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The prevalence of dementia is currently increasing worldwide. This syndrome produces a deterioration in cognitive function that cannot be reverted. However, an early diagnosis can be crucial for slowing its progress. The Clock Drawing Test (CDT) is a widely used paper-and-pencil test for cognitive assessment in which an individual has to manually draw a clock on a paper. There are a lot of scoring systems for this test and most of them depend on the subjective assessment of the expert. This study proposes a computer-aided diagnosis (CAD) system based on artificial intelligence (AI) methods to analyze the CDT and obtain an automatic diagnosis of cognitive impairment (CI). This system employs a preprocessing pipeline in which the clock is detected, centered and binarized to decrease the computational burden. Then, the resulting image is fed into a Convolutional Neural Network (CNN) to identify the informative patterns within the CDT drawings that are relevant for the assessment of the patient’s cognitive status. Performance is evaluated in a real context where patients with CI and controls have been classified by clinical experts in a balanced sample size of [Formula: see text] drawings. The proposed method provides an accuracy of [Formula: see text] in the binary case-control classification task, with an AUC of [Formula: see text]. These results are indeed relevant considering the use of the classic version of the CDT. The large size of the sample suggests that the method proposed has a high reliability to be used in clinical contexts and demonstrates the suitability of CAD systems in the CDT assessment process. Explainable artificial intelligence (XAI) methods are applied to identify the most relevant regions during classification. Finding these patterns is extremely helpful to understand the brain damage caused by CI. A validation method using resubstitution with upper bound correction in a machine learning approach is also discussed.

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.

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.

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)

Early View: Online Version of Record before inclusion in an issue., 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‐3β (GSK3β) 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 GSK3β 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 GSK3β 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., MACG is supported by a GVA-Predoctoral fellowship from Generalitat Valenciana, Spain. This study was funded by Instituto de Salud Carlos III (ISCIII), Fondo de Investigaciones Sanitaria (grants CP11/00067 and PI17/00261 to MSGA); co-financed by Fondo Europeo de Desarrollo Regional and through CIBERNED, ISCIII, Spain.

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.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.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.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.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.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.

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.

Describe PSP Study Group, the ProPSP Study Group, and the Movement Disorder Society–Endorsed PSP Study Group., [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., This work was supported by the Munich Cluster for Systems Neurology (Synergy), the Volkswagen Stiftung, the Lower Saxony Ministry for Science, the Niedersächsisches Vorab, and the Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies). This project was also supported by the German Center for Neurodegenerative Diseases e.V. (DZNE), German PSP Gesellschaft, and the International Parkinson & Movement Disorder Society.

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.

The progressive ageing 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 ageing 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 powerful 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 ageing, 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 the ageing phenomenon.

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.

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.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.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).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.

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

IMPORTANCE: 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) which is considered a prodromal stage of latter dementia.OBJECTIVE: To examine the impact of individual and neighborhood dimensions of SES, as well as their interaction, on the risk of developing MCI in a sample of older adults that were followed-up for seven years.DESIGN, SETTING, AND PARTICIPANTS: 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 neighborhood, 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.MAIN OUTCOMES AND MEASURES: Based on data referred to as individual-level (one´s educational attainment, occupation, parent´s level of education) and neighborhood-level (district´s income, unemployment rate, housing price, percentage of people with no formal qualifications, with higher education, and with white-collar employs) different composite measures of SES were built and quartiles were considered for further analyses. MCI diagnoses were agreed between neurologists and neuropsychologists at consensus meetings.RESULTS: 1180 participants aged 70 years and older were enrolled in this study (mean age at baseline, 74.9 years; 63.5% females). Of these, 199 cases of MCI (16.9%) were diagnosed at any point of the follow-up. The individual and neighborhood dimensions of SES played different roles in the dynamics of the MCI occurrence through ageing. Most importantly, the risk of developing MCI was almost double for lower SES quartiles when compared to the highest one.CONCLUSIONS AND RELEVANCE: 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 as a means of fostering healthy ageing and reducing dementia burden.

