José Luis Dobato

Quality of life (QoL) in community-dwelling and institutionalized Alzheimer's disease (AD) patients.

The purpose of this study was to describe and compare QoL and its determinants in two groups of patients with AD that differed in place of residence: community or nursing home. This study covered 200 patients with AD (mean age 79.3 ± 8.2 years, 74% female). Fifty-four per cent of the subjects were living in a nursing home and 46% lived at home. QoL was measured using the Alzheimers Disease Related Quality of Life Scale (ADRQL). The ADRQL was answered by the family caregiver (community group) or the professional caregiver (nursing home group). Descriptive statistics, Chi-square test, Mann-Whitney test and multiple regression analysis were used to compare sociodemographic and clinical variables between the two study groups. The institutionalized patients were predominantly women (87.0% vs. 58.7%, p<0.001), were older (84 years vs. 74 years, p<0.001), and had more advanced dementia (Global Deterioration Scale (GDS)>5 79.6% vs. 19.6%, p<0.001). ADRQL total score was higher (i.e., better QoL) for patients living at home than for institutionalized patients (72.6 ± 19.9 vs. 64.8 ± 18.2, p<0.01). Neuropsychiatric symptoms, severity of dementia, depression and functional dependence were significant predictors of worst QoL. Once those variables were controlled a marginal effect of setting on QoL was found, which favored the nursing home (β=0.20, p<0.05).

Clinical and Anatomical Correlates of Gait Dysfunction in Alzheimer's Disease

We conducted a cross-sectional study to investigate the clinical and anatomical correlates of gait dysfunction in advanced Alzheimers disease (AD). A comprehensive clinical protocol that included cognitive, functional, behavioral, and motor variables was administered to patients with probable AD (n = 100), possible AD (n = 17), and AD with cerebrovascular disease (AD + CVD) (n = 27). Gait dysfunction was evaluated with the Rating Scale for Gait Evaluation in Cognitive Deterioration and magnetic resonance imaging was analyzed in 94 patients (volumetry study) and 78 patients (diffusion tensor imaging study). Univariate correlations, multivariate regression, and statistical parametric mapping analyses were conducted in the total sample and in the subsample of patients with probable AD. Mean age was 82.5 (SD 6.3, range 56 to 98), 83.3% were female patients, and 95.1% displayed moderate to severe dementia. Parkinsonism, patient setting (nursing home), dementia severity, apathy, and (worse) cognitive performance significantly predicted gait dysfunction in the total sample (p < 0.05, R(2) = 0.58), whereas parkinsonism, patient setting, and limb weakness due to non-AD conditions predicted gait dysfunction in probable AD (p < 0.05, R(2) = 0.57). Gait dysfunction was related to atrophy in the motor cortex, the middle cingulate, the anterior insula, the right caudate (total sample only), and the anterior lobe of the cerebellum (p < 0.01, corrected). Significant correlations were also observed between gait dysfunction and damage in several white matter locations (p < 0.001, uncorrected). The present results are congruent with a model of multi-system gray matter degeneration, with progressive damage to critical regions (i.e., motor cortex, cingulate, insula, and cerebellum) producing gait dysfunction and, eventually, gait loss in AD.

Reduced serum progranulin level might be associated with Parkinson's disease risk

Common genetic variants (rs5848 and rs646776) have been reported as regulators of blood progranulin (GRN) levels in healthy individuals.

Promoting Research in Advanced Dementia: Early Clinical Results of the Alzheimer Center Reina Sofía Foundation

The Alzheimer Center Reina Sofía Foundation (ACRSF) was envisaged to address the complex and multi-disciplinary research and care needs posed by Alzheimers disease (AD) and other neurodegenerative dementias. Patients may be admitted at ACRSF either as inpatients (i.e., nursing home) or outpatients (i.e., day-care center). The research program includes clinical, social, biochemical, genetic, and magnetic resonance investigations, as well as brain donation. We present the inception of the clinical research protocol for the ACRSF, the early results, and the amendments to the protocol. Foreseen as distinct populations, inpatient and outpatient results are presented separately. Data were collected from 180 patients (153 inpatients, 27 outpatients) (86% AD), with informed consent for participation in the research program of the ACRSF. Most patients (95%) had moderate to severe dementia. Nursing home patients were older, displayed marked gait dysfunction, and were significantly more dependent in the activities of daily living (ADL), compared to the day-care patients (p < 0.05). Some cognitive, ADL, and quality of life (QoL) scales were eliminated from the protocol due to floor effect or lack of specificity of contents for advanced dementia. New measurements were added for evaluation of cognition, apathy, agitation, depression, ADL, motor function, and QoL. The final assessment is expected to be sensitive to change in all the clinical aspects of advanced degenerative dementia, to promote multidisciplinary and, desirably, inter-center collaborative research and, eventually, to contribute to the improvement of treatment and care for these patients.

