Effect of long-term physical exercise and multidomain interventions on cognitive function and the risk of mild cognitive impairment and dementia in older adults: A systematic review with meta-analysis.

INTRODUCTION: Recent studies have suggested that sustained multidomain interventions, including physical exercise, may be beneficial in preventing cognitive decline. This review aims to assess the impact of prolonged physical exercise and multidomain strategies on overall cognitive faculties and dementia risk among community-dwelling older adults without dementia. METHODS: We systematically searched PubMed, Web of Science, PsychInfo, and CINHAL databases from inception until April 1, 2024, for randomized controlled trials that investigated the effects of long-term (≥ 12 months) physical exercise or multidomain interventions on non-demented, community-dwelling older adults. The primary outcomes assessed were changes in global cognition and the risk of mild cognitive impairment (MCI) or dementia. Standardized mean differences (SMD) and risk ratios (RR) with 95 % confidence intervals were computed using a random-effects inverse-variance method with the Hartung-Knapp-Sidik-Jonkman adjustment for effect size calculation. The Cochrane Risk-of-Bias-2 tool (RoB-2) was used for bias assessment, and the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was applied to evaluate the certainty of evidence. RESULTS: Sixteen trials, including 11,402 participants (mean age 73.2 [±5.5] years; 62.3 % female) were examined. The risk of bias was low. Moderate-certainty evidence indicated that physical exercise interventions had modest to no effect on cognitive function (k= 9, SMD: 0.05; 95 % CI: -0.04-0.13; p = 0.25), whereas multidomain interventions were significantly impactful (k=7, SMD: 0.09; 95 % CI: 0.04-0.15; p < 0.01). Physical exercise interventions did not alter MCI risk (k= 4, RR: 0.98; 95 % CI: 0.73-1.31; p = 0.79) or dementia onset (k= 4, RR: 0.61; 95 % CI: 0.25-1.52; p = 0.19), with very low-to low-certainty evidence, respectively. CONCLUSIONS: Integrative multidomain strategies incorporating physical exercise may benefit the global cognitive function of older adults. However, long-term physical exercise alone did not yield any cognitive gains. The effectiveness of such exercise interventions to mitigate the overall risk of incident MCI and dementia warrants further research.

A Drosophila model for Meniere's disease: Dystrobrevin is required for support cell function in hearing and proprioception.

Meniere's disease (MD) is an inner ear disorder characterised by recurrent vertigo attacks associated with sensorineural hearing loss and tinnitus. Evidence from epidemiology and Whole Exome Sequencing (WES) suggests a genetic susceptibility involving multiple genes, including α-Dystrobrevin (DTNA). Here we investigate a Drosophila model. We show that mutation, or knockdown, of the DTNA orthologue in Drosophila, Dystrobrevin (Dyb), results in defective proprioception and impaired function of Johnston's Organ (JO), the fly's equivalent of the inner ear. Dyb and another component of the dystrophin-glycoprotein complex (DGC), Dystrophin (Dys), are expressed in support cells within JO. Their specific locations suggest that they form part of support cell contacts, thereby helping to maintain the integrity of the hemolymph-neuron diffusion barrier, which is equivalent to a blood-brain barrier. These results have important implications for the human condition, and notably, we note that DTNA is expressed in equivalent cells of the mammalian inner ear.

Brief cognitive tests as a decision-making tool in primary care. A population and validation study.

INTRODUCTION AND OBJECTIVES: Brief cognitive tests (BCT) are used in primary care (PC) for the detection of cognitive impairment (CI). Still, there are little data on their diagnostic utility (DU) in a community setting. This work evaluates the DU at the population level of Fototest, T@M, AD8 questionnaire and MMSE. It provides new cut-off points (CoP) validated in a CI early detection program. MATERIAL AND METHODS: In the population and validation samples, the evaluation was carried out in two phases, a first of screening and administration of BCT and a second of clinical diagnosis, blinded to the results of the BCT, applying the current NIA-AA criteria. The DU of BCT in the population sample was evaluated with the area under the ROC curve (aROC). Youden index and the CoP with the best specificity that ensured a sensitivity of 80% were used to decide on the most appropriate CoP. The sensitivity, specificity, and predictive values for these CoP were calculated in the validation sample. RESULTS: 260 participants (23.1% with CI) from the population sample and 177 (42.4% with CI) from the validation sample were included. The Fototest has the best UD at the population level (aROC 0.851), which improves with the combination of Fototest and AD8 (aROC 0.875). The proposed CoP are AD8 ≥ 1, Fototest ≤ 35, T@M ≤ 40, and MMSE ≤ 26. CONCLUSION: BCT are helpful in detecting CI in PC. This work supports the use of more demanding PoC.