Alzheimer’s Disease (AD) is a complex, multifactorial and comorbid condition. The asymptomatic behavior in early stages of the disease is a paramount obstacle to formulate a preclinical and predictive model of AD. Not surprisingly, the AD drug approval rate is one of the lowest in the industry, an exiguous 0.4%. The identification of risk factors, preferably obtained by the subject herself, is sorely needed given that the incidence of Alzheimer’s disease grows exponentially with age [Ferri et al., 2005], [Ganguli and Rodriguez, 2011].During the last 7 years, researchers at Proyecto Vallecas have collected information about the project’s volunteers, aged 70 or more. The Proyecto Vallecas dataset includes information about a wide range of factors including magnetic resonance imaging, genetic, demographic, socioeconomic, cognitive performance, subjective memory complaints, neuropsychiatric disorders, cardiovascular, sleep, diet, physical exercise and self assessed quality of life. The subjects in each visit were diagnosed as healthy, mild cognitive impairment (MCI) or dementia.In this study we perform Exploratory Data Analysis to summarize the main characteristics of this unique longitudinal dataset. The objective is to characterize the evolution of the collected features over time and most importantly, how their dynamics are related to cognitive decline. We show that the longitudinal dataset of Proyecto Vallecas, if conveniently exploited, holds promise to identifying either factors promoting healthy aging and risk factors related to cognitive decline.

The effect of different educational indices on clinical diagnosis of dementia requires more investigation.We compared the differential influence of two educational indices (EIs): years of schooling and level of education (i.e., null/low literacy, can read and write, primary school, and secondary school) on global cognition, functional performance, and the probability of having a dementia diagnosis.A total of 3,816 participants were selected from the population-based study of older adults "Neurological Disorders in Central Spain" (NEDICES). The 37-item version of the Mini-Mental State Examination (MMSE-37) and the Pfeffer's questionnaire were applied to assess cognitive and functional performance, respectively. The diagnosis of dementia was performed by expert neurologists according to Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria. Logistic regression models adjusted for potential confounders were carried out to test the association between the two EIs and dementia diagnosis.Both EIs were significantly associated with cognitive and functional scores, but individuals with null/low literacy performed significantly worse on MMSE-37 than literates when these groups were compared in terms of years of schooling. The two EIs were also related to an increased probability of dementia diagnosis in logistic models, but the association's strength was stronger for level of education than for years of schooling.Literacy predicted cognitive performance over and above the years of schooling. Lower education increases the probability of having a dementia diagnosis but the impact of different EIs is not uniform.

Introduction To avoid bias and optimize statistical power of disease-modifying therapeutic trials, it is critical to include homogeneous populations with similar rate of progression over time. Patients with Progressive Supranuclear Palsy (PSP)-Parkinsonism phenotype have overall slower disease progression than those with PSP-Richardson syndrome phenotype. However, it is unclear if the progression rate of PSP-Parkinsonism is the same when the PSP-Parkinsonism converts to PSP Richardson syndrome. We aimed to determine and compare disease progression rate of patients with the two most common PSP phenotypes: PSP-Parkinsonism and PSP Richardson syndrome, participating in the TAUROS trial. Methods 138 patients, 56 with PSP-Parkinsonism and 82 with PSP-Richardson syndrome, with similar clinical severity at baseline, were followed up to 60 weeks. PSP-Parkinsonism allocation was based on experts’ judgement and PSP-Richardson on probable NINDS-PSP criteria. Global disease progression was measured by the PSP Rating Scale as primary outcome measure and several secondary outcome measures. Results PSP-Richardson syndrome patients had significantly faster progression based on the primary and three secondary outcome measures: the Dementia Rating Scale-2, Frontal Assessment Battery, and lexical fluency scale. Analyses including only patients with a baseline symptom duration under five years showed similar results. PSP phenotype was the strongest predictor for disease progression. Conclusion This research showed that even when disease severity and clinical features at baseline are similar, patients with PSP- Richardson syndrome progressed significantly faster than those with PSP-Parkinsonism. Therefore, unless stratified by phenotype, future therapeutic clinical trials should not lump PSP patients with these phenotypes as a single disorder even if they have similar disease severity at screening.

