients from 20 centers in Italy, aiming to evaluate the prevalence and patterns of cognitive impairment across five domains of learning and memory, complex attention, executive function, language and perceptual-motor function. We assessed cognitive function using a neuropsychological battery of 10 tests and calculated test and domain z-scores using population norms (age or age/education). We defined cognitive impairment as a z-score ≤ -1.5.
Participants' median age was 70.9 years (range 21.6-94.1) and 262 (38.8%) were women. Proportions of impairment on each domain were as follows: perceptual-motor function 31.5% (150/476), language 41.2% (273/662), executive function 41.7% (281/674), learning and memory 42.2% (269/638), complex attention 48.8% (329/674). Among 474 participants with data for all domains, only 28.9% (n = 137) were not impaired on any domain, with 25.9% impaired on a single domain (n = 123), 17.3% on two (n = 82), 13.9% on three (n = 66), 9.1% on four (n = 43) and 4.9% (n = 23) on all five. Across patients, patterns of impairment combinations were diverse.
In conclusion, cognitive impairment is extremely common in hemodialysis patients, across numerous domains, and patients often experience multiple deficits simultaneously. Clinical care should be tailored to meet the needs of patients with different types of cognitive impairment and future research should focus on identifying risk factors for cognitive decline.
The aim of this multicenter, retrospective study is to investigate the role of clinical characteristics and therapeutic intervention on ALS prognosis. The study included patients diagnosed from ...January 1, 2009 to December 31, 2013 in 13 Italian referral centers for ALS located in 10 Italian regions. Caring neurologists collected a detailed phenotypic profile and follow-up data until death into an electronic database. One center collected also data from a population-based registry for ALS. 2648 incident cases were collected. The median survival time from onset to death/tracheostomy was 44 months (SE 1.18, CI 42–46). According to univariate analysis, factors related to survival from onset to death/tracheostomy were: age at onset, diagnostic delay, site of onset, phenotype, degree of certainty at diagnosis according to revised El Escorial criteria (R-EEC), presence/absence of dementia, BMI at diagnosis, patients’ provenance. In the multivariate analysis, age at onset, diagnostic delay, phenotypes but not site of onset, presence/absence of dementia, BMI, riluzole use, R-EEC criteria were independent prognostic factors of survival in ALS. We compared patients from an ALS Registry with patients from tertiary centers; the latter ones were younger, less frequently bulbar, but more frequently familial and definite at diagnosis. Our large, multicenter study demonstrated the role of some clinical and demographic factors on ALS survival, and showed some interesting differences between referral centers’ patients and the general ALS population. These results can be helpful for clinical practice, in clinical trial design and to validate new tools to predict disease progression.
Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship ...between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease.
Lumbar puncture (LP) has become increasingly common for people with Huntington's disease (HD) both to administer intrathecal investigational medicinal products and to collect cerebrospinal fluid to ...develop biological markers to track disease stage and progression. We aimed to investigate the safety profile of LP in people with HD, building on a recently published work by increasing the sample size and more specifically, increasing the representation of the premanifest population and healthy controls. We conducted a multi-study cross-sectional analysis including eligible participants from the HDClarity (304 Huntington's disease gene expansion carriers and 91 controls) and HD-YAS studies (54 premanifest and 48 controls), enrolled between February 2016 and September 2019. We investigated the odds of any adverse events, headaches, and back pain independently. Intergroup comparisons and adjusted event odds were derived using hierarchical logistic regressions. A total of 669 LP procedures involving 497 participants were included in this analysis. There were 184 (27.5%) LP procedures associated with one or more adverse events. The two most common adverse events were: post LP headache and back pain. Younger age and female gender were found to be associated with a higher risk of developing adverse events. There was no difference in the rate of adverse events between the disease subgroups after adjusting for covariates such as age and gender. Our results suggest that the LP is safe and tolerable in premanifest and manifest HD subjects, providing useful reassurance about the procedure to the HD community.
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