Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer's Disease

Depression and Alzheimer’s disease (AD) are among the most common clinical diagnosis in older people. The relation between depression and AD is complex: depression has been shown to be a risk factor, prodromal symptom and a consequence of AD. Increased understanding of the underlying mechanisms of depression in AD may lead to early detection and differential diagnosis, and is crucial for development of novel and mechanism-based treatments. The first two studies of this doctoral thesis are exploring the associations between depressive symptoms and biomarkers of amyloid deposition and neuronal injury in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD. The aims of the third study were to describe the use of antidepressants in patients with dementia and to explore the association between mortality risk and the use of antidepressants 3 years before the dementia diagnosis. CAIDE Dementia Risk Score is taking into account midlife risk and protective factors; age, educational level, gender, systolic blood pressure, body mass index, cholesterol level and physical activity and APOE genotyping, and can predict dementia over 20 years. The last study was focused on exploring the associations between CAIDE Dementia Risk Score and biomarkers of amyloid deposition, neuronal injury and small vessel pathology in SCI and MCI patients. Additionally we explored the capacity of CAIDE Dementia Risk Score to predict dementia in a memory clinic population. Data were obtained from Memory Clinic Karolinska University Hospital Huddinge Sweden (Study I, II and IV). In study III, two large national registries were merged: the Swedish Dementia Registry (SveDem) and the Swedish Prescribed Drug Register. In study I, analysis of the three different cerebrospinal fluid biomarkers; amyloid beta (CSF Aβ), total-tau (CSF t-tau), and phosphorylated-tau did not support the hypothesis that more severe amyloid or tau pathologies are associated with more severe depressive symptoms. In contrast, SCI and AD patients with depressive symptoms tended to have lower CSF p-tau levels and, in particular, lower CSF t-tau levels than those without depression, indicating less severe neuronal injury. In study II, we used two different analysis methods of MRI to measure medial temporal lobe atrophy and hippocampus volume. Using manual tracing of the hippocampi we found smaller left hippocampus volume in SCI patients with depressive symptoms compared to those without depressive symptoms. In contrast, AD patients with depressive symptoms had less medial temporal lobe atrophy compared with those without depressive symptoms. In study III, 20,050 patients with incident dementia diagnosed in memory clinics and registered in SveDem were included. Information on the total number of medication and all antidepressants dispensed at the time of dementia diagnosis and at the first, the second and the third year prior to dementia diagnosis was obtained from the Swedish Prescribed Drug Register. During a median follow up of 2 years, 5168 (25.8%) dementia patients died. At the time of dementia diagnosis, 5,004 (25.0%) patients were on antidepressant treatment. Use of antidepressant treatment for 3 consecutive years prior to a dementia diagnosis was associated with a lower mortality risk for all dementia disorders in general and particularly in AD. In study IV, a higher CAIDE Dementia Risk Score was associated with higher CSF t-tau levels, more severe medial temporal lobe atrophy and more severe white matter changes. For the CAIDE score including APOE, a score above 9 points was associated with lower CSF Aβ, more severe medial temporal lobe atrophy and more severe white matter changes. CAIDE Dementia Risk Score (version with APOE) performed better at predicting AD compared with CAIDE Dementia Risk Score without APOE. Conclusion: We found that depressive symptoms in patients with AD and SCI are not associated with more amyloid deposition nor more neuronal injury compared with AD and SCI patients without depressive symptoms. Thus our results are consistent with the hypothesis that the mechanisms underlying depression differ between older people with and without AD. Our results have shown that use of antidepressants in prodromal AD stages is associated with a lower mortality risk. Further longitudinal studies are needed to better understand the associations between the use of antidepressants and mortality risk in dementia

Regional Disconnection in Alzheimer Dementia and Amyloid-Positive Mild Cognitive Impairment: Association Between EEG Functional Connectivity and Brain Glucose Metabolism.