Background: Little is known about the long-term acceptance and effects of cognitive and motor stimulation interventions (CMSI) in Alzheimer’s disease (AD). Objective: To evaluate a replicable CMSI program for mild cognitive impairment (MCI) and mild-to-moderate AD persons. Methods: Eighty-four non-institutionalized subjects with AD were randomized to receive either CMSI, administered by a single care provider, or standard support. Cognition, activities of daily living (ADL), mood, and study partner’s subjective burden were assessed by blinded raters. Data on institutionalization, psychiatric medications, and demise were collected by the study physicians. Random effects model and survival analyses were conducted, after 2 and 3 years of study. Results: Three-year assessments could be performed by the physician in 85% and by the blinded rater in 66% of subjects. Significant benefits were observed in basic ADL at the 2- and 3-year assessments, whereas instrumental ADL showed benefits only up to the second year of intervention (p < 0.05). Conclusion: Long-term cognitive-motor stimulation is well accepted and produces functional benefits in subjects with AD, with no extra subjective burden in the partner.

The influence of education and oral word-reading ability on cognitive performance was examined in a sample of 1510 nondemented elders differing in socioeconomic status (SES) from three Spanish communities.All individuals were enrolled in the Neurological Disorders in Central Spain, a population-based epidemiological study in central Spain. They completed a detailed demographic survey and a short standardized neuropsychological battery assessing psychomotor speed, attention, language, and memory. The Word Accentuation Test (WAT) was used as measure of oral reading ability. The influence of education and oral reading on cognitive performance was determined by multiple linear regression models, first controlling for demographics (age and sex), and subsequently for the WAT score and education. The contribution of socioeconomic conditions was addressed by stratifying the sample into groups of high and low SES.The WAT showed a significant independent effect on cognitive scores, generally greater than that predicted by demographics. The higher predictive power of oral word reading on cognitive scores compared to education was consistent across the three communities. Although the variance explained by WAT was very similar in areas with diverse SES (low vs. high), WAT scores accounted for slightly more variance in naming and memory tasks in low SES areas. In contrast, the variance explained by WAT was higher for verbal fluency and the Trail-Making Test in areas with high SES.Oral word-reading ability predicts cognitive performance better than years of education across individuals with different SES. The influence of WAT may be modulated by SES and cognitive task properties.

It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 weeks. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale; Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clinical Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examined. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clinical efficacy in patients with mild-to-moderate PSP.

It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high-resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: -1.3% ± 1.4% vs. -3.1% ± 2.3%, respectively), cerebrum (-1.3% ± 1.5% vs. -3.2% ± 2.1%, respectively), parietal lobe (-1.6% ± 1.9% vs. -4.1% ± 3.0%, respectively), and occipital lobe (-0.3% ± 1.8% vs. -2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.

This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.

Background and Purpose— Evidence of drug efficacy in vascular dementia (VaD) is scanty. Therapeutic trials should address VaD subtypes. We studied the efficacy and safety of the calcium antagonist nimodipine in subcortical VaD. Methods— 242 patients defined as affected by subcortical VaD based on clinical (ICD-10) and computed tomography criteria were randomized to oral nimodipine 90 mg/d or placebo. Results— 230 patients (121 nimodipine, mean age 75.2±6.1; 109 placebo, 75.4±6.0) were valid for the intention-to-treat analysis. At 52 weeks, the Sandoz Clinical Assessment Geriatric scale 5-point variation (primary outcome measure) did not differ significantly between the 2 groups. However, patients on nimodipine performed better than placebo patients in lexical production ( P 2 P P Conclusions— Nimodipine may be of some benefit in subcortical VaD. Confirming previous results, the safety analysis of this study shows that in this high-risk population, nimodipine might protect against cardiovascular comorbidities.

This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies.The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life.The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies.The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.