Validez de un registro poblacional automatizado de demencia basado en las bases de datos clínicas / Validity of a computerized population registry of dementia based on clinical databases

Introducción: El manejo de la información mediante soportes digitales permite abordajes innovadores de la identificación de los casos de demencia mediante búsquedas automatizadas en las bases de datos clínicas con sistemas de codificación de los diagnósticos. El objetivo de este trabajo fue analizar la validez de un registro de demencia en Gipuzkoa basado en los sistemas de registro administrativos y clínicos existentes en el Servicio Vasco de Salud.MétodosEs un estudio descriptivo basado en la evaluación de las fuentes de datos disponibles. Primero, mediante revisión de historias clínicas se evaluó la validez diagnóstica en 2 muestras de casos identificados y no identificados como demencia. Se midió la sensibilidad, especificidad y valor predictivo positivo y negativo del diagnóstico de demencia. Posteriormente se buscaron los casos de demencia vivos a fecha 31 de diciembre de 2016 en toda la población guipuzcoana y se recogieron variables sociodemográficas y clínicas.ResultadosLas 2 muestras de validación incluyeron 986 casos y 327 no casos. La sensibilidad calculada fue del 80,2% y la especificidad del 99,9%. El valor predictivo negativo fue del 99,4% y el positivo del 95,1%. Los casos registrados en toda la población guipuzcoana fueron 10.551 que supone un 65% de los casos previstos según la literatura. Un 40% tomaban medicación antisicótica. La población institucionalizada fue del 25%.ConclusionesUn registro de demencias basado en las bases de datos clínicas y administrativas es válido y factible. Su principal aportación es mostrar la dimensión que tiene la demencia en el ámbito del sistema sanitario. (AU)

Introduction: The handling of information through digital media allows innovative approaches for identifying cases of dementia through computerized searches within the clinical databases that include systems for coding diagnoses. The aim of this study was to analyze the validity of a dementia registry in Gipuzkoa based on the administrative and clinical databases existing in the Basque Health Service.MethodsThis is a descriptive study based on the evaluation of available data sources. First, through review of medical records, the diagnostic validity was evaluated in 2 samples of cases identified and not identified as dementia. The sensitivity, specificity and positive and negative predictive value of the diagnosis of dementia were measured. Subsequently, the cases of living dementia in December 31, 2016 were searched in the entire Gipuzkoa population to collect sociodemographic and clinical variables.ResultsThe validation samples included 986 cases and 327 no cases. The calculated sensitivity was 80.2% and the specificity was 99.9%. The negative predictive value was 99.4% and positive value was 95.1%. The cases in Gipuzkoa were 10,551, representing 65% of the cases predicted according to the literature. Antipsychotic medication were taken by a 40% and a 25% of the cases were institutionalized.ConclusionsA registry of dementias based on clinical and administrative databases is valid and feasible. Its main contribution is to show the dimension of dementia in the health system. (AU)

Validity of a computerised population registry of dementia based on clinical databases.

INTRODUCTION: The handling of information through digital media allows innovative approaches for identifying cases of dementia through computerised searches within the clinical databases that include systems for coding diagnoses. The aim of this study was to analyse the validity of a dementia registry in Gipuzkoa based on the administrative and clinical databases existing in the Basque Health Service. METHODS: This is a descriptive study based on the evaluation of available data sources. First, through review of medical records, the diagnostic validity was evaluated in two samples of cases identified and not identified as dementia. The sensitivity, specificity and positive and negative predictive value of the diagnosis of dementia were measured. Subsequently, the cases of living dementia in December 31, 2016 were searched in the entire Gipuzkoa population to collect sociodemographic and clinical variables. RESULTS: The validation samples included 986 cases and 327 no cases. The calculated sensitivity was 80.2% and the specificity was 99.9%. The negative predictive value was 99.4% and positive value was 95.1%. The cases in Gipuzkoa were 10 551, representing 65% of the cases predicted according to the literature. Antipsychotic medication were taken by a 40% and a 25% of the cases were institutionalised. CONCLUSIONS: A registry of dementias based on clinical and administrative databases is valid and feasible. Its main contribution is to show the dimension of dementia in the health system.

Utility of stent double palliation for esophageal cancer with airway involvement: the extremis of care.

Primary esophageal cancer (EC) frequently presents as a locally advanced disease with airway involvement. Placement of combined esophageal and airway stents has been reported in small series to be an effective palliation strategy. Our aims are to present the largest cohort of EC patients who underwent double stent palliation and to evaluate the safety and efficacy of this approach. Longitudinal cohort study of patients with primary EC undergoing two-stage esophageal and airway stent placement at an oncology referral institute (January 2000-January 2019). Assessments: baseline demographics and clinical variables; baseline and week 2 dysphagia, dyspnea and performance status (PS) scores; baseline and week 8 body mass index (BMI); overall survival. Statistics: paired t-test; Kaplan-Meier method. Seventy patients (89% men, mean age 60.20 ± 8.41) underwent double stenting. Esophageal stent was placed for esophageal stenosis and dysphagia (n = 41; placement of a second stent due to recurrence in nine cases) or esophagorespiratory fistulas (ERFs) (n = 29); airway stent was required for ERF sealing (n = 29 + 7 new ERFs after esophageal stent) and to ensure airway patency due to malignant stenosis (n = 29; placement of a second stent due to recurrence in 13 cases) or compression (n = 5). There were 13, endoscopically managed, major complications after esophageal stent [hemorrage (n = 1), migration (n = 5) and new fistulas (n = 7)]. As for airway stents, four major complications were recorded [hemorrage (n = 1) and three deaths due to respiratory infection and ultimately respiratory failure 3-7 days after the procedure]. Overall, patients showed significant improvement in dysphagia and dyspnea symptoms (3.21 vs. 1.31 e 15.56 vs. 10.87; P < 0.001). There was a PS improvement for 89.2% (n = 58) of the patients. BMI at week 8 was comparable to baseline records. Mean survival was 137.83 ± 24.14 days (95% CI: 90.51-185.15). Survival was longer for better PS (PS1, 249.95 days; PS2, 83.74 days; PS3, 22.43 days; PS4, 30.00 days). This is the largest comprehensive assessment of double stent palliation in advanced incurable EC. For both esophageal or airway stenosis and fistula, placement of combined esophageal and airway stents was a feasible, effective, fast-acting and safe modality for symptom palliation and body mass maintenance. Patient autonomy followed symptom improvement. Since it is impossible to provide treatment for cure in most of these cases, this endoscopic strategy, performed in differentiated units with the required technical capacity, may guarantee treatment for the relief of palliative EC.

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.

Obesity parameters, physical activity, and physical fitness are correlated with serum dipeptidyl peptidase IV activity in a healthy population.

OBJECTIVE: To determine whether obesity, physical fitness, and physical activity parameters are associated with the enzymatic activity of serum dipeptidyl peptidase IV (sDPPIV) in a sample of healthy women and men. DESIGN AND METHODS: We have correlated parameters of obesity, physical fitness, and physical activity with sDPPIV activity in 374 healthy subjects (age: 60.7 ± 6.9 years, body mass index: 26.1 ± 4.1 kg/m2). Enzymatic activity was analyzed using spectrofluorimetry, body composition was assessed by impedanciometry, physical fitness data were obtained using the Senior Fitness Test, and physical activity data were collected by accelerometer. Pearson's partial correlation analysis was applied to determine the relationship between DPPIV activity and the rest of parameters and significantly correlated variables were introduced into linear regression models to predict DPPIV. RESULTS: Serum DPPIV activity was negatively associated with obesity parameters such as body mass (r = -0.112), body mass index (BMI) (r = -0.147), waist circumference (r = -0.164), waist-to-hip ratio (-0.104), and percentage of fat mass (r = -0.185). Serum DPPIV activity was positively associated with cardiovascular fitness (r = 0.138), total amount of physical activity (r = 0.153), and time spent doing light exercise (r = 0.184). Regression models revealed sex differences in enzyme activity with overall activity higher in women than in men (ß = 0.437, p < 0.001). Further, percent fat mass was an independent negative predictor of DPPIV activity (ß = -0.184, p = 0.001). Serum DPPIV activity was positively predicted based on the amount of time spent doing light physical activity (ß = 0.167, p = 0.001). CONCLUSION: Our results demonstrate that sDPPIV activity is positively associated with healthier parameters regarding fatness, fitness and physical activity.

Biomarcadores por tomografia por emisión de positrones (PET): imagen de la patología de Alzheimer y la neurodegeneración al servicio del diagnóstico clínico / PET biomarkers: Use of imaging techniques in Alzheimer disease and neurodegeneration clinical diagnosis

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Sex differences in the aging pattern of renin-angiotensin system serum peptidases.

