Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding.

BACKGROUND: There are currently no drug therapies modifying the natural history of patients suffering Alzheimer's disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented. OBJECTIVES: To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion. DESIGN: A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates. PARTICIPANTS: A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions. RESULTS: The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables. CONCLUSIONS: Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.

Combination of white matter hyperintensities and Aß burden is related to cognitive composites domain scores in subjective cognitive decline: the FACEHBI cohort.

BACKGROUND: To explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aß) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD). METHODS: Two hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI), 18F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables. RESULTS: Adjusted multiple linear regression models showed that FreeSurfer (B - .245; 95% CI - .1.676, - .393, p = .016) and ß burden (SUVR) (B - .180; 95% CI - 2.140, - .292; p = .070) were associated with face-name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face-name associative performance indicated that those individuals with either higher WMH load or higher Aß burden showed the worst performance on the face-name associative memory CCs domain score. CONCLUSIONS: Our results suggest that increased WMH load and increased Aß are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.

Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease.

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

Plasma Aß42/40 Ratio Detects Early Stages of Alzheimer's Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study.

BACKGROUND: Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer's disease (AD) in large population screening strategies. OBJECTIVES: This study evaluated the potential of plasma ß-amyloid (Aß) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years. DESIGN: Total plasma Aß42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern. RESULTS: Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF). CONCLUSIONS: TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundació ACE Healthy Brain Initiative (FACEHBI).

BACKGROUND: Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aß) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aß species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results. METHODS: The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(18F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aß40 and Aß42 peptides. The association between Aß40 and Aß42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aß levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aß plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis. RESULTS: FBB-PET global SUVR correlated weakly but significantly with Aß42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R2 = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aß measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aß FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aß measurements (p value for interaction = 0.105). CONCLUSION: Brain and plasma Aß levels are partially correlated in individuals diagnosed with SCD. Aß plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

FACEHBI: A Prospective Study of Risk Factors, Biomarkers and Cognition in a Cohort of Individuals with Subjective Cognitive Decline. Study Rationale and Research Protocols.

BACKGROUND: Long-term longitudinal studies with multimodal biomarkers are needed to delve into the knowledge of preclinical AD. Subjective cognitive decline has been proposed as a risk factor for the development of cognitive impairment. Thus, including individuals with SCD in observational studies may be a cost-effective strategy to increase the prevalence of preclinical AD in the sample. OBJECTIVES: To describe the rationale, research protocols and baseline characteristics of participants in the Fundació ACE Healthy Brain Initiative (FACEHBI). DESIGN: FACEHBI is a clinical trial (EudraCT: 2014-000798-38) embedded within a long-term observational study of individuals with SCD. SETTING: Participants have been recruited at the memory clinic of Fundació ACE (Barcelona) from two different sources: patients referred by a general practitioner and individuals from an Open House Initiative. PARTICIPANTS: 200 individuals diagnosed with SCD with a strictly normal performance in a comprehensive neuropsychological battery. MEASUREMENTS: Individuals will undergo an extensive neuropsychological protocol, risk factor assessment and a set of multimodal biomarkers including florbetaben PET, structural and functional MRI, diffusion tensor imaging, determination of amyloid species in plasma and neurophthalmologic assessment with optical coherence tomography. RESULTS: Two hundred individuals have been recruited in 15 months. Mean age was 65.9 years; mean MMSE was 29.2 with a mean of 14.8 years of education. CONCLUSIONS: FACEHBI is a long-term study of cognition, biomarkers and lifestyle that has been designed upon an innovative symptom-based approach using SCD as target population. It will shed light on the pathophysiology of preclinical AD and the role of SCD as a risk marker for the development of cognitive impairment.

Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene.

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10(-)(9)).

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

GAB2 gene does not modify the risk of Alzheimer's disease in Spanish APOE 4 carriers.