Aim To validate the ‘Prueba Cognitiva de Leganes’ (PCL) as a screening tool for cognitive impairment in elderly people with little formal education. Methods The PCL is a simple cognitive test with 32 items that includes two scores of orientation and memory and a global score of 0–32 points. It was applied to a population sample of 527 elderly people over 70 with low educational level, who were independently diagnosed by consensus between two neurologists as having normal cognitive function, age associated cognitive decline (AACD, IPA-OMS criteria) or dementia (DSM-IV criteria). Individuals with severe visual or hearing defects and those who rejected the exam were excluded from the study. The PCL was validated in a sample of 375 individuals: 300 normal, 42 with AACD and 33 with dementia. The sensitivity, specificity, accuracy and likelihood ratios, as well as the ROC curves for dementia and for AACD-dementia, were calculated. The confounding effect of sociodemographic variables was assessed by logistic regression analysis and convergent validity by partial correlations of the PCL with other cognitive tests. Inter-rater reliability was evaluated with the intraclass correlation coefficient. Results The PCL identified dementia (cut-off ≤22) and AACD-dementia (cut-off ≤26), with the following diagnostic parameters, respectively: sensitivity 93.9%–80%, specificity 94.7%–84.3%, positive likelihood ratio 17.8–5.1, negative likelihood ratio 0.06–0.24, and accuracy 94.6%–83.4%. The areas under the ROC curve were 0.985 (95% Confidence Intervals (CI) 0.967–0.995) and 0.904 (95% CI: 0.870–0.932) respectively. The intraclass correlation coefficient was 0.79 (0.74–0.83). Conclusion The PCL is a simple instrument, which is both valid and reliable, for the screening of dementia in population samples of individuals with low educational level. This instrument could be useful in primary health care. Copyright © 2003 John Wiley & Sons, Ltd.

The Objective of this research was to study the relationship of angiotensin converting enzyme (ACE) genotype with serum triglycerides concentration in stroke patients. The insertion/deletion (I/D) ACE polymorphism was identified by using polymerase chain reaction in 122 prospectively studied ischemic stroke patients (age 45–91 years). Serum triglycerides concentration was determined at admission and 3 months after the stroke, and compared between the ACE genotype groups (37 D/D, 68 D/I, 17 I/I). All clinical characteristics were similar in the three groups. Patients with D/D genotype had mean serum triglycerides concentration significantly higher in acute (179.0±111.8 mg/dl) and chronic phase (176.4±121.6 mg/dl) than those with I/I genotype (acute phase: 108.7±36.1 mg/dl, P =0.019; chronic phase: 116.0±44.3 mg/dl, P =0.021). The results showed that serum triglycerides concentration is elevated in stroke patients with the DD ACE genotype and it may be related to the risk of cerebrovascular disease associated with this polymorphism.

Summary Background Dementia with Lewy bodies is a common form of dementia in the elderly, characterised clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other neuropsychiatric features. Neuroleptic medication can provoke severe sensitivity reactions in patients with dementia of this type. Many deficits in cholinergic neurotransmission are seen in the brain of patients with Lewy-body dementia; therefore, drugs enhancing central cholinergic function represent a rationally-based therapeutic approach to this disorder. Rivastigmine, a cholinesterase inhibitor, was tested in a group of clinically characterised patients with Lewy-body dementia. Methods A placebo-controlled, double-blind, multicentre study was done in 120 patients with Lewy-body dementia from the UK, Spain, and Italy. Individuals were given up to 12 mg rivastigmine daily or placebo for 20 weeks, followed by 3 weeks rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis. Findings Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine (37, 63%), than on placebo (18, 30%), showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks with a substantial attentional component. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. After drug discontinuation differences between rivastigmine and placebo tended to disappear. Known adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) were seen more frequently with rivastigmine than with placebo, but safety and tolerability of the drug in these mostly multimorbid patients were judged acceptable. Interpretation Rivastigmine 6–12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually.

