Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type.

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-ß 42 (Aß42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aß42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aß42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aß42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

Downstream Migration and Fragmentation of a Spontaneous Calcific Embolus after Thrombolysis in a Patient with Ischemic Stroke.

We report a successful treatment experience with systemic thrombolysis in a patient with acute ischemic stroked caused by spontaneous calcific embolus, which resulted in clinical improvement and embolus fragmentation.

Depression and Suicide Risk in Mild Cognitive Impairment: The Role of Alzheimer's Disease Biomarkers.

BACKGROUND: Patients with depression and mild cognitive impairment (MCI) are at greater risk of developing dementia. Depression involves a higher risk of suicidal ideation (SI) and suicide attempts (SA). Biomarkers of Alzheimer's Disease (AD) could help to clarify the role of depression and SI in AD. METHOD: Fifty-nine participants aged > 50 with criteria of MCI positive (MCI-AD) (n=22) and negative (MCI-Non AD) (n=24) AD and healthy controls (HC) (n=13) were evaluated. We used the Geriatric Depression Scale (GDS-30) and the GDS-SI factor to measure depression and indirect risk for suicide, respectively. Additionally, AD biomarkers such as amyloid-ß (Aß), hyperphosphorilated tau (P-tau), and total tau (T-tau) in cerebrospinal fluid (CSF) were analyzed. RESULTS: No significant differences between the groups were found in depression. However, in the MCI-AD group, lower P-tau and T-tau levels were related to higher GDS-SI scores, suggesting that MCI-AD patients with lower AD pathology are at a higher risk of suicide. CONCLUSIONS: The result highlights the importance of considering SI in the initial phases of AD, and the potential role of AD biomarkers in early detection of symptoms.

From Face-to-Face to Home-to-Home: Validity of a Teleneuropsychological Battery.

BACKGROUND: Over the last decade, teleneuropsychology has increased substantially. There is a need for valid neuropsychological batteries to be administered home-to-home. Since 2006, the neuropsychological battery of Fundació ACE (NBACE) has been administered face-to-face in our clinical settings. Recently, we adapted the NBACE for teleneuropsychology use to be administered home-to-home (NBACEtn). OBJECTIVE: The aims of the present study are: 1) to determine the home-to-home NBACE equivalence compared to its original face-to-face version; and 2) to examine home-to-home NBACE discriminant capacity by differentiating among cognitively healthy, mild cognitive impairment, or mild dementia subjects and comparing it with the face-to-face version. METHODS: Data from 338 individuals assessed home-to-home (NBACEtn) were contrasted with 7,990 participants assessed with its face-to-face version (NBACE). Exploratory and confirmatory factorial structure, and invariance analysis of the two versions of the battery were performed. RESULTS: Exploratory and confirmatory factor analysis supported the four-factor model (attention, memory, executive, and visuospatial/constructional functions). Configural, metric, and scalar measurement invariance was found between home-to-home and face-to-face NBACE versions. Significant differences in most of the neuropsychological variables assessed were observed between the three clinical groups in both versions of administration. No differences were found between the technological devices used by participants (computer or tablet and mobile devices). CONCLUSION: For the first time, invariance analysis findings were addressed by determining a teleneuropsychological battery's equivalence in comparison with its face-to-face version. This study amplifies the neuropsychological assessment's applicability using a home-to-home format, maintaining the original measure's structure, interpretability, and discriminant capacity.

Neuropsychiatric Profile as a Predictor of Cognitive Decline in Mild Cognitive Impairment.

Introduction: Mild cognitive impairment is often associated with affective and other neuropsychiatric symptoms (NPS). This co-occurrence might have a relevant impact on disease progression, from MCI to dementia. Objective: The aim of this study was to explore the trajectories of cognitive decline in an MCI sample from a memory clinic, taking into consideration a perspective of isolated cognitive functions and based on NPS clusters, accounting for the different comorbid symptoms collected at their baseline visit. Methods: A total of 2,137 MCI patients were monitored over a 2.4-year period. Four clusters of NPS (i.e., Irritability, Apathy, Anxiety/Depression and Asymptomatic) were used to run linear mixed models to explore the interaction of cluster with time on cognitive trajectories using a comprehensive neuropsychological battery (NBACE) administered at baseline and at the three subsequent follow-ups. Results: A significant interaction between cluster and time in cognitive decline was found when verbal learning and cued-recall were explored (p = 0.002 for both memory functions). For verbal learning, the Irritability cluster had the largest effect size (0.69), whereas the Asymptomatic cluster showed the smallest effect size (0.22). For cued-recall, the Irritability cluster had the largest effect size among groups (0.64), and Anxiety/Depression had the smallest effect size (0.21). Conclusions: In MCI patients, the Irritability and Apathy NPS clusters shared similar patterns of worsening in memory functioning, which could point to these NPS as risk factors of a faster cognitive decline, acting as early prognostic markers and helping in the diagnostic process.

Metabolomics study to identify plasma biomarkers in alzheimer disease: ApoE genotype effect.

Alzheimer Disease (AD) is the main cause of dementia, and it has a great social and economic impact worldwide. It is a complex multifactorial disease, and we still do not know enough about its causes. For this reason, omics studies could be a useful tool for the search for new biomarkers and for enhancing the knowledge of different metabolic pathways that may be altered in the initial stages of the disease. Metabolomic analysis was carried out for plasma samples from early AD patients and healthy controls. Obtained data were normalized and analyzed by volcano plot and supervised orthogonal-least-squares-discriminant analysis. Fifteen variables were selected as the most important variables for the groups' discrimination, and the different levels of 6 identified metabolites could discriminate between patients with different ApoE4 genotypes (ε4-carriers and non ε4-carriers). In conclusion, ApoE4 genotype is associated with changes in lipid metabolomics profile in AD patients, and it could be relevant for the development of AD since early stages.

Lipid peroxidation biomarkers correlation with medial temporal atrophy in early Alzheimer Disease.

Alzheimer Disease (AD) is a pathology that causes millions of deaths every year and it also generates severe economic consequences for families and public health systems. Oxidative stress is related to neurodegenerative diseases damage. In fact, brain lipid oxidation could produce brain atrophy. The main objective of this study is the evaluation of atrophy and lipid peroxidation damage in AD patients. We studied medial temporal brain atrophy by magnetic resonance imaging (MRI) and a set of lipid peroxidation biomarkers from plasma samples, respectively. The participants were AD patients in early stages (n = 80) and healthy controls (n = 32). Some lipid peroxidation compounds (neuroprostanes, isoprostanes, neurofurans, isofurans, 17-epi-17-F2t-dihomo-IsoP, PGF2α) in plasma showed statistically significant correlation with medial temporal atrophy. So, they were selected to generate an AD diagnosis model, showing an AUC-ROC of 0.900, close to accuracy achieved by the model based on neuroimaging analysis (AUC-ROC 0.929). In addition, the new model showed suitable specificity, so it could be used as screening test. The developed model based on plasma biomarkers could reflect white and grey matter lipid peroxidation, which occurs in medial temporal lobe in early AD patients. Nevertheless, more studies are needed in this field in order to evaluate specificity against other dementias or neurodegenerative diseases.

Plasma metabolomics in early Alzheimer's disease patients diagnosed with amyloid biomarker.

An untargeted metabolomics study has been carried out using plasma samples from patients with Mild Cognitive Impairment due to Alzheimer's disease patients (MCI-AD, n = 29) and healthy people (n = 29)). They have been classified following the National Institute on Aging and Alzheimer's Association (NIA-AA) recommendations and cerebrospinal fluid biomarkers. The analytical method was based on liquid chromatography coupled to high resolution mass spectrometry. The data process from the corresponding metabolic profiles retained 1158 molecular features in positive and 424 in negative ionization mode. Differences between metabolomic profiles from MCI-AD patients and healthy participants were investigated using a penalized logistic regression analysis (ElasticNet), and being able to select automatically the most informative variables (53 molecular features). From the molecular features selected for the elastic net models, 16 variables were preliminarily identified by The Human Metabolome Database (amino acids, lipids…). However, only 4 of these variables were tentatively identified by MS/MS and all ions fragmentation modes, being choline the only confirmed metabolite. Regarding their metabolic pathways, they could be involved in cholinergic system, energy metabolism, amino acids and lipids pathways. To conclude, this is a reliable approach to early AD mechanisms, and choline has been identified as a promising AD diagnosis metabolite. SIGNIFICANCE: The untargeted analysis carried out in human plasma samples from early Alzheimer's disease patients and healthy individuals, and the use of sophisticated statistical tools, identified some metabolic pathways and plasma biomarkers. Preliminarily, cholinergic system, energy metabolism, and aminoacids and lipids pathways may be involved in early Alzheimer's disease development.

New screening approach for Alzheimer's disease risk assessment from urine lipid peroxidation compounds.

Alzheimer Disease (AD) standard biological diagnosis is based on expensive or invasive procedures. Recent research has focused on some molecular mechanisms involved since early AD stages, such as lipid peroxidation. Therefore, a non-invasive screening approach based on new lipid peroxidation compounds determination would be very useful. Well-defined early AD patients and healthy participants were recruited. Lipid peroxidation compounds were determined in urine using a validated analytical method based on liquid chromatography coupled to tandem mass spectrometry. Statistical studies consisted of the evaluation of two different linear (Elastic Net) and non-linear (Random Forest) regression models to discriminate between groups of participants. The regression models fitted to the data from some lipid peroxidation biomarkers (isoprostanes, neuroprostanes, prostaglandines, dihomo-isoprostanes) in urine as potential predictors of early AD. These prediction models achieved fair validated area under the receiver operating characteristics (AUC-ROCs > 0.68) and their results corroborated each other since they are based on different analytical principles. A satisfactory early screening approach, using two complementary regression models, has been obtained from urine levels of some lipid peroxidation compounds, indicating the individual probability of suffering from early AD.

Plasma lipid peroxidation biomarkers for early and non-invasive Alzheimer Disease detection.

INTRODUCTION: Alzheimer Disease (AD) standard diagnosis is based on evaluations and biomarkers that are non-specific, expensive, or requires invasive sampling. Therefore, an early, and non-invasive diagnosis is required. As regards molecular mechanisms, recent research has shown that lipid peroxidation plays an important role. METHODS: Well-defined participants groups were recruited. Lipid peroxidation compounds were determined in plasma using a validated analytical method. Statistical studies consisted of an elastic-net-penalized logistic regression adjustment. RESULTS: The regression model fitted to the data included six variables (lipid peroxidation biomarkers) as potential predictors of early AD. This model achieved an apparent area under the receiver operating characteristics (AUC-ROCs) of 0.883 and a bootstrap-validated AUC-ROC of 0.817. Calibration of the model showed very low deviations from real probabilities. CONCLUSION: A satisfactory early diagnostic model has been obtained from plasma levels of 6 lipid peroxidation compounds, indicating the individual probability of suffering from early AD.

Depression and Suicide Risk in Mild Cognitive Impairment: The Role of Alzheimer’s Disease Biomarkers / Depresión y Riesgo de Suicidio en el Deterioro Cognitivo Leve: el Rol de los Biomarcadores de la Enfermedad de Alzheimer

Background: Patients with depression and mild cognitive impairment (MCI) are at greater risk of developing dementia. Depression involves a higher risk of suicidal ideation (SI) and suicide attempts (SA). Biomarkers of Alzheimer’s Disease (AD) could help to clarify the role of depression and SI in AD. Method: Fifty-nine participants aged > 50 with criteria of MCI positive (MCI-AD) (n=22) and negative (MCI-Non AD) (n=24) AD and healthy controls (HC) (n=13) were evaluated. We used the Geriatric Depression Scale (GDS-30) and the GDS-SI factor to measure depression and indirect risk for suicide, respectively. Additionally, AD biomarkers such as amyloid-ß (Aß), hyperphosphorilated tau (P-tau), and total tau (T-tau) in cerebrospinal fluid (CSF) were analyzed. Results: No significant differences between the groups were found in depression. However, in the MCI-AD group, lower P-tau and T-tau levels were related to higher GDS-SI scores, suggesting that MCI-AD patients with lower AD pathology are at a higher risk of suicide. Conclusions: The result highlights the importance of considering SI in the initial phases of AD, and the potential role of AD biomarkers in early detection of symptoms.(AU)

Antecedentes: Los pacientes con depresión y deterioro cognitivo leve (DCL) tienen un alto riesgo de desarrollar demencia. La depresión implica un alto riesgo de ideación suicida (IS) e intentos de suicidio (AS). Los biomarcadores de la enfermedad de Alzheimer (EA) pueden clarificar el papel de la depresión e IS en la EA. Método: Cincuenta y nueve participantes >50 años con criterios de DCL-EA positivo (DCL-EA; 22) y negativo (DCL-NoEA; 24) y 13 controles sanos. La depresión fue evaluada con la Escala Geriátrica de Depresión (GDS-30) y la IS con el factor GDS-IS. Además, se midieron los siguientes biomarcadores en el líquido cefalorraquídeo: ß-amiloide (ß-A), tau hiperfosforilada (H-tau) y total (T-tau). Resultados: No se encontraron diferencias significativas entre los tres grupos de participantes en depresión o en IS. Sin embargo, en el grupo DCL-EA, niveles más bajos de H-tau y T-tau, indicadores de menor patología EA, se relacionaron significativamente con mayor riesgo de suicidio indirecto. Conclusiones: Este resultado subraya la importancia de considerar la IS en fases iniciales de EA, y el potencial papel de los biomarcadores de EA para detectar sus síntomas.(AU)

Short- and long-term outcomes in non-aneurysmal non-perimesencephalic subarachnoid hemorrhage.

OBJECTIVE: Our aim was to assess the short- and long-term prognosis in patients suffering from non-aneurysmal non-perimesencephalic SAH (Na-NPM-SAH). METHODS: Based on admission CT-scan, SAH was categorized as perimesencephalic (PM) or non-perimesencephalic (NPM). Based on digital subtraction angiography (DSA) results, patients were classified as normal DSA (Na-SAH) or aneurysmal SAH (aSAH). Between 1997 and 2010, 67 of 571 patients with non-traumatic SAH (11.7%) suffered from non-aneurysmal non-perimesencephalic SAH. Retrospective analyses of the 67 patients were undertaken, and compared with the aneurysmal SAH group. Long-term follow-up was assessed. RESULTS: The cohort consisted of 67 Na-NPM-SAH patients, mean age 54.8 years (range: 21-84), 56.7% male. Acute phase: 10.4% mortality and 3% rebleeding (two patients) during the acute phase. Long-term: extensive follow-up was possible in all except one of the survivors at discharge. Mortality was 6.6% during the 510 patient-years follow-up period (median follow-up time per patient, 8.95 years); rebleeding rate was 0-1.6%. An aneurysmal source was found in 13% of patients who underwent a second angiography. Aneurysmal SAH: 312 patients, with confirmed aneurysm by angiography. The mortality rate for Na-NPM-SAH during the acute phase was 10.4%, vs. 20% for aneurysmal SAH in the general database, p = 0.049. DISCUSSION: Na-NPM-SAH patients without an identifiable bleeding source on initial angiography might have a more benign short- and long-term prognosis than aneurysmal SAH patients. Our study confirms an important diagnostic advantage of a second arteriography. Still, despite the major concern of an undetected aneurysm, the long-term rebleeding rate was low in this subgroup of patients.

Immunoproteomic studies on paediatric opsoclonus-myoclonus associated with neuroblastoma.

We aimed to identify new cell-membrane antigens implicated in opsoclonus-myoclonus with neuroblastoma. The sera of 3 out of 14 patients showed IgG electron-microscopy immunogold reactivity on SH-SY5Y neuroblastoma cells. Immunoprecipitation experiments using rat brain synaptosomes and SH-SY5Y cells led to the identification of: (1) thirty-one nuclear/cytoplasmic proteins (including antigens HuB, HuC); (2) seven neuronal membrane proteins, including the Shaw-potassium channel Kv3.3 (KCNC3), whose genetic disruption in mice causes ataxia and generalized muscle twitching. Although cell-based assays did not demonstrate direct antigenicity, our findings point to Shaw-related subfamily of the potassium voltage-gated channels complexed proteins as hypothetical antigenic targets.

Characterisation of DWI-MRI confirmed cerebral infarcts in patients with subarachnoid haemorrhage and their association with MMP-9 levels.

OBJECTIVES: It has been suggested that metalloproteinase-9 (MMP-9) could predict the onset of cerebral vasospasm after subarachnoidal haemorrhage (SAH). The aim of this study was to analyse, in patients with SAH, the difference between patients with MRI ischaemic infarcts and patients without, and to investigate the role of metalloproteases as a prognostic factor for ischaemic infarcts. METHODS: Sixty eight consecutive patients with SAH and diffusion-weighted magnetic resonance imaging (DWI-MRI) done 3 weeks after SAH. We define two groups, with and without DWI-MRI infarcts. Blood samples were taken at entry, 3 days and 1 week MMP-9 was determined through ELISA method. RESULTS: Forty per cent were male, with a mean age of 54 ± 14 years. Twenty five patients, 36.8%, had DWI-MRI infarcts; in patients with MRI infarcts, SAH was more severe (Fisher = 4 52 vs 25.6%, P = 0.037), with more morbi-mortality (Rankin>3 48 vs 18.6%, P = 0.014), and more symptomatic vasospasm (28 vs 7%, P = 0.031). Levels of MMP-9 were higher than controls, but there were no significant differences between patients with and without infarcts (first determination no infarcts 39.40 ng/ml ± 35.40 vs infarcts 49.75 ng/ml ± 34.54, P > 0.005, 3 days no infarcts 72.10 ng/ml ± 70.95 vs infarcts 62.28 ± 33.84, P > 0.005, 1 week no infarcts 148.48 ng/ml ± 142.73 vs infarcts 91.5 ng/ml ± 1.20, P > 0.005). CONCLUSION: Thirty eight percent in a well-studied series of patients with SAH have DWI-MRI infarcts; the infarcts were associated to SAH severity, SAH outcome and symptomatic vasospasm. Metalloproteinase-9 was higher in SAH patients than in controls, but it could not discriminate the infarct patients.