OBJECTIVES: The genetic basis of Alzheimer's disease (AD) is being analyzed in multiple whole genome association studies (WGAS). The GAB2 gene has been proposed as a modifying factor of APOE epsilon 4 allele in a recent case-control WGAS conducted in the US. Given the potential application of these novel results in AD diagnostics, we decided to make an independent replication to examine the GAB2 gene effect in our series. DESIGN: We are conducting a multicenter population-based study of AD in Spain. PARTICIPANTS: We analyzed a total of 1116 Spanish individuals. Specifically, 521 AD patients, 475 controls from the general population and 120 neurologically-normal elderly controls (NNE controls). METHODS: We have genotyped GAB2 (rs2373115 G/T) and APOE rs429358 (SNP112)/rs7412 (SNP158) polymorphisms using real time-PCR technologies. RESULTS: As previously reported in Spain, APOE epsilon 4 allele was strongly associated with AD in our series (OR=2.88 [95% C.I. 2.16- 3.84], p=7.38E-11). Moreover, a large effect for epsilone 4/epsilone 4 genotype was also observed (OR=14.45 [95% C.I., 3.34-125.2], p=1.8E-6). No difference between the general population and the NNE controls series were observed for APOE genotypes (P > 0.61). Next, we explored GAB2 rs2373115 SNP singlelocus association using different genetic models and comparing AD versus controls or NNE controls. No evidence of association with AD was observed for this GAB2 marker (p > 0.17). To evaluate GAB2-APOE genegene interactions, we stratified our series according to APOE genotype and case-control status, in accordance with the original studies. Again, no evidence of genetic association with AD was observed in any strata of GAB2-APOE loci pair (p > 0.34). CONCLUSION: GAB2 rs2373115 marker does not modify the risk of Alzheimer's disease in Spanish APOE epsilon 4 carriers.

A randomised pilot study to assess the efficacy of an interactive, multimedia tool of cognitive stimulation in Alzheimer's disease.

OBJECTIVE: To determine the usefulness of an interactive multimedia internet-based system (IMIS) for the cognitive stimulation of Alzheimer's disease. METHODS: This is a 24-week, single-blind, randomised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer's disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20-min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Secondary outcome measures were: Mini-Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest. RESULTS: After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS-Cog and MMSE, which was maintained through 24 weeks of follow-up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of difficulty in all cases. CONCLUSION: Although both the IPP and IMIS improved cognition in patients with Alzheimer's disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for 24 weeks.

[Behavioral pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD): Spanish validation]. / Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD): validación española.

INTRODUCTION: The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) is a screening instrument for the evaluation of behavioral disturbances in Alzheimer's patients. Our aim was to validate the BEHAVE-AD test in Spanish, intended for use in routine clinical practice. METHOD: We assessed the validity of the BEHAVEAD in 79 nursing-home patients with diagnosis criteria of dementia, scoring 4 or higher on the Global Deterioration Scale (GDS) scale, by developing a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and BEHAVE-AD tests. Both instruments were rated by an expert clinician. In order to study the concurrent validity of some of the BEHAVE-AD subscales, we compared the Cohen-Mansfield Agitation Inventory (CMAI) and the Hamilton Depression Rating Scale (HDRS) tests. RESULTS: The Pearson correlation index between the BEHAVE-AD test and the NPI-Q, was significant but moderate (r=0.694). Pearson's correlation between BEHAVEAD's symptoms scale and NPI-Q's severity scale was r=0.698. When comparing BEHAVE-AD's global evaluation scale (caregiver's disturbance) and NPI-Q's distress scale, the correlation index was 0.535. CONCLUSIONS: The BEHAVE-AD Spanish version offers the possibility to use a screening tool for the detection of neuropsychiatric symptoms in dementia patients, also applicable to nursing home residents, administered by an expert clinician.

Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD): validación española / Behavioral Pathology in Alzheimer's Disease Rating Sca1e (BEHAVE-AD): Spanish validation

Introducción. La Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) es un instrumento de cribado para la detección de sintomatología conductual en pacientes con demencia de tipo Alzheimer. El objetivo fue la validación española de la BEHAVE-AD para su incorporación en la práctica clínica diaria. Método. Estudio de la validez de la BEHAVE-AD en 79 pacientes con criterios diagnósticos de demencia en régimen de residencia, con puntuación de 4 o superior en la Global Deterioration Scale (GDS), mediante una validación cruzada entre el Neuropsychiatric Inventory-Questionnaire (NPI-Q) y la BEHAVE-AD. Administración de ambas escalas por parte de un clínico entrenado. Administración de las escalas Inventario de Agitación del Anciano de Cohen-Mansfield (IAACM) y Hamilton Depression Rating Scale (HDRS) para estudiar la validez convergente de dos de los dominios de la BEHAVE-AD. Resultados. índice de correlación de Pearson entre la BEHAVE-AD y el NPI-Q moderadamente significativo (r=0,694). Correlación de Pearson entre la escala de sintomatología de la BEHAVE-AD y la escala de gravedad del NPI-Q de 0,698 y entre la escala de evaluación global (perturbación en el cuidador) y la escala de estrés del NPI-Q de 0,535 puntos. Conclusiones. Esta versión en español de la BEHAVE-AD ofrece la posibilidad de aplicar un test de cribado de la sintomatología neuropsiquiátrica en pacientes con demencia, siendo también aplicable a usuarios de residencia, administrado por un clínico entrenado

Introduction. The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHA VE-AD) is a screening instrument for the evaluation of behavioral disturbances in Alzheimer's patients. Our aim was to validate the BEHA VE-AD test in Spanish, intended for use in routine clinical practice. Method. We assessed the validity of the BEHA VEAD in 79 nursing-home patients with diagnosis criteria of dementia, scoring 4 or higher on the Global Deterioration Scale (GDS) scale, by developing a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and BEHA VE-AD tests. Both instruments were rated by an expert clinician. In order to study the concurrent validity of some of the BEHA VE-AD subscales, we compared the Cohen-Mansfield Agitation Inventory (CMAI) and the Hamilton Depression Rating Scale (HDRS) tests. Results. The Pearson correlation index between the BEHA VE-AD test and the NPI-Q, was significant but moderate (r = 0.694). Pearson's correlation between BEHA VEAD's symptoms scale and NPI-Q's severity scale was r=0.698. When comparing BEHA VE-AD's global evaluation scale (caregiver's disturbance) and NPI-Q's distress scale, the correlation index was 0.535. Conclusions. The BEHA VE-AD Spanish version offers the possibility to use a screening tool for the detection of neuropsychiatric symptoms in dementia patients, also applicable to nursing home residents, administered by an expert clinician

[Neuropsychiatric Inventory-Nursing Home version (NPI-NH): Spanish validation]. / Neuropsychiatric Inventory-Nursing Home version (NPI-NH): validación española.

INTRODUCTION: The Neuropsychiatric Inventory-Nursing Home version (NPI-NH) is a screening instrument to be used by the nursing staff to evaluate neuropsychiatric symptoms in dementia patients in the nursing home setting. The aim of the present study was to validate the NPI-NH in Spanish. METHODS: We assessed the validity of the NPI-NH in 80 patients who were also nursing home residents, comparing the responses of nursing home staff on the NPI-NH with that filled out by the external observer. We developed a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and both NPI-NH. We determined the concurrent validity of the domains "depression" and "agitation/aggression" of the NPI-NH with the Cohen-Mansfield Agitation Inventory (IAACM, Spanish version) and the Hamilton Depression Rating Scale (HDRS). RESULTS: Among the totals of the NPI-NH of the nursing staff and the NPI-Q, the convergent validity was r = 0.536 and r = 0.669 for the occupational disruptiveness scale (distress in NPI-Q). The Pearson correlation index between the NPI-Q and NPI-NH of the observations was r = 0.342. The convergent validity between the NPINH of the nursing home staff and NPI-NH of the observers with the Pearson correlation index was r = 0.274. CONCLUSIONS: The NPI-NH Spanish version offers the possibility to use a screening tool for detecting neuropsychiatric symptoms in dementia patients in the nursing home setting. It should be administered by adequately trained staff to avoid limitations in the evolutive control of behavioral changes.