Objectives[ To describe the baseline demographic\ neuropsychiatric and neurological data of a large selected clinical sample of patients with dementia with Lewy Bodies "DLB# from an international multicentre trial with rivastigmine[ To examine the usefulness of the Consensus Criteria for the diagnosis of DLB in di}erent countries[ Methods[ Seventeen centres from Spain\ the UK and Italy recruited patients diagnosed clinically as probable DLB according to recent Consensus Criteria "McKeith et al[\ 0885#[ A standard clinical protocol including inclu! sion:exclusion criteria\ collection of demographic and medical data\ cognitive "Mini Mental State Examination] MMSE#\ motor "Uni_ed Parkinson|s Disease Rating Scale] UPDRS# and neuropsychiatric "Neuropsychiatric Inven! tory] NPI# examinations\ was applied after obtaining informed consent[ Data were summarised and compared across countries with uni! and multivariate analyses[ Results[ One hundred and twenty patients were recruited] 45[6) males\ mean "SD# age 62[8 "5[3# years\ range 46 76 years[ Sixty percent ful_lled all three core diagnostic features of DLB\ and 39) only two "{parkinsonism| 81[3)\ {cognitive ~uctuations| 78[0)\ {visual hallucinations| 66[2)#[ {Systematised delusions| "35)# and {repeated falls| "31)# were the most frequent supportive diagnostic features[ There were no di}erences across countries in demo! graphic\ diagnostic or clinical features[ Patients showed a wide range of psychopathology which was weakly correlated with cognitive impairment[ Some mild extrapyramidal signs "EPS# were observed in most patients[ Conclusions[ The Consensus Criteria for DLB can be consistently applied across many di}erent sites for multicentre studies[ {Parkinsonism| and {cognitive ~uctuations| as core features and {systematised delusions| and {repeated falls| as supportive features are the most frequent diagnostic clues[ Neuropsychiatric disturbances\ in particular apathy\ delusions\ hallucinations and anxiety\ and mild symmetric EPS are frequent in DLB and are only related weakly to cognitive impairment[ Copyright 1999 John Wiley + Sons\ Ltd[

A longitudinal study of the relationship between education and age of onset, rate of progression and cerebral lesion burden in a series of autopsy-confirmed demented patients with clinical and 6-monthly psychometric follow-up and autopsy was carried out. The study was conducted at the London Health Sciences Centre University Campus of the University of Western Ontario on 87 patients with pathologically confirmed Alzheimer's disease (60), dementia with Lewy bodies (11) or dementia with Lewy bodies plus Alzheimer's disease (16). Their educational attainment was classified as below high school, high school or above high school, and was similar to that of the age-adjusted general Ontario population. The age of onset of dementia, age at death, progression of cognitive decline, amount of neurodegenerative changes (senile plaques, neurofibrillary tangles and Lewy bodies) and cerebrovascular lesions (infarcts, lacunar state and white matter rarefaction) were assessed. Less educated patients became demented later and died later, but cognitive function declined at the same rate in all educational groups and there was no difference in the burden of neurodegenerative lesions between them. However, the less educated patients had more cerebrovascular lesions. It can be concluded that higher education does not modify the course of Alzheimer's disease, but lower education relates to the occurrence of cerebral infarcts. Our results suggest that a 'brain battering' model related to the higher prevalence of small vascular lesions in less educated individuals may explain their increased risk of dementia described by epidemiological studies better than the prevalent 'brain reserve' hypothesis.

SummaryCreutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be infectious, sporadic, or hereditary. The 200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for >70% of families with CJD worldwide. Prevalence of the 200K variant of familial CJD is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation–associated chromosomes, we selected microsatellite markers flanking the PRNP gene on chromosome 20p12-pter and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results show that Libyan, Tunisian, Italian, Chilean, and Spanish families share a major haplotype, suggesting that the 200K mutation may have originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin show another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan are different from the Mediterranean or eastern European haplotypes. On the bais of this study, we conclude that founder effect and independent mutational events are responsible for the current geographic distribution of hereditary CJD associated with the 200K mutation.