BACKGROUND: Serum peptidases, such as angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (ACE2), neutral endopeptidase (NEP), aminopeptidase N (APN), and aminopeptidase A (APA), are important elements of the renin-angiotensin system (RAS). Dysregulation of these enzymes has been associated with hypertension and cardiovascular risk. In the present study, serum activities of RAS peptidases were analyzed to evaluate the existence of sexual differences, with a possible different pattern in pre- and post-andropausal/post-menopausal participants. METHODS: One hundred and eighteen healthy men and women between 41 and 70 years of age (58 women and 60 men) were recruited to participate in the study. Serum RAS-regulating enzymes were measured by spectrofluorimetry. Enzymatic activity was recorded as units of enzyme per milliliter of serum (U/mL). RESULTS: Significantly lower serum APA activity was observed in men with respect to women; no sex differences were detected for ACE, ACE2, NEP, or APN. Significantly lower APA and ACE serum activity were observed in older men compared to older women. In contrast, younger (<55 years) men had significantly higher values of NEP serum activity than younger women. Significantly lower ACE serum activity was detected in older men compared to younger men. In women, significantly higher ACE2 serum activity was observed in older women compared to younger women. CONCLUSIONS: These results suggest a differential effect of aging on the activity of RAS enzymes in men and women, especially with respect to the breakpoint of andropausia/menopausia, on the critical serum enzymatic activities of the RAS, which could correlate with sexual differences in cardiovascular risk.

Stents in patients with esophageal cancer before chemoradiotherapy: high risk of complications and no impact on the nutritional status.

Preoperative chemoradiotherapy is the standard of care for locally advanced esophageal cancer, causing persistent deterioration in the nutritional status. We performed a prospective study to evaluate the safety and efficacy of esophageal double-covered self-expandable metal stents in patients with esophageal cancer before chemoradiotherapy. The nutritional status and dysphagia were prospectively recorded. Eleven patients were included: eight were moderate and three were severely malnourished. After stent placement, dysphagia improved in all patients. With regard to complications, one patient developed an esophageal perforation that required urgent esophagectomy. Four patients presented stent migration. Three of these patients required enteral nutrition and none was submitted to surgery because of poor nutritional status. Of the other six patients, only four were operated upon. Stent placement presented a high complication rate and did not prevent weight loss or malnutrition. Other alternatives, including naso-gastric tube placement or endoscopic percutaneous gastrostomy or jejunostomy, should be considered.

Recomendaciones para la utilización de biomarcadores de imagen PET en el proceso diagnóstico de las enfermedades neurodegenerativas que cursan con demencia: documento de consenso SEMNIM y SEN / Recommendations for the use of PET imaging biomarkers in the diagnosis of neurodegenerative conditions associated with dementia: SEMNIM and SEN consensus

Los nuevos criterios diagnósticos para la enfermedad de Alzheimer (EA) reconocen el interés de los biomarcadores, tanto para mejorar la especificidad en sujetos en fase de demencia, como para facilitar el diagnóstico precoz del proceso fisiopatológico de la EA en personas en fases prodrómicas. La disponibilidad actual de biomarcadores de imagen PET de disfunción neuronal (PET-FDG) y de depósito de proteína beta amiloide (PET-Amiloide), ofrecen a los especialistas clínicos involucrados en la evaluación de pacientes con deterioro cognitivo la oportunidad de aplicar los nuevos criterios en su práctica clínica. Sin embargo, resulta imprescindible que las sociedades científicas implicadas en la utilización de las nuevas herramientas de apoyo al diagnóstico clínico se pongan de acuerdo en cuales deben de ser las recomendaciones para su utilización clínica. En este trabajo se lleva a cabo una revisión sistemática de la literatura sobre el uso de PET-amiloide y PET-FDG, tanto en el proceso diagnóstico de la EA como de otras enfermedades neurodegenerativas que cursan con demencia. Asimismo, se proponen una serie de recomendaciones consensuadas por la Sociedad Española de Medicina Nuclear y la Sociedad Española de Neurología a modo guía para la utilización adecuada de los biomarcadores de imagen PET (AU)