Neuropsychiatric Inventory-Nursing Home version (NPI-NH): validación española / Neuropsychiatric Inventory - Nursing Horne version (NPI-NH): Spanish validation

Introducción. El Neuropsychiatric Inventory-Nursing Home version (NPI-NH) es un instrumento de cribado para evaluar por el personal de enfermería o auxiliar la sintomatología neuropsiquiátrica en pacientes con demencia ingresados en residencia. El objetivo del presente estudio fue validar la versión española del NPI-NH. Métodos. Estudio de la validez del NPI-NH en 80 pacientes con demencia ingresados en residencia mediante la comparación entre la escala contestada por el auxiliar y la cumplimentada por el observador externo. Validación cruzada entre el Neuropsychiatric Inventory-Questionnaire (NPI-Q) y ambos NPI-NH. Estudio de la validez convergente de los dominios «depresión» y «agitación/agresividad» del NPI-NH con las escalas Inventario de Agitación del Anciano Cohen-Mansfield (lAACM) y Hamilton Depression Rating Scale (HDRS). Resultados. Entre los totales del NPI-NH auxiliares y el NPI-Q la validez convergente fue de r = 0,536 Y de r = 0,669 para la escala de interrupción ocupacional (estrés en NPI-Q). Entre el NPI-Q y el NPI-NH de las observaciones el índice de correlación de Pearson fue de r = 0,342. La validez convergente entre el NPI-NH de los auxiliares y NPI-NH de los observadores mediante el índice de correlación de Pearson fue de r = 0,273. Conclusiones. La versión española del NPI-NH ofrece la posibilidad de aplicar un test de cribado de sintomatología neuropsiquiátrica en pacientes con demencia alojados en una residencia geriátrica. Debe ser administrado por personal debidamente entrenado para evitar limitaciones en el control evolutivo de los cambios de conducta

Introduction. The Neuropsychiatric Inventory-Nursing Horne version (NPI-NH) is a screening instrument to be used by the nursing staff to evaluate neuropsychiatric symptoms in dementia patients in the nursing home setting. The aim of the present study was to validate the NPI-NH in Spanish. Methods. We assessed the validity of the NPI-NH in 80 patients who were also nursing home residents, comparing the responses of nursing home staff on the NPI-NH with that filled out by the external observer. We developed a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and both NPI-NH. We determined the concurrent validity of the domains «depression» and «agitation/aggression» of the NPI-NH with the Cohen-Mansfield Agitation Inventory (IAACM, Spanish version) and the Hamilton Depression Rating Scale (HDRS). Results. Among the totals of the NPI-NH of the nursing staff and the NPI-Q, the convergent validity was r = 0.536 and r = 0.669 for the occupational disruptiveness scale (distress in NPI-Q). The Pearson correlation index between the NPI-Q and NPI-NH of the observations was r = 0.342. The convergent validity between the NPINH of the nursing home staff and NPI-NH of the observers with the Pearson correlation index was r = 0.274. Conclusions. The NPI-NH Spanish version offers the possibility to use a screening tool for detecting neuropsychiatric symptorns in dementia patients in the nursing home setting. It should be administered by adequately trained staff to avoid limitations in the evolutive control of behavioral changes

Micronutrient supplementation in mild Alzheimer disease patients.

OBJECTIVE: To evaluate if nutritional supplementation with or without micronutrient enhancement prevent weight loss and the progression of the disease in mild Alzheimer's Disease (AD) patients. DESIGN: Mild AD patients were recruited from an Alzheimer Day Centre. Subjects received oral liquid supplements with (Study-group: S) or without (Control-group: C) micronutrient enhancement. Intake assessment, nutritional status, biochemical parameters, cognitive function, and eating behaviour disorders were determined at baseline and at 6 months of treatment. RESULTS: At baseline both groups were not different in any variable measured. They were norm nourished, with normal biochemical parameters. Blandford scale demonstrated a mild alteration of feeding behaviour, the cognitive scale classified the patients as impaired and there was presence of memory complaints. After 6 months of nutritional supplements, a similar increase in energy consumption was observed in both groups of patients (P<0.05). In the within-group analysis, we found a trend (P=0.05) to increase body mass index; a significant increase in triceps skin fold thickness, mid-upper-arm circumference and serum magnesium, zinc and selenium, and a significant reduction in serum vitamin E (P<0.001, each). Serum cholesterol decreased substantially only in the S-group (P=0.025). No significant differences at baseline, within-group, neither between-group analysis in feeding behaviour nor in cognitive function were observed. CONCLUSIONS: According to our results no benefits in the progression of the disease was observed with micronutrient enhancement supplements. Effectiveness of nutritional supplements in preventing weight loss in mild AD patients showed a similar behaviour as observed in other populations. Due to the beneficial evolution of serum cholesterol in the S-group, this intervention deserves further investigation.

