Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.

Controversial Past, Splendid Present, Unpredictable Future: A Brief Review of Alzheimer Disease History.

Background: The concept of Alzheimer disease (AD)-since its histological discovery by Alzheimer to the present day-has undergone substantial modifications. Methods: We conducted a classical narrative review of this field with a bibliography selection (giving preference to Medline best match). Results: The following subjects are reviewed and discussed: Alzheimer's discovery, Kraepelin's creation of a new disease that was a rare condition until the 1970's, the growing interest and investment in AD as a major killer in a society with a large elderly population in the second half of the 20th century, the consolidation of the AD clinicopathological model, and the modern AD nosology based on the dominant amyloid hypothesis among many others. In the 21st century, the development of AD biomarkers has supported a novel biological definition of AD, although the proposed therapies have failed to cure this disease. The incidence of dementia/AD has shown a decrease in affluent countries (possibly due to control of risk factors), and mixed dementia has been established as the most frequent etiology in the oldest old. Conclusions: The current concept of AD lacks unanimity. Many hypotheses attempt to explain its complex physiopathology entwined with aging, and the dominant amyloid cascade has yielded poor therapeutic results. The reduction in the incidence of dementia/AD appears promising but it should be confirmed in the future. A reevaluation of the AD concept is also necessary.

Validez discriminante y concordancia interobservador de 2 métodos de puntuación del test del reloj / Discriminant validity and inter-rater concordance of two scoring systems for the clock test

Objetivos Comparar la validez discriminante y la fiabilidad interobservador de los 2 métodos de corrección del test del reloj más usados en España. Metodología Se han evaluado 2 colecciones de dibujos del reloj obtenidos en un contexto clínico (116 casos; 56,8% mujeres, edad media 73,1±7,7 años) y en una cohorte de voluntarios (2.039 dibujos de 579 sujetos; 59,5% mujeres, edad media 78,3±3,8 años). Todos los sujetos fueron clasificados como sin deterioro cognitivo (DC−) o con deterioro cognitivo (DC+) tras una extensa evaluación clínica y neuropsicológica. Evaluadores expertos han valorado estos dibujos de forma independiente y sin conocimiento del diagnóstico con los métodos de Sunderland y Solomon estandarizados en español por Cacho (rango: 0 a 10) y del Ser (rango: 0 a 7), respectivamente. Se ha calculado la validez discriminante de cada método mediante el área bajo la curva ROC (aROC) en las 2 muestras, y la fiabilidad interobservador mediante el coeficiente de correlación intraclase (CCI) y el coeficiente kappa en la muestra clínica que fue valorada por los 2 evaluadores. Resultados No hay diferencias significativas en la validez discriminante de los métodos de Sunderland y Solomon en ninguna de las muestras (clínica: aROC: 0,73 [IC 95%: 0,64-0,81] y 0,77 [IC 95%: 0,69-0,85], respectivamente, p=0,19; voluntarios: aROC: 0,69 [IC 95%: 0,67-0,71] y 0,72 [IC 95%: 0,69-0,73], respectivamente, p=0,08). Los puntos de corte ≤8 y ≤5 clasifican correctamente al 71 y 73% de la muestra clínica y al 82 y 84% de la muestra de voluntarios, respectivamente. Los 2 métodos tienen una buena concordancia en la muestra clínica (AU)

Objective To compare the discriminant validity and inter-rater reliability of the two scoring systems for the Clock test that are most used in Spain. Methodology Two collections of clock drawings obtained in a clinical context (116 cases; 56.8% women, mean age 73.1±7.7 years) and in a cohort of volunteers (2039 drawings of 579 subjects; 59.5% women, mean age 78.3±3.8 years) have been assessed. All subjects were classified as cognitively normal (CN) or cognitively impaired (CI) after extensive clinical and neuropsychological evaluation. Expert raters have evaluated these drawings independently and without knowledge of the diagnosis using the Sunderland and Solomon systems standardized in Spanish by Cacho (range 0 to 10) and del Ser (range 0 to 7) respectively. The discriminant validity of each method was calculated in the two samples using the area under the ROC curve (aROC), and the inter-rater reliability was calculated in the clinical sample, that was assessed by the two evaluators, using the intraclass correlation coefficient (ICC) and the kappa coefficient. Results There are no significant differences in the discriminant validity of the Sunderland and Solomon systems in any of the samples (clinical: aROC 0.73 [CI95%: 0.64-0.81] and 0.77 [CI95%: 0.69-0.85] respectively, P=.19; volunteers: aROC 0.69 [CI95%: 0.67-0.71] and 0.72 [CI95%: 0.69-0.73] respectively, P=.08). The cut-off points ≤8 and ≤5 correctly classify 71% and 73% of the clinical sample and 82% and 84% of the volunteer sample, respectively. Both systems have good agreement in the clinical sample (Sunderland: ICC 0.90 [CI95%: 0.81-0.93], kappa 0.76 [CI95%: 0.70-0.83]; Solomon: 0.92 [CI95%: 0.88-0.95] and 0.77 [CI95%: 0.71-0.83] respectively), somewhat higher in the second, although the differences are not significant (AU)

[Discriminant validity and inter-rater concordance of two scoring systems for the clock test]. / Validez discriminante y concordancia interobservador de 2 métodos de puntuación del test del reloj.

OBJECTIVE: To compare the discriminant validity and inter-rater reliability of the two scoring systems for the Clock test that are most used in Spain. METHODOLOGY: Two collections of clock drawings obtained in a clinical context (116 cases; 56.8% women, mean age 73.1±7.7 years) and in a cohort of volunteers (2039 drawings of 579 subjects; 59.5% women, mean age 78.3±3.8 years) have been assessed. All subjects were classified as cognitively normal (CN) or cognitively impaired (CI) after extensive clinical and neuropsychological evaluation. Expert raters have evaluated these drawings independently and without knowledge of the diagnosis using the Sunderland and Solomon systems standardized in Spanish by Cacho (range 0 to 10) and del Ser (range 0 to 7) respectively. The discriminant validity of each method was calculated in the two samples using the area under the ROC curve (aROC), and the inter-rater reliability was calculated in the clinical sample, that was assessed by the two evaluators, using the intraclass correlation coefficient (ICC) and the kappa coefficient. RESULTS: There are no significant differences in the discriminant validity of the Sunderland and Solomon systems in any of the samples (clinical: aROC 0.73 [CI95%: 0.64-0.81] and 0.77 [CI95%: 0.69-0.85] respectively, P=.19; volunteers: aROC 0.69 [CI95%: 0.67-0.71] and 0.72 [CI95%: 0.69-0.73] respectively, P=.08). The cut-off points ≤8 and ≤5 correctly classify 71% and 73% of the clinical sample and 82% and 84% of the volunteer sample, respectively. Both systems have good agreement in the clinical sample (Sunderland: ICC 0.90 [CI95%: 0.81-0.93], kappa 0.76 [CI95%: 0.70-0.83]; Solomon: 0.92 [CI95%: 0.88-0.95] and 0.77 [CI95%: 0.71-0.83] respectively), somewhat higher in the second, although the differences are not significant. CONCLUSIONS: The discriminant validity and inter-observer reliability of these two Clock Test correction systems are similar. Solomon's method, shorter and simpler, may be more advisable in pragmatic terms.

Sex differences for cognitive decline in progressive supranuclear palsy.

INTRODUCTION: Cognitive dysfunction is a core clinical feature of progressive supranuclear palsy (PSP), with executive function being most markedly affected. In other neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, there are a growing number of reports demonstrating that cognition is differentially impacted in men and women. In PSP, however, the sex differences in cognitive decline have yet to be fully characterized. METHODS: Data were obtained from the TAUROS trial for 139 participants with mild-to-moderate PSP (62 women, 77 men). Sex differences in longitudinal change in cognitive performance were evaluated with linear mixed models. Exploratory subgroup analyses assessed whether sex differences varied by baseline executive dysfunction, PSP phenotype, or baseline age. RESULTS: In the primary whole group analyses, there were no sex differences for change in cognitive performance. Among participants with normal executive function at baseline, men declined more severely on executive function and language tests. Among the PSP-Parkinsonism subgroup, men declined more severely on category fluency. Across people aged≥65, men had a worse decline on category fluency, whereas across people aged <65, women had a worse decline on DRS construction. CONCLUSION: In people with mild-to-moderate PSP, there are no sex differences in cognitive decline. However, the rate of cognitive decline may differ for women and men based on the level of baseline executive dysfunction, PSP-phenotype and age. Further studies are needed to clarify how sex differences in PSP clinical progression vary by disease stage and to examine the contributions of co-pathology to these observed sex differences.

Oral Microbiota, Its Equilibrium and Implications in the Pathophysiology of Human Diseases: A Systematic Review.

Imbalances of the oral microbiota and dysbiosis have traditionally been linked to the occurrence of teeth and oral diseases. However, recent findings indicate that this microbiota exerts relevant influence in systemic health. Dysbiosis of the oral microbiota is implicated in the apparition and progression of cardiovascular, neurodegenerative and other major human diseases. In fact, the oral microbiota are the second most diverse and largely populated microbiota of the human body and its relationships with systemic health, although widely explored, they still lack of proper integration. The purpose of this systematic review is thus to widely examine the implications of oral microbiota in oral, cardiovascular and neurodegenerative diseases to offer integrative and up-to-date interpretations. To achieve that aim, we identified a total of 121 studies curated in PUBMED from the time interval January 2003-April 2022, which after careful screening resulted in 79 studies included. The reviewed scientific literature provides plausible vias of implication of dysbiotic oral microbiota in systemic human diseases, and encourages further research to continue elucidating the highly relevant and still poorly understood implications of this niche microbiota in systemic health. PROSPERO Registration Number: CRD42022299692. This systematic review follows relevant PRISMA guidelines.

Education and Literacy as Risk Factors of Dementia after Stroke and Transient Ischemic Attack: NEDICES Study.

BACKGROUND: A protective effect of education on cognitive decline after stroke has been claimed, but evidence from prospective population-based cohorts is very limited. The differential role of literacy and education on dementia after stroke remains unexplored. OBJECTIVE: This research addresses the role of education and literacy in dementia incidence after stroke and transient ischemic attack (TIA). METHODS: 131 participants with stroke or TIA were identified within the population-based NEDICES study (N = 5,278 persons). Participants were fully assessed at baseline (1994-1995) and incident dementia diagnosis was made by expert neurologists (DSM-IV criteria) after a mean follow-up of 3.4 years. Adjusted Cox regression analyses were applied to test the association between education, literacy, and dementia risk. RESULTS: Within the 131 subjects with stroke or TIA, 19 (14%) developed dementia at follow-up. The Cox's regression model (age and sex adjusted) showed that low education (HR = 3.48, 95% CI = 1.28, 9.42, p = 0.014) and literacy (HR = 3.16, 95% CI = 1.08, 9.22, p = 0.035) were significantly associated with a higher dementia risk. Low education was also associated with dementia when main confounders (i.e., cognitive/functional performance) were considered in the Cox's model. However, after including stroke recurrence, only low/null literacy (versus education) remained as significant predictor of dementia. Finally, low/null literacy showed an effect over-and-above education on dementia risk when both factors were introduced in the adjusted Cox's regression. CONCLUSION: These findings underline the importance of literacy to estimate cognitive decline after stroke in low-educated populations.

The health status: the ignored risk factor in dementia incidence. NEDICES cohort.

BACKGROUND: The causes of the dementia decrease in affluent countries are not well known but health amelioration could probably play a major role. Nevertheless, although many vascular and systemic disorders in adult life are well-known risk factors (RF) for dementia and Alzheimer disease (AD), health status is rarely considered as a single RF. AIM: To analyse whether the health status and the self-perceived health (SPH) could be RF for dementia and AD and to discuss its biological basis. METHODS: We analysed different objective health measures and SPH as RF for dementia and AD incidence in 4569 participants of the NEDICES cohort by means of Cox-regression models. The mean follow-up period was 3.2 (range: 0.03-6.6) years. RESULTS: Ageing, low education, history of stroke, and "poor" SPH were the main RF for dementia and AD incidence, whereas physical activity was protective. "Poor" SPH had a hazard ratio = 1.66 (95% CI 1.17-2.46; p = 0.012) after controlling for different confounders. DISCUSSION: According to data from NEDICES cohort, SPH is a better predictor of dementia and AD than other more objective health status proxies. SPH should be considered a holistic and biologically rooted indicator of health status, which can predict future development of dementia and AD in older adults. CONCLUSIONS: Our data indicate that it is worthwhile to include the SPH status as a RF in the studies of dementia and AD incidence and to explore the effect of its improvement in the evolution of this incidence.

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study.

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

MADRID+90 study on factors associated with longevity: Study design and preliminary data.

The progressive aging of the population represents a challenge for society. In particular, a strong increase in the number of people over 90 is expected in the next two decades. As this phenomenon will lead to an increase in illness and age-related dependency, the study of long-lived people represents an opportunity to explore which lifestyle factors are associated with healthy aging and which with the emergence of age-related diseases, especially Alzheimer's type dementia. The project "Factors associated with healthy and pathologically aging in a sample of elderly people over 90 in the city of Madrid" (MADRID+90) brings together a multidisciplinary research team in neurodegenerative diseases that includes experts in epidemiology, neurology, neuropsychology, neuroimaging and computational neuroscience. In the first phase of the project, a stratified random sampling was carried out according to the census of the city of Madrid followed by a survey conducted on 191 people aged 90 and over. This survey gathered information on demographics, clinical data, lifestyles and cognitive status. Here, the main results of that survey are showed. The second phase of the project aims to characterize individual trajectories in the course of either healthy and pathological aging, from a group of 50 subjects over 90 who will undergo a comprehensive clinical examination comprised of neurological and cognitive testing, MRI and EEG. The ultimate goal of the project is to characterize the biophysical and clinical profiles of a population that tends to receive little attention in the literature. A better understanding of the rapidly increasing group of nonagenarians will also help to design new policies that minimize the impact and future social and economic consequences of rapidly aging societies.

Residence, Clinical Features, and Genetic Risk Factors Associated with Symptoms of COVID-19 in a Cohort of Older People in Madrid.

BACKGROUND: The older population has been especially affected by the severe acute respiratory syndrome coronavirus 2 pandemic (COVID-19). OBJECTIVE: The aim of the study was to explore the incidence, severity, mortality rate, clinical features, and risk factors of symptoms of COVID-19 in home-dwelling older people, and its association with type of residence, cognitive deterioration, and neurodegenerative diseases. METHODS: Data about symptoms of COVID-19 were collected through a telephone survey in the cohort of 913 older volunteers of the Vallecas Project, aged 75-90 years, most of them (902) home-dwelling, in Madrid, Spain. The association of demographic and anthropometric measures, genetic polymorphisms, comorbidities, life habits, type of residence, and frailty surrogates were explored as potential risk factors for the incidence, severity, and mortality of COVID-19 in the older population. FINDINGS: Sixty-two cases reported symptoms compatible with COVID-19; 6 of them had died, 4 in their home and 2 in the nursing home. Moderate/severe cases were significantly older and more frequently males. The APOE ε4 allele was associated with the presence of symptoms of COVID-19. Higher systolic blood pressure, more intense smoking habit, more alcohol intake, lower consumption of coffee and tea, and cognitive impairment were associated with disease severity. CONCLUSIONS: The estimated incidence of symptomatic COVID-19 in this older cohort of Madrid was 6.8%, with an overall mortality rate of 0.7% (18.2% in those living in a nursing home) and a fatality rate of 9.9%. Our exploratory study indicates that life habits, other clinical conditions and, the ε4 variant of the APOE gene are associated with the presence and clinical severity of coronavirus infection.

A Modified Progressive Supranuclear Palsy Rating Scale.

BACKGROUND: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status. OBJECTIVE: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones. METHODS: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy. RESULTS: The modified scale retained 14 items (yielding 0-2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months). CONCLUSIONS: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society.

Predementia constructs: Mild cognitive impairment or mild neurocognitive disorder? A narrative review.

BACKGROUND: Predementia is a heuristic umbrella concept to classify older adults with cognitive impairment who do not suffer dementia. Many diagnostic entities have been proposed to address this concept, but most of them have not had widespread acceptance. AIMS: To review clinical definitions, epidemiologic data (prevalence, incidence) and rate of conversion to dementia of the main predementia constructs, with special interest in the two most frequently used: mild cognitive impairment (MCI) and minor neurocognitive disorder (miNCD). METHODS: We have selected in three databases (MEDLINE, Web of Science and Google scholar) the references from inception to 31 December 2019 of relevant reviews, population and community-based surveys, and clinical series with >500 participants and >3 years follow-up as the best source of evidence. MAIN RESULTS: The history of predementia constructs shows that MCI is the most referred entity. It is widely recognized as a clinical syndrome harbinger of dementia of several etiologies, mainly MCI due to Alzheimer's disease. The operational definition of MCI has shortcomings: vagueness of its requirement of "preserved independence in functional abilities" and others. The recent miNCD construct presents analogous difficulties. Current data indicate that it is a stricter predementia condition, with lower prevalence than MCI, less sensitivity to cognitive decline and, possibly, higher conversion rate to dementia. CONCLUSIONS: MCI is a widely employed research and clinical entity. Preliminary data indicate that the clinical use of miNCD instead of MCI requires more scientific evidence. Both approaches have common limitations that need to be addressed.

Tau phosphorylation by glycogen synthase kinase 3ß modulates enzyme acetylcholinesterase expression.

In Alzheimer's disease (AD), the enzyme acetylcholinesterase (AChE) co-localizes with hyperphosphorylated tau (P-tau) within neurofibrillary tangles. Having demonstrated that AChE expression is increased in the transgenic mouse model of tau Tg-VLW, here we examined whether modulating phosphorylated tau levels by over-expressing wild-type human tau and glycogen synthase kinase-3ß (GSK3ß) influences AChE expression. In SH-SY5Y neuroblastoma cells expressing higher levels of P-tau, AChE activity and protein increased by (20% ± 2%) and (440% ± 150%), respectively. Western blots and qPCR assays showed that this increment mostly corresponded to the cholinergic ACHE-T variant, for which the protein and transcript levels increased ~60% and ~23%, respectively. Moreover, in SH-SY5Y cells differentiated into neurons by exposure to retinoic acid (10 µM), over-expression of GSK3ß and tau provokes an imbalance in cholinergic activity with a decrease in the neurotransmitter acetylcholine in the cell (45 ± 10%). Finally, we obtained cerebrospinal fluid (CSF) from AD patients enrolled on a clinical trial of tideglusib, an irreversible GSK3ß inhibitor. In CSF of patients that received a placebo, there was an increase in AChE activity (35 ± 16%) respect to basal levels, probably because of their treatment with AChE inhibitors. However, this increase was not observed in tideglusib-treated patients. Moreover, CSF levels of P-tau at the beginning measured by commercially ELISA kits correlated with AChE activity. In conclusion, this study shows that P-tau can modulate AChE expression and it suggests that AChE may possibly increase in the initial phases of AD.

Impact of individual and neighborhood dimensions of socioeconomic status on the prevalence of mild cognitive impairment over seven-year follow-up.

Objectives: There is strong evidence about the association between low socioeconomic status (SES) and higher risk of dementia. However, it has not been conveniently addressed so far the role of SES on the incidence of mild cognitive impairment (MCI). This study examines the impact of individual and neighbourhood dimensions of SES, as well as their interaction, on the risk of developing MCI in a sample of older adults.Method: Data from the Vallecas Project cohort, an ongoing community-based longitudinal study for early detection of cognitive impairment and dementia, were used to build two indices of SES namely individual and neighbourhood, as well as a global SES as a combination of both, and to investigate their effects on MCI conversion by means of a multivariate-adjusted Cox proportional hazard model.Results: A total of 1180 participants aged 70 years and older were enrolled in this study. Of these, 199 cases of MCI (16.9%) were diagnosed at any point of the follow-up. The individual and neighbourhood dimensions of SES played different roles in the dynamics of the MCI occurrence through aging. Most importantly, the risk of developing MCI was almost double for lower SES quartiles when compared to the highest one.Conclusion: The incidence of MCI in older adults was related to both individual characteristics and socioeconomic context. Public health strategies should be holistic and focus not only on promoting the classical individual preventive measures, but also on reducing social inequalities to foster healthy aging and reduce dementia burden.

Antiseizure medication withdrawal in seizure-free patients with PCDH19-related epilepsy: A multinational cohort survey.

PURPOSE: PCDH19-related epilepsy is usually refractory to current antiseizure medications (ASM), but seizures are easier to control especially after the second decade of life. Nonetheless, there is no evidence regarding the withdrawal of ASM in this clinical scenario. We aimed to evaluate the outcomes of attempts to discontinue ASM in seizure-free patients with PCDH19-related epilepsy. METHODS: This survey was a cross-sectional study of patients with PCDH19-related epilepsy open between June 2019 and February 2020 and implemented in collaboration with international patient advocacy groups. Caregivers or patients were asked to fill out an anonymous questionnaire of clinical data about the attempts of ASM reduction. RESULTS: The survey received 42 unique responses with collected data of 77 attempts of ASM withdrawal. Median age at the ASM reduction was 10 years and mean duration of the previous seizure-free period was 35.8 months. Overall, 88.3 % had seizure recurrence (p < 0.001). After seizure recurrence, the medication had to be increased above the previous ASM dose in 36.5 % and come back to the previous one in 25.4 % cases. 5.2 % did not become seizure-free again. Only 2.6 % cases had their ASM totally withdrawn. Patients without seizure recurrence were significantly older and showed longer seizure-free period (p < 0.001). CONCLUSION: This pilot study in PCDH19-related epilepsy shows that the withdrawal of ASM seems to be associated with a high risk of seizure recurrence. Despite this novel methodology is useful for rare diseases, it has some limitations and biases. Additional studies are warranted in more extensive samples.

Salivary lactoferrin as biomarker for Alzheimer's disease: Brain-immunity interactions.

OBJECTIVE: We aim to explain why salivary lactoferrin (Lf) levels are reduced in patients suffering mild cognitive impairment (MCI) and sporadic Alzheimer's disease (sAD).1 We also will discuss if such Lf decrease could be due to a downregulation of the sAD associated systemic immunity. BACKGROUND: Several non-neurological alterations have been described in sAD, mainly in skin, blood cell, and immunological capacities. We reviewed briefly the main pathophysiological theories of sAD (amyloid cascade, tau, unfolder protein tau, and amyloid deposits) emphasizing the most brain based hypotheses such as the updated tau-related neuron skeletal hypothesis; we also comment on the systemic theories that emphasize the fetal origin of the complex disorders that include the low inflammatory and immunity theories of sAD. NEW/UPDATED HYPOTHESIS: Lf has important anti-infectious and immunomodulatory roles in health and disease. We present the hypothesis that the reduced levels of saliva Lf could be an effect of immunological disturbances associated to sAD. Under this scenario, two alternative pathways are possible: first, whether sAD could be a systemic disorder (or disorders) related to early immunological and low inflammatory alterations; second, if systemic immunity alterations of sAD manifestations could be downstream of early sAD brain affectations. MAJOR CHALLENGES FOR THE HYPOTHESIS: The major challenge of the Lf as early sAD biomarker would be its validation in other clinical and population-based studies. It is possible the decreased salivary Lf in early sAD could be related to immunological modulation actions, but other different unknown mechanisms could be the origin of such reduction. LINKAGE TO OTHER MAJOR THEORIES: This hypothesis is in agreement with two physiopathological explanations of the sAD as a downstream process determined by the early lesions of the hypothalamus and autonomic vegetative system (neurodegeneration), or as a consequence of low neuroinflammation and dysimmunity since the early life aggravated in the elderly (immunosenescence).