Introduction: The disconnection hypothesis of Alzheimer's disease (AD) is supported by growing neuroimaging and neurophysiological evidence of altered brain functional connectivity in cognitively impaired individuals. Brain functional modalities such as [18F]fluorodeoxyglucose positron-emission tomography ([18F]FDG-PET) and electroencephalography (EEG) measure different aspects of synaptic functioning, and can contribute to understanding brain connectivity disruptions in AD. Aim: This study investigated the relationship between cortical glucose metabolism and topographical EEG measures of brain functional connectivity in subjects along AD continuum. Methods: Patients diagnosed with mild cognitive impairment (MCI) and AD (n = 67), and stratified into amyloid-positive (n = 32) and negative (n = 10) groups according to cerebrospinal fluid Aβ42/40 ratio, were assessed with [18F]FDG-PET and resting-state EEG recordings. EEG-based neuroimaging analysis involved standardized low-resolution electromagnetic tomography (sLORETA), which estimates functional connectivity from cortical sources of electrical activity in a 3D head model. Results: Glucose hypometabolism in temporoparietal lobes was significantly associated with altered EEG functional connectivity of the same regions of interest in clinically diagnosed MCI and AD patients and in patients with biomarker-verified AD pathology. The correlative pattern of disrupted connectivity in temporoparietal lobes, as detected by EEG sLORETA analysis, included decreased instantaneous linear connectivity in fast frequencies and increased lagged linear connectivity in slow frequencies in relation to the activity of remaining cortex. Conclusions: Topographical EEG measures of functional connectivity detect regional dysfunction of AD-vulnerable brain areas as evidenced by association and spatial overlap with the cortical glucose hypometabolism in MCI and AD patients. Impact statement The association between glucose hypometabolism, as evidenced by [18F]FDG-PET ([18F]fluorodeoxyglucose positron-emission tomography), and altered electroencephalography (EEG) functional connectivity metrics within temporoparietal lobes provides link between synaptic, neurophysiological, and metabolic impairment in mild cognitive impairment and Alzheimer's disease patients. This study reported alterations in EEG measures of both instantaneous and lagged linear connectivity across distinct frequency bands, both of which were shown to be important for inter- and intrahemispheric communication and function of memory systems in general. EEG-based imaging of brain functional connectivity has a potential to serve as a noninvasive, low-cost, and widely available alternative in assessing synaptic and network dysfunction in cognitively impaired patients

Decreased Electroencephalography Global Field Synchronization in Slow-Frequency Bands Characterizes Synaptic Dysfunction in Amnestic Subtypes of Mild Cognitive Impairment

Background: Mild cognitive impairment (MCI) is highly prevalent in a memory clinic setting and is heterogeneous regarding its clinical presentation, underlying pathophysiology, and prognosis. The most prevalent subtypes are single-domain amnestic MCI (sd-aMCI), considered to be a prodromal phase of Alzheimer’s disease (AD), and multidomain amnestic MCI (md-aMCI), which is associated with multiple etiologies. Since synaptic loss and dysfunction are the closest pathoanatomical correlates of AD-related cognitive impairment, we aimed to characterize it in patients with sd-aMCI and md-aMCI by means of resting-state electroencephalography (EEG) global field power (GFP), global field synchronization (GFS), and novel cerebrospinal fluid (CSF) synaptic biomarkers. / Methods: We included 52 patients with sd-aMCI (66.9 ± 7.3 years, 52% women) and 30 with md-aMCI (63.1 ± 7.1 years, 53% women). All patients underwent a detailed clinical assessment, resting-state EEG recordings and quantitative analysis (GFP and GFS in delta, theta, alpha, and beta bands), and analysis of CSF biomarkers of synaptic dysfunction, neurodegeneration, and AD-related pathology. Cognitive subtyping was based on a comprehensive neuropsychological examination. The Mini-Mental State Examination (MMSE) was used as an estimation of global cognitive performance. EEG and CSF biomarkers were included in a multivariate model together with MMSE and demographic variables, to investigate differences between sd-aMCI and md-aMCI. / Results: Patients with sd-aMCI had higher CSF phosphorylated tau, total tau and neurogranin levels, and lower values in GFS delta and theta. No differences were observed in GFP. The multivariate model showed that the most important synaptic measures for group separation were GFS theta, followed by GFS delta, GFP theta, CSF neurogranin, and GFP beta. / Conclusion: Patients with sd-aMCI when compared with those with md-aMCI have a neurophysiological and biochemical profile of synaptic damage, neurodegeneration, and amyloid pathology closer to that described in patients with AD. The most prominent signature in sd-aMCI was a decreased global synchronization in slow-frequency bands indicating that functional connectivity in slow frequencies is more specifically related to early effects of AD-specific molecular pathology

Quantitative Electroencephalography Analyzed by Statistical Pattern Recognition as a Diagnostic and Prognostic Tool in Mild Cognitive Impairment:Results from a Nordic Multicenter Cohort Study

Aim: To examine diagnostic and prognostic potential of quantitative electroencephalography (qEEG) analyzed by the statistical pattern recognition (SPR) method in patients with cognitive impairment. We compared the differential diagnostic ability of SPR to visual EEG analysis. Correlation between SPR findings and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers were evaluated. Methods: It is a multicenter cohort study involving 129 patients, (mild cognitive impairment [MCI], AD, and healthy controls). Standardized EEG was performed at baseline. Patients were continuously clinically evaluated. Results: Receiver Operating Characteristic curves showed a low discriminative ability of SPR and no ability to predict clinical progression in patients with MCI. Moderate correlation between SPR analysis and CSF AD biomarkers was found. Conclusion: The diagnostic and prognostic abilities of qEEG were low. The SPR method was superior to the visual EEG analysis. The qEEG method correlates well to CSF AD biomarkers, suggesting association with pathology in AD

Fast Alpha Activity in EEG of Patients With Alzheimer's Disease Is Paralleled by Changes in Cognition and Cholinergic Markers During Encapsulated Cell Biodelivery of Nerve Growth Factor.

Background Basal forebrain cholinergic neurons are dependent on nerve growth factor (NGF) for growth and survival and these cells are among the first to degenerate in Alzheimer's disease (AD). Targeted delivery of NGF has been suggested as a potential therapy for AD. This hypothesis was tested in a clinical trial with encapsulated cell biodelivery of NGF (NGF-ECB) in AD patients. Three of six patients showed improved biomarkers for cognition by the end of the study. Here, we report on the effects of targeted delivery of NGF on human resting EEG. Materials and methods NGF-ECB implants were implanted bilaterally in the basal forebrain of six AD patients for 12 months. EEG recordings and quantitative analysis were performed at baseline, 3 and 12 months of NGF delivery, and analyzed for correlation with changes in Mini-mental state examination (MMSE) and levels of the cholinergic marker choline acetyltransferase (ChAT) in cerebrospinal fluid (CSF). Results We found significant correlations between the topographic variance of EEG spectral power at the three study points (baseline, 3 and 12 months) and changes in MMSE and CSF ChAT. This possible effect of NGF was identified in a narrow window of alpha frequency 10-11.5 Hz, where a stabilization in MMSE score during treatment was related to an increase in EEG alpha power. A similar relation was observed between the alpha power and ChAT. More theta power at 6.5 Hz was on the contrary associated with a decrease in CSF ChAT during the trial period. Conclusion In this exploratory study, there was a positive correlative pattern between physiological high-frequency alpha activity and stabilization in MMSE and increase in CSF ChAT in AD patients receiving targeted delivery of NGF to the cholinergic basal forebrain

Parametri rodnosti različitih sorti jarog ječma (Hordeum vulgare L)