The Word Accentuation Test assesses the accentuation of 30 infrequent Spanish words written without the accentuation mark and is an easy-to-use tool for estimating premorbid intelligence of Spanish-speaking people. Its intraobserver (0.97) and interobserver (0.93) reliabilities and its correlation with the Wechsler Adult Intelligence Scale (.837) and Raven's Progressive Matrices (.655) are high, offering a good prediction of general intelligence. It is resistant to mental deterioration; 20 demented and 40 controls matched by sex, age, and education obtained similar scores. The discrepancies between current and predicted scores in Raven's scale can diagnose mild-moderate dementia with 0.79 accuracy (sensitivity, 0.78; specificity, 0.82).

We studied the validity of a complete (S-IQCODE) and a shortened (SS- IQCODE) Spanish version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the diagnosis of dementia in a clinical setting. Fifty-three consecutive outpatients were assessed with an extensive workup and followed up for 6 months in a specialized clinic for the diagnosis and management of dementia. Thirty eight (71%) were finally diagnosed as demented. The Mini-Mental State Examination (MMSE) had a slightly greater diagnostic power than did the S-IQCODE and the SS-IQCODE (sensitivity 89% vs. 84% and 79%; specificity 80% vs. 73% for both; positive predictive value 92% vs. 89% and 88%; negative predictive value 75% vs. 65% and 58%), but without statistical significance. Both the S-IQCODE and SS-IQCODE were independent of previous education of the patients. The best diagnostic results were obtained when the cognitive scores of the patient in the MMSE and the report of the relative in the S-IQCODE were simultaneously considered. We conclude that the IQCODE, in a complete as well as in a shortened form, is a good diagnostic instrument in the clinical setting that can enhance the validity of other cognitive tests.

Incontinence is a hallmark of dementia, but little is known about its inception in different types of dementing disease. We recorded the dates of onset of dementia and of urinary incontinence in 73 demented patients followed for 5.6 +/- 2.5 years. The pathologic diagnosis was Alzheimer's disease (AD) in 29 cases, diffuse Lewy body disease (DLBD) in 11 cases, AD with Lewy bodies (AD+LB) in 13 cases, and AD with vascular lesions (AD+VL) in 20 cases. The onset of urinary incontinence was significantly earlier in DLBD cases (3.2 +/- 1.4 years after dementia onset) than in AD (5.9 +/- 2.5), AD+LB (5.8 +/- 2.4), and AD+VL (6.5 +/- 2.3) (p < 0.01). At the onset of bladder incontinence, the mean score in the Extended Dementia Scale was significantly higher (i.e., cognition was better) in DLBD cases (109.3 +/- 70.8) than in AD (21.3 +/- 40.4), AD+LB (45.6 +/- 45.1), and AD+VL (39.2 +/- 54.9) cases (p < 0.01). Urinary incontinence is associated with severe cognitive decline in pure AD but usually precedes severe mental failure in DLBD cases. This temporal pattern of cognitive decline and incontinence could be useful in differentiating these two dementing illnesses.

Most of the present screening tests for the detection of dementia fail with mild dementia. Jorm et al. recently presented the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), a simple instrument with good diagnostic validity that uses a close relative to obtain information on the cognitive decline of a patient. We used a Spanish adaptation of this questionnaire (S-IQCODE) validated in a population-based sample, and a shortened form (SS-IQCODE) obtained after analyzing the items and reducing them to only 17. The S-IQCODE and the SS-IQCODE have greater diagnostic validity for mild dementia than the Mini-Mental State Examination (MMSE) (sensitivity: 86% for both versus 57%; specificity: 92 and 91% versus 84%, positive predictive value: 54 and 50% versus 29%; negative predictive value: 91 and 90% versus 81%) and, unlike the MMSE, are independent of the age, education, and previous intelligence of the subjects. According to the results of this study, the SS-IQCODE could be a useful screening test for the detection of mild dementia in the Spanish-speaking aged population, with greater diagnostic power and less contamination by independent variables than the MMSE.