The new diagnostic criteria for Alzheimer's disease (AD) acknowledges the interest given to biomarkers to improve the specificity in subjects with dementia and to facilitate an early diagnosis of the pathophysiological process of AD in the prodromal or pre-dementia stage. The current availability of PET imaging biomarkers of synaptic dysfunction (PET-FDG) and beta amyloid deposition using amyloid-PET provides clinicians with the opportunity to apply the new criteria and improve diagnostic accuracy in their clinical practice. Therefore, it seems essential for the scientific societies involved to use the new clinical diagnostic support tools to establish clear, evidence-based and agreed set of recommendations for their appropriate use. The present work includes a systematic review of the literature on the utility of FDG-PET and amyloid-PET for the diagnosis of AD and related neurodegenerative diseases that occur with dementia. Thus, we propose a series of recommendations agreed on by the Spanish Society of Nuclear Medicine and Spanish Society of Neurology as a consensus statement on the appropriate use of PET imaging biomarkers (AU)

Osteonecrosis de los maxilares relacionada con el tratamiento con bifosfonatos / Bisphosphonate-related osteonecrosis of the jaw

Los bifosfonatos, análogos estables de los pirofosfatos inorgánicos, han demostrado su eficacia para el tratamiento de las lesiones osteolíticas asociadas a metástasis óseas o al mieloma múltiple, la hipercalcemia maligna, la enfermedad de Paget y la osteoporosis. Numerosas publicaciones durante los últimos a˜nos consideran que la osteonecrosis de los maxilares está asociada al tratamiento con bifosfonatos. El manejo diagnóstico y terapéutico de los pacientes con osteonecrosis de los maxilares es de una enorme dificultad. Es importante que los pacientes sean informados del riesgo de presentar esta complicación para tener la oportunidad de recibir procedimientos dentales previos al inicio del tratamiento. Las medidas preventivas deben realizarse antes, durante y después del tratamiento con bifosfonatos. Ante una osteonecrosis de los maxilares establecida, la actitud debe ser conservadora: enjuagues con clorhexidina y antibióticos. El tratamiento quirúrgico debe reservarse para aquellos pacientes que presenten síntomas (AU)

The bisphosphonates are stable inorganic pyrophosphate analogs that have demonstrated their efficacy in treatment of osteolytic lesions associated with bony metastases, and multiple myeloma, malignant hypercalcemia, Paget’s disease, and osteoporosis. Several publications within the last few years have suggested that osteonecrosis of the jaw is associated with bisphosphonate therapy. The diagnosis and management strategies of the patients with bisphosphonate-related osteonecrosis of the jaw is very difficult. It is important for patients to be informed of the risk of this complication, so that they have the opportunity to assess the need for dental treatment before starting therapy. Preventive measures must be taken before during, and after treatment with bisphosphonates. If osteonecrosis of the jaw is present, management should be conservative: oral chlorhexidine and antibiotics. Surgical treatment should be reserved for those patients who are symptomatic (AU)

[Bisphosphonate-related osteonecrosis of the jaw]. / Osteonecrosis de los maxilares relacionada con el tratamiento con bifosfonatos.

The bisphosphonates are stable inorganic pyrophosphate analogs that have demonstrated their efficacy in treatment of osteolytic lesions associated with bony metastases, and multiple myeloma, malignant hypercalcemia, Paget's disease, and osteoporosis. Several publications within the last few years have suggested that osteonecrosis of the jaw is associated with bisphosphonate therapy. The diagnosis and management strategies of the patients with bisphosphonate-related osteonecrosis of the jaw is very difficult. It is important for patients to be informed of the risk of this complication, so that they have the opportunity to assess the need for dental treatment before starting therapy. Preventive measures must be taken before, during, and after treatment with bisphosphonates. If osteonecrosis of the jaw is present, management should be conservative: oral chlorhexidine and antibiotics. Surgical treatment should be reserved for those patients who are symptomatic.

Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of Alzheimer's disease dementia.

PURPOSE: To introduce, evaluate and validate a voxel-based analysis method of ¹8F-FDG PET imaging for determining the probability of Alzheimer's disease (AD) in a particular individual. METHODS: The subject groups for model derivation comprised 80 healthy subjects (HS), 36 patients with mild cognitive impairment (MCI) who converted to AD dementia within 18 months, 85 non-converter MCI patients who did not convert within 24 months, and 67 AD dementia patients with baseline FDG PET scan were recruited from the AD Neuroimaging Initiative (ADNI) database. Additionally, baseline FDG PET scans from 20 HS, 27 MCI and 21 AD dementia patients from our institutional cohort were included for model validation. The analysis technique was designed on the basis of the AD-related hypometabolic convergence index adapted for our laboratory-specific context (AD-PET index), and combined in a multivariable model with age and gender for AD dementia detection (AD score). A logistic regression analysis of different cortical PET indexes and clinical variables was applied to search for relevant predictive factors to include in the multivariable model for the prediction of MCI conversion to AD dementia (AD-Conv score). The resultant scores were stratified into sixtiles for probabilistic diagnosis. RESULTS: The area under the receiver operating characteristic curve (AUC) for the AD score detecting AD dementia in the ADNI database was 0.879, and the observed probability of AD dementia in the six defined groups ranged from 8% to 100% in a monotonic trend. For predicting MCI conversion to AD dementia, only the posterior cingulate index, Mini-Mental State Examination (MMSE) score and apolipoprotein E4 genotype (ApoE4) exhibited significant independent effects in the univariable and multivariable models. When only the latter two clinical variables were included in the model, the AUC was 0.742 (95% CI 0.646 - 0.838), but this increased to 0.804 (95% CI 0.714 - 0.894, bootstrap p=0.027) with the addition of the posterior cingulate index (AD-Conv score). Baseline clinical diagnosis of MCI showed 29.7% of converters after 18 months. The observed probability of conversion in relation to baseline AD-Conv score was 75% in the high probability group (sixtile 6), 34% in the medium probability group (merged sixtiles 4 and 5), 20% in the low probability group (sixtile 3) and 7.5% in the very low probability group (merged sixtiles 1 and 2). In the validation population, the AD score reached an AUC of 0.948 (95% CI 0.625 - 0.969) and the AD-Conv score reached 0.968 (95% CI 0.908 - 1.000), with AD patients and MCI converters included in the highest probability categories. CONCLUSION: Posterior cingulate hypometabolism, when combined in a multivariable model with age and gender as well as MMSE score and ApoE4 data, improved the determination of the likelihood of patients with MCI converting to AD dementia compared with clinical variables alone. The probabilistic model described here provides a new tool that may aid in the clinical diagnosis of AD and MCI conversion.

Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

Progression of Alzheimer disease in Europe: data from the European ICTUS study.

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden.

The impact of silent vascular brain burden in cognitive impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) detected by magnetic resonance imaging (MRI) of the brain are associated with dementia and cognitive impairment in the general population and in Alzheimer's disease. Their effect in cognitive decline and dementia associated with Parkinson's disease (PD) is still unclear. METHODS: We studied the relationship between WMHs and cognitive state in 111 patients with PD classified as cognitively normal (n = 39), with a mild cognitive impairment (MCI) (n = 46) or dementia (n = 26), in a cross-sectional and follow-up study. Cognitive state was evaluated with a comprehensive neuropsychological battery, and WMHs were identified in FLAIR and T2-weighted MRI. The burden of WMHs was rated using the Scheltens scale. RESULTS: No differences in WMHs were found between the three groups in the cross-sectional study. A negative correlation was observed between semantic fluency and the subscore for WMHs in the frontal lobe. Of the 36 non-demented patients re-evaluated after a mean follow-up of 30 months, three patients converted into MCI and 5 into dementia. Progression of periventricular WMHs was associated with an increased conversion to dementia. A marginal association between the increase in total WMHs burden and worsening in the Mini Mental State Examination was encountered. CONCLUSIONS: White matter hyperintensities do not influence the cognitive status of patients with PD. Frontal WMHs have a negative impact on semantic fluency. Brain vascular burden may have an effect on cognitive impairment in patients with PD as WMHs increase overtime might increase the risk of conversion to dementia. This finding needs further confirmation in larger prospective studies.

Extenders containing dimethylformamide associated or not with glycerol are ineffective for ovine sperm cryopreservation.

The study aimed at testing the effectiveness of dimethylformamide, alone or combined with glycerol, as cryoprotectant for freezing ram semen. Ejaculates from nine rams were cryopreserved in Tris-based extenders, containing 5% of glycerol, association of dimethylformamide with glycerol, in four proportions achieving 5% of cryoprotectors in the media and pure dimethylformamide (2, 3, 4 and 5%) in replacement to glycerol. The samples were diluted to 100 × 10(6) sptz/ml and stored in 0.25-ml straws in liquid nitrogen. After thawing (37 °C for 30 s), motility was preserved better by the extender containing 5% of glycerol (p < 0.05). The extenders containing pure dimethylformamide, or more than 2% in combination with glycerol, provided sperm motilities close to zero. Plasma and acrosomal membrane integrity were preserved better (p < 0.05) in the extender containing 5% glycerol. It can be concluded that dimethylformamide, alone or combined with glycerol, has no beneficial effects on ovine semen cryopreservation.