This paper presents the results of Kragujevac spring barley varieties (Jadran and Dunavac). The experiment was conducted at the experimental field of the Center for Small Grains, Kragujevac during two growing seasons. Investigated the grain yield (t ha-1), 1000 grain weight (g) and test weight (kg hl-1). By examining the physical properties of grain, variety Jadran is made slightly larger two-year average grain yield (3.127 t ha-1). The average value for 1000 kernel weight and test weight in both years was slightly higher in the variety Dunavac.U radu su prikazani rezultati istraživanja kragujevačkih jarih sorti ječma (Jadran i Dunavac). Ogled je postavljen na oglednom polju Centra za strna žita, Kragujevac tokom dve vegetacijske sezone. Istraživan je prinos zrna, masa 1000 zrna i hektolitarska masa. Prosečan prinos zrna u posmatranom dvogodišnjem periodu kretao se u intervalu od 2,674 t ha-1 do 3,127 t ha-1, dok se vrednost za masu 1000 zrna kretala u intervalu od 44,16 g do 44,48 g. Sorta Jadran je ostvarila nešto veći dvogodišnji prosečan prinos zrna (3,127 t ha-1). Prosečna vrednost za masu 1000 zrna i hektolitarsku masu u obe godine istraživanja bila je nešto veća kod sorte Dunavac

Uticaj godine na prinos i kvalitet zrna ozimih sorti pšenice

The small-scale trials over two years (2009/10th and 2010/11th), examined the six varieties of winter wheat (Vizija, Takovčanka, Kg 56 S, Kruna, Aleksandra and Planeta). Studied grain yield (t ha-1), weight of 1000 grains (g) and test weight (kg hl-1). Estimates were statistically significant differences for grain yield between varieties and years. Cultivars Vizija, Kg 56 S, Takovčanka and the Kruna have conducted surveys have shown a high degree of adaptability conditions of production of wheat and had a satisfactory yield in the examined vegetation seasons.U mikroogledima tokom dve godine (2009/10.-2010/11.), ispitivano je šest sorti ozime pšenice (Vizija, Takovčanka, Kg 56 S, Kruna, Aleksandra i Planeta). Istraživan je prinos zrna (t ha-1), masa 1000 zrna (gr) i hektolitarska masa (kg hl-1). Procenjene su statistički signifikantne razlike za prinos zrna između sorti i godina. Sorte Vizija, Kg 56 S, Takovčanka i Kruna su u sprovedenim ispitivanjima pokazale visok stepen adaptabilnosti uslovima proizvodnje pšenice i imale su zadovoljavajući prinos u ispitivanim godinama

Lifestyle Factors Are Important Contributors to Subjective Memory Complaints among Patients without Objective Memory Impairment or Positive Neurochemical Biomarkers for Alzheimer’s Disease

Background/Aims: Many patients presenting to a memory disorders clinic for subjective memory complaints do not show objective evidence of decline on neuropsychological data, have nonpathological biomarkers for Alzheimer’s disease, and do not develop a neurodegenerative disorder. Lifestyle variables, including subjective sleep problems and stress, are factors known to affect cognition. Little is known about how these factors contribute to patients’ subjective sense of memory decline. Understanding how lifestyle factors are associated with the subjective sense of failing memory that causes patients to seek a formal evaluation is important both for diagnostic workup purposes and for finding appropriate interventions and treatment for these persons, who are not likely in the early stages of a neurodegenerative disease. The current study investigated specific lifestyle variables, such as sleep and stress, to characterize those patients that are unlikely to deteriorate cognitively. Methods: Two hundred nine patients (mean age 58 years) from a university hospital memory disorders clinic were included. Results: Sleep problems and having much to do distinguished those with subjective, but not objective, memory complaints and non-pathological biomarkers for Alzheimer’s disease. Conclusions: Lifestyle factors including sleep and stress are useful in characterizing subjective memory complaints from objective problems. Inclusion of these variables could potentially improve health care utilization efficiency and guide interventions