Neuroimaging studies which investigate brain activity underlying declarative memory processes typically use artificial, unimodal laboratory stimuli. In contrast, we developed a paradigm which much more closely approximates real-life situations of information encoding.

Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia