Impairments in sleep and brain molecular clearance in people with cognitive deterioration and biological evidence of AD: a report of four cases.

BACKGROUND: Recent evidence suggests that the failure of the glymphatic system - the brain's waste clearance system, which is active during sleep - plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. CASE REPORT: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5-6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. CONCLUSION: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology.

Citicoline May Prevent Cognitive Decline in Patients with Cerebrovascular Disease.

Introduction: Neuroprotective drugs such as citicoline could improve cognitive performance and quality of life. We studied the effect of citicoline treatment and its association with Vascular Risk Factors (VRF) and APOE on cognition in patients with Subjective Cognitive Complaints (SCC) and Mild Cognitive Impairment (MCI). Methods: This is an observational and prospective study with citicoline during 12 months follow-up. Eighty-one subjects who met criteria for SCC/MCI, aged 50-75 years with VRF were included and prescribed citicoline 1g/day. Subjects with previous cognitive impairment and any other central nervous system affection were excluded. Wilcoxon Signed Ranks test and paired samples t-test were used to analyze the change in neuropsychological performance. Results: Mean age of the sample was 68.2 (SD 6.8) years and 26 (32.09%) were females. Fifteen subjects (24.6%) were APOE-ε4 carriers, fifty-six (76.7%) had hypertension, fifty-eight (79.5%) had dyslipidemia, twenty-one (28.8%) had diabetes mellitus and twenty-six (35.6%) had cardiopathy. Thirty-two (43.8%) subjects were diagnosed as SCC and forty-one (56.16%) as MCI. During the follow-up, Tweny-six patients (81.25%) in the group of SCC remained stable, six subjects (18.8%) converted to MCI. Twelve patients (29.9%) with MCI reverted to SCC and twenty-nine patients (70.7%) remained stable. At follow-up, SCC subjects had an improvement in the global language domain (p=0.03), naming (p<0.001), attention (p=0.01) and visuospatial abilities (p<0.01). MCI group showed an improvement in the screening test (p=0.03), delayed memory (p<0.01), global cognition (p=0.04) and in cognitive flexibility (p=0.03). Presence of APOE-ε4 had no impact on the above findings. Discussion: SCC subjects showed an improvement in language and attention domains, while those with MCI performed better after 12 months in total scores of MoCA and RBANS domains, some converting back to SCC. This supports the idea that citicoline may prevent cognitive decline in patients with cognitive deficits.

Ischemia preconditioning induces an adaptive response that defines a circulating metabolomic signature in ischemic stroke patients.

Transient ischemic attacks (TIAs) before an acute ischemic stroke (AIS) could induce ischemic tolerance (IT) phenomena. with an endogenous neuroprotective role (Ischemic preconditioning. IPC). A consecutive prospective cohort of patients with AIS were recruited from 8 different hospitals. Participants were classified by those with non-previous recent TIA vs. previous TIA (within seven days. TIA ≤7d). A total of 541 AIS patients were recruited. 40 (7.4%). of them had previous TIA ≤7d. In line with IPC. patients with TIA ≤7d showed: 1) a significantly less severe stroke at admission by NIHSS score. 2) a better outcome at 7-90 days follow-up and reduced infarct volumes. 3) a specific upregulated metabolomics/lipidomic profile composed of diverse lipid categories. Effectively. IPC activates an additional adaptive response on increasing circulation levels of structural and bioactive lipids to facilitate functional recovery after AIS which may support biochemical machinery for neuronal survival. Furthermore. previous TIA before AIS seems to facilitate the production of anti-inflammatory mediators that contribute to a better immune response. Thus. the IT phenomena contributes to a better adaptation of further ischemia. Our study provides first-time evidence of a metabolomics/lipidomic signature related to the development of stroke tolerance in AIS patients induced by recent TIA.

Inflammatory Response of Ischemic Tolerance in Circulating Plasma: Preconditioning-Induced by Transient Ischemic Attack (TIA) Phenomena in Acute Ischemia Patients (AIS).

Introduction: Ischemic tolerance (IT) refers to a state where cells are resistant to the damaging effects caused by periods of ischemia. In a clinical scenario, the IT phenomenon would be activated by a recent transient ischemic attack (TIA) before an ischemic stroke (IS). The characterization of inflammatory protein expression patterns will contribute to improved understanding of IT. Methods: A total of 477 IS patients from nine hospitals, recruited between January 2011 and January 2016, were included in the current study and divided in three groups: 438 (91.9%) patients without previous TIA (group 1), 22 (4.6%) patients who suffered TIA 24 h before IS (group 2), and 17 (3.5%) patients who suffered TIA between 24 h and 7 days prior to IS (group 3). An inflammatory biomarker panel (IL-6, NT-proBNP, hsCRP, hs-Troponin, NSE, and S-100b) on plasma and a cytokine antibody array was performed to achieve the preconditioning signature potentially induced by TIA phenomena. Primary outcome was modified rankin scale (mRs) score at 90 days. Results: Recent previous TIA was associated with better clinical outcome at 90 days (median mRS of group 1: 2.0 [1.0-4.0]; group 2: 2.0 [0.0-3.0]; group 3: 1.0 [0-2.5]; p = 0.086) and smaller brain lesion (group 1: 3.7 [0.7-18.3]; group 2: 0.8 [0.3-8.9]; group 3: 0.6 [0.1-5.5] mL; p = 0.006). All inflammation biomarkers were down regulated in the groups of recent TIA prior to IS compared to those who did not suffer a TIA events. Moreover, a cytokine antibody array revealed 30 differentially expressed proteins between the three groups. Among them, HRG1-alpha (Fold change 74.4 between group 1 and 2; 74.2 between group 1 and 3) and MAC-1 (Fold change 0.05 between group 1 and 2; 0.06 between group 1 and 3) expression levels would better stratify patients with TIA 7 days before IS. These two proteins showed an earlier inflammation profile that was not detectable by the biomarker panel. Conclusion: Inflammatory pathways were activated by transient ischemic attack, however the period of time between this event and a further ischemic stroke could be determined by a protein signature that would contribute to define the role of ischemic tolerance induced by TIA.

Depression and Apathy After Transient Ischemic Attack or Minor Stroke: Prevalence, Evolution and Predictors.

Few previous studies have focused on affective impairment after transient ischemic attack (TIA) and/or minor stroke. The aim was to establish the prevalence, evolution and predictors of post-stroke depression (PSD) and post-stroke apathy (PSA) over a 12-month follow-up period. We prospectively included TIA and minor stroke patients (NIHSS ≤4) who had undergone magnetic resonance imaging <7 days. PSD was diagnosed according to DSM-5 criteria and PSA was defined based on an Apathy Evaluation Scale (AES-C) score of ≥37. Clinical and neuroimaging variables (presence and patterns of lesion, cerebral bleeds and white matter disease) were analysed in order to find potential predictors for PSD and PSA. Follow-up was performed at 10 days and after 2, 6, 9 and 12 months. 82 patients were included (mean 66.4 [standard deviation11.0] years) of whom 70 completed the follow-up. At 10 days, 36 (43.9%) and 28 (34.1%) patients respectively were diagnosed with PSD and PSA. At 12 months, 25 of 70 (35.7%) patients still had PSA, but only 6 of 70 (8.6%) had PSD. Beck Depression Inventory-II score, mini mental state examination (MMSE) and a previous history of depression or anxiety were predictors for PSD. While MMSE score, The Montgomery Asberg Depression Rating Scale and having previously suffered a stroke were also risk factors for PSA. Acute basal ganglia lesion and periventricular leukoaraiosis were associated with PSA while deep leukorariosis with PSD. Despite the presence of few or only transient symptoms, PSD and PSA frequent appear early after TIA and minor stroke. Unlike PSD, apathy tends to persist during follow-up.

Revisión sistemática de las características y pronóstico de los sujetos que sufren un ictus criptogénico no lacunar de mecanismo embólico / A systematic review of the characteristics and prognosis of subjects who suffer an embolic stroke of undetermined source

Introducción. Recientemente ha surgido el concepto de ictus criptogénico no lacunar de mecanismo embólico - del inglés embolic stroke of undetermined source (ESUS)- para caracterizar mejor a los pacientes con ictus criptogénico. Pacientes y métodos. Se realiza una revisión sistemática de los estudios publicados desde 2014 hasta la actualidad, valorando la epidemiología, las características clínicas y el pronóstico de los pacientes con ESUS y su proporción entre los pacientes con ictus criptogénico. Resultados. Se identificaron 10 estudios con un total de 14.810 pacientes. La frecuencia de ESUS varió entre el 6 y el 42%. Se observó un porcentaje elevado de pacientes con ictus criptogénico que cumplían los criterios de ESUS (37-82%). La edad media de estos pacientes era de 65-68 años. La gravedad media del ictus, medida por la National Institutes of Health Stroke Scale, se estableció en 3-7 puntos. Se observó una alta variabilidad en la proporción de fibrilación auricular (detectada durante el seguimiento) relacionada con la técnica de monitorización del electrocardiograma. En cinco estudios, hasta en uno de cada dos pacientes se observó alguna fuente de cardioembolismo menor, la más frecuente, la persistencia del foramen oval permeable. El riesgo de recurrencia fue del 5-14,5%. Conclusión. La aplicación de los nuevos criterios de ESUS define mejor a los pacientes con ictus criptogénico. La aplicación del concepto de ESUS exige no sólo una monitorización de electrocardiograma adecuada, sino exploraciones complementarias de rutina para descartar la presencia de fuentes de cardioembolismo menor y de otras fuentes de embolismo diferentes a la fibrilación auricular

Introduction. The concept of embolic stroke of undetermined source (ESUS) has recently appeared to better characterize patients with cryptogenic stroke. Patients and methods. A systematic review of studies published since 2014 was performed to evaluate the epidemiology, clinical features and prognosis of patients with ESUS and their proportion among patients with cryptogenic stroke. Results. Ten studies were identified with a total of 14,810 patients. The frequency of ESUS varied between 6% and 42%. We observed a high percentage of patients with cryptogenic stroke who met ESUS criteria (37-82%). The mean age of these patients was 65-68 years. The mean severity of the stroke, as measured using the National Institutes of Health Stroke Scale, was found to be 3-7 points. A high degree of variability was seen in the proportion of atrial fibrillation (detected during follow-up) related to the electrocardiogram monitoring technique. In five studies, some minor source of cardioembolism was observed in one out of every two patients, the most frequent being the persistence of patent foramen ovale. The risk of recurrence was 5-14.5%. Conclusion. The application of the new ESUS criteria provides a better definition of patients with cryptogenic stroke. Applying the concept of ESUS requires not only adequate electrocardiogram monitoring, but also routine complementary examinations to rule out the presence of minor sources of cardioembolism and other sources of embolism other than atrial fibrillation

A Current Estimation of the Early Risk of Stroke after Transient Ischemic Attack: A Systematic Review and Meta-Analysis of Recent Intervention Studies.

OBJECTIVE: Recent studies have demonstrated that there is a decrease in the risk of subsequent stroke after transient ischemic attack (TIA) when urgent care (UC) is administered. However, no meta-analysis has been developed with contemporaneous TIA studies. We perform a systematic review and a meta-analysis to establish the risk of early stroke recurrence (SR) considering data from studies that offered UC to TIA patients. METHODS: We searched for studies, without language restriction, from January 2007 to January 2015 according to PRISMA guidelines. We included studies with TIA patients who underwent UC and reported the proportion of SR at 90 days. We excluded studies that were centered on less than 100 patients and cohorts including both stroke and TIA, if stroke risk after TIA was not described. For its relevance, we included the TIAregistry.org study published in 2016. We performed both fixed and random effects meta-analyses to determine SR and assess sources of heterogeneity. RESULTS: From 4,103 identified citations, we selected 15 papers that included 14,889 patients. There was great variation in terms of the number of patients included in each study, ranging from 115 to 4,160. Seven studies were TIA clinic based. The mean age and the percentage of men were similar among studies, ranging from 62.4 to 73.1 years and 45.1-62%, respectively. The reported risk of stroke ranged from 0 to 1.46% 2 days after TIA (9 studies included), 0-2.55% 7 days after TIA (11 studies included), 1.91-2.85% 30 days after TIA (4 studies included), and 0.62-4.76% 90 days after TIA (all studies included). The pooled stroke risk was 3.42% (95% CI 3.14-3.74) at 90 days, 2.78% (95% CI 2.47-3.12) at 30 days, 2.06% (95% CI 1.83-2.33) at 7 days and 1.36% (95% CI 1.15-1.59) at 2 days. Although we did not find statistically significant heterogeneity in SR among studies, those with a higher proportion of patients with motor weakness had a significantly higher risk of SR. No statistically significant association was observed between TIA clinic management and SR. CONCLUSION: The pooled early SR is lower than in previous meta-analyses and homogeneous for all studies with an urgent assessment and management strategy regardless of vascular risk factors and clinical characteristics. Therefore, the best setting for TIA management can be individualized for each center.

Metabolomics Predicts Neuroimaging Characteristics of Transient Ischemic Attack Patients.

BACKGROUND: Neuroimaging is essential for the diagnosis and prognosis of transient ischemic attack (TIA). The discovery of a plasmatic biomarker related to neuroimaging findings is of enormous interest because, despite its relevance, magnetic resonance diffusion weighted imaging (DWI) is not always available in all hospitals that attend to TIA patients. METHODS: Metabolomic analyses were performed by liquid chromatography coupled to mass spectrometry in order to establish the metabolomic patterns of positive DWI, DWI patterns and acute ischemic lesion volumes. We used these methods with an initial TIA cohort of 129 patients and validated them with a 2nd independent cohort of 152 patients. FINDINGS: Positive DWI was observed in 115 (40.9%) subjects and scattered pearls in one arterial territory was the most frequent lesion pattern (35.7%). The median acute ischemic lesion volume was 0.33 (0.15-1.90)cm3. We detected a specific metabolomic profile common to both cohorts for positive DWI (11 molecules including creatinine, threoninyl-threonine, N-acetyl-glucosamine, lyso phosphatidic acid and cholesterol-related molecules) and ischemic lesion volume (10 molecules including lysophosphatidylcholine, hypoxanthine/threonate, and leucines). Moreover lysophospholipids and creatinine clearly differed the subcortical DWI pattern from other patterns. INTERPRETATION: There are specific metabolomic profiles associated with representative neuroimaging features in TIA patients. Our findings could allow the development of serum biomarkers related to acute ischemic lesions and specific acute ischemic patterns.

Actualización de la depresión postictus: nuevos retos en pacientes con ictus minor o ataque isquémico transitorio / Update on post-stroke depression: posing new challenges in patients with a minor stroke or transient ischaemic attack

Introducción. El ictus es una de las principales causas de discapacidad en la población adulta. El desarrollo de síntomas depresivos es la complicación afectiva más frecuente. Hasta ahora, en la mayoría de los estudios sobre depresión postictus se ha excluido a los pacientes que han sufrido un ictus minor o un ataque isquémico transitorio (AIT), si bien es un subgrupo igualmente vulnerable a esta enfermedad. Objetivo. Revisar los estudios publicados de depresión postictus para dilucidar los aspectos que ya se han demostrado ampliamente y los que necesitan mayor evidencia. Desarrollo. La depresión postictus es frecuente tanto en los pacientes con ictus establecido como en los pacientes con ictus minor o AIT. Aunque existen discrepancias en la definición utilizada, aproximadamente uno de cada tres pacientes desarrollará esta complicación. Se han identificado factores de riesgo de depresión postictus con un amplio respaldo científico (sexo femenino, antecedentes de depresión u otros trastornos psiquiátricos, gravedad del ictus y afectación funcional) y otros sin él (calidad de vida, deterioro cognitivo y biomarcadores de neuroimagen). Las principales limitaciones metodológicas halladas son la confusión entre depresión postictus y sintomatología depresiva, la variabilidad en las escalas de evaluación usadas y la variabilidad en el momento temporal de la evaluación del estado de ánimo. Hasta ahora son muy pocos los estudios en el ictus minor o el AIT. Conclusiones. Se necesitan nuevos estudios con mejor diseño que ayuden a establecer el riesgo de depresión postictus a diferentes tiempos tras el ictus, el ictus minor o el AIT, y establecer la importancia de los factores descritos previamente (AU)

Introduction. Stroke is a leading cause of disability in adults. The development of depressive symptoms is the most common emotional complication. To date, most studies of post-stroke depression have excluded patients who have suffered a minor stroke or transient ischaemic attack (TIA), although they are equally vulnerable subgroups of this sickness. Aim. We present a review of published studies of post-stroke depression to elucidate aspects that have already been widely demonstrated and those who need more evidence. Development. The post-stroke depression is both frequent in patients with established stroke and minor stroke or TIA. Although there are discrepancies in the definition used, in up to one out of three patients will develop this complication. We have identified risk factors of post-stroke depression with a broad scientific background (female, history of depression or other psychiatric disorders, stroke severity, functional impairment) and other without it (quality of life, cognitive impairment and neuroimaging biomarkers). The main methodological limitations found are: confusion between poststroke depression and depressive symptoms; variability in rating scales used; and temporal variability in the time of the evaluation of mood. To date very few studies focused on minor stroke or TIA. Conclusions. Further studies are required with improved design in order to help establish the risk of post-stroke depression at different times after the stroke, minor stroke or TIA and the importance of all the factors described above (AU)

Demencias rápidamente progresivas, ¿son todas enfermedades priónicas? / No disponible

Las demencias rápidamente progresivas (DRP) se definen como un deterioro cognitivo y funcional de carácter grave y de curso subagudo en menos de 2 años. Su etiología es muy variada, y el origen puede ser infeccioso, neurodegenerativo, vascular, inflamatorio o tóxico-metabólico. La DRP más frecuente es la enfermedad de Creutzfeldt-Jakob (ECJ), pero es de vital importancia descartar otras etiologías que puedan ser tratables y reversibles (AU)

Rapidly progressive dementia (DRP) are defined as cognitive and behavioral decline within two years. Its etiology is varied and may have an infectious, neurodegenerative, vascular, inflammatory or toxic-metabolic. The most common DRP is Creutzfeldt-Jakob disease (CJD), but it is vital to rule out other etiologies that may be treatable and reversible (AU)