Effects of commonly prescribed drugs on cognition and mild cognitive impairment in healthy elderly people.

BACKGROUND: Chronic drug intake has been associated with negative and positive cognitive effects in elderly people, although subjacent conditions may be confounding factors. AIM: To study the effects on cognitive performance of commonly prescribed medications in a cohort of cognitively normal older adults. METHODS: Medication intake was recorded during two years in 1087 individuals 70-85 years old, without neurological or psychiatric conditions. The influence of every drug, drug family and therapeutic group on six cognitive scores and on the conversion to mild cognitive impairment over two years was ascertained by cross-sectional and longitudinal analyses controlling for demographic and clinical variables. RESULTS: Small effects of several drugs on information processing were found in cross-sectional analyses but only confirmed for a positive effect of vitamin D in case-control analyses. Longitudinal analyses showed no drug effects on the cognitive slopes. Several hypotensive drugs reduced, whereas bromazepam and glucose lowering drugs increased, the conversion rate to mild cognitive impairment with very small effects (R2=0.3-1%). CONCLUSIONS: Cognitively healthy elderly individuals show minimal negative effects on information processing associated with chronic intake of some drugs probably related to the subjacent condition. Some drugs slightly affect the rate of conversion to mild cognitive impairment. Positive effects of vitamin D, chondroitin, atorvastatin and antihypertensive drugs, and negative effects of antidepressants and benzodiazepines, should be further explored in studies with longer follow-up.

Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations.

BACKGROUND: Progressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP. OBJECTIVES: To determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS. METHODS: Multicenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity. RESULTS: The earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity. CONCLUSION: The PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Longitudinal magnetic resonance imaging in progressive supranuclear palsy: A new combined score for clinical trials.

BACKGROUND: Two recent, randomized, placebo-controlled phase II/III trials (clinicaltrials.gov: NCT01110720, NCT01049399) of davunetide and tideglusib in progressive supranuclear palsy (PSP) generated prospective, 1-year longitudinal datasets of high-resolution T1-weighted three-dimensional MRI. OBJECTIVE: The objective of this study was to develop a quantitative MRI disease progression measurement for clinical trials. METHODS: The authors performed a fully automated quantitative MRI analysis employing atlas-based volumetry and provide sample size calculations based on data collected in 99 PSP patients assigned to placebo in these trials. Based on individual volumes of 44 brain compartments and structures at baseline and 52 weeks of follow-up, means and standard deviations of annualized percentage volume changes were used to estimate standardized effect sizes and the required sample sizes per group for future 2-armed, placebo-controlled therapeutic trials. RESULTS: The highest standardized effect sizes were found for midbrain, frontal lobes, and the third ventricle. Using the annualized percentage volume change of these structures to detect a 50% change in the 1-year progression (80% power, significance level 5%) required lower numbers of patients per group (third ventricle, n = 32; midbrain, n = 37; frontal lobe, n = 43) than the best clinical scale (PSP rating scale total score, n = 58). A combination of volume changes in these 3 structures reduced the number of required patients to only 20 and correlated best with the progression in the clinical scales. CONCLUSIONS: We propose the 1-year change in the volumes of third ventricle, midbrain, and frontal lobe as combined imaging read-out for clinical trials in PSP that require the least number of patients for detecting efficacy to reduce brain atrophy. © 2017 International Parkinson and Movement Disorder Society.