Possible increased risk for Alzheimer's disease associated with neprilysin gene.

Neprilysin has recently been reported to be the major physiological Abeta-degradating enzyme. In this study we describe a new biallelic polymorphism in the 3'UTR of the neprilysin gene in a representative population sample. The (*)159C/C genotype was found to be associated with an increased risk for Alzheimer's disease in an age-dependent manner. Adjusting for sex and APOE status, an odds ratio of 2.74 (p < 0.05) was observed among patients under 75 years old.

[Neuropsychiatric inventory questionnaire (NPI-Q): Spanish validation of an abridged form of the Neuropsychiatric Inventory (NPI)]. / Neuropsychiatric Inventory Questionnaire (NPI-Q): validación española de una forma abreviada del Neuropsychiatric Inventory (NPI)*

BACKGROUND: The Neuropsychiatric Inventory (NPI) is a validated clinical instrument for the evaluation of psychopathology in dementia. OBJECTIVE: To validate a brief questionnaire form of the NPI (NPI-Q) in Spanish from NPI-Q original version, intended for use in routine clinical practice. PATIENTS AND METHOD: We have developed a crossed validated form between NPI and NPI-Q in 120 Alzheimer's disease patients. RESULTS: Test-retest reliability of the NPI-Q, using Pearson correlation index was r = 0.89 for total symptom scale and r = 0.90 for distress scale. The prevalence of analogous symptom ratings differed by less than 6.7%. Convergent validity between NPI-Q and NPI, using Pearson correlation index was r = 0.879 for total symptom and r = 0.92 for distress scale. CONCLUSIONS: The NPI-Q Spanish version offers the possibility to use a reliable and brief instrument that can be used as a screening in the evaluation of neuropsychiatric symptoms in dementia and associated caregiver distress. It may be suitable for use in general clinical practice and it could be used as a brief neuropsychiatric interview.

Neuropsychiatric Inventory Questionnaire (NPI-Q): validación española de una forma abreviada del Neuropsychiatric Inventory (NPI) / Neuropsychiatric Inventory Questionnaire (NPI-Q): Spanish validation of a brief clinical form of the Neuropsychiatric inventory (NPI)

FUNDAMENTOS: El Neuropsychiatric Inventory (NPI) es un instrumento validado para la evaluación clínica de la sintomatología neuropsiquiátrica para las enfermedades que cursan con demencia. OBJETIVO: Ofrecer una validación en castellano de un instrumento breve que se ha desarrollado desde el NPI, llamado NPI-Q, diseñado para el uso en la práctica clínica diaria como método de cribado. PACIENTES Y MÉTODO: Se ha desarrollado una validación cruzada entre NPI y NPI-Q en 120 pacientes con enfermedad de Alzheimer. RESULTADOS: El test-retest de la escala NPI-Q, mediante el empleo del índice de correlación de Pearson, fue de r = 0,89 para la escala de total de presencia de síntomas y de r = 0,90 para la escala de estrés del cuidador. La prevalencia de síntomas análogos difiere en menor del 6,7 per cent. La validez convergente entre el NPI-Q y el NPI, usando el índice de correlación de Pearson, fue r = 0,879 para la escala gravedad y r = 0,92 para la escala de estrés. CONCLUSIONES: La versión castellana del NPI-Q ofrece la posibilidad de usar un instrumento válido y fiable, a la par que breve, lo que favorece su uso como método de cribado en la evaluación de los síntomas neuropsiquiátricos en la demencia, así como para la valoración del agotamiento emocional provocado en el cuidador, pudiendo ser utilizada en la práctica clínica diaria, ya como entrevista breve, ya en forma autoadministrada. (AU)