Genetic variation in the tau protein phosphatase- 2A pathway is not associated with Alzheimer's disease risk

BackgroundTau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in AD brain is the result of upregulation of tau kinases and downregulation of tau phosphatases.MethodsIn a group of 729 Spanish late-onset Alzheimers disease (AD) patients and 670 healthy controls, we examined variations into a set of candidate genes (PPP2CA, PPP2R2A, ANP32A, LCMT1, PPME1 and PIN1) in the tau protein phosphatase-2A (PP2A) pathway, to address hypotheses of genetic variation that might influence AD risk.ResultsThere were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by age, gender or APOE ε4 allele.ConclusionOur negative findings in the Spanish population argue against the hypothesis that genetic variation in the tau protein phosphatase-2A (PP2A) pathway is causally related to AD risk

The Vallecas Project: A Cohort to Identify Early Markers and Mechanisms of Alzheimer’s Disease

Introduction Alzheimer’s disease (AD) is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late-onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers) may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects. Methods We launched the Vallecas Project (VP), a cohort study of non-demented people aged 70–85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods. Results A total of 1169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9), 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one ε4 allele of the apolipoprotein E gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI) 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI). Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for 4 years after the baseline. Conclusion We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention.

Genetic variation in the tau kinases pathway may modify the risk and age at onset of alzheimer's disease

Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimers disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24 × 10-5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10-5) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10-4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset).

Screening for progranulin mutations by serum protein dosage in common neurodegenerative disorders.

Sirs: Mutations in progranulin gene (GRN) are a major cause (5– 10% of all patients) of frontotemporal dementia (FTD) [1]. Less frequently, the spectrum of clinical presentations associated with GRN mutations includes other neurodegenerative disorders, such as corticobasal syndrome (CBS), dementia with Lewy bodies (DLB), Parkinson’s disease (PD), Alzheimer’s disease (AD) or mild cognitive impairment (MCI). Most pathogenic GRN mutations are expected to create functional null alleles leading to a loss of GRN transcript and strongly reduced plasma or serum progranulin levels. Therefore, blood progranulin dosage can predict GRN mutation status in patients with FTD or other clinical phenotypes [2], and avoids initially sequencing thewhole gene, which is technically more complicated and expensive. We sought to test the usefulness of serum progranulin level for screening of GRN mutations in patients with other common neurodegenerative phenotypes different from FTD. We determined serum progranulin levels using an ELISA kit (Adipogen Inc, Seoul, Korea) in 973 subjects, including 126 controls, 344 AD patients, 304 PD patients, 131 MCI patients, 27 FTD patients and 41 patients with other phenotypes including CBS and DLB. Patients and control samples were Caucasians originating from northern Spain (Santander) and the central area of Spain (Madrid). Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. The study was approved by the ethical committees of the University Hospital “Marqués de Valdecilla” and Alzheimer Center Reina Sofia Foundation. The mean concentrations of progranulin in the serum of patients with PD (319.6 ng/ml, SD 146) and FTD (246.7 ng/ml, SD 117) were significantly lower than that of control subjects (371.5 ng/ml, SD 205; p 1⁄4 0.015 and p 1⁄4 0.025 respectively, Bonferroni corrected), whereas mean serum GRN level in the group of AD (331.4 ng/ml, SD 148), MCI (344.4 ng/ml, SD 135) and patients with other phenotypes (385.2 ng/ml, SD 168) did not differ significantly from controls. A previous analysis of the same cohort of controls, PD andMCI patients has been recently reported [3]. For predicting GRN mutation status, a plasma cut-off value of 110 ng/ml has been reported to be close to 100% of specificity and sensitivity [2]. Consequently, we selected a higher threshold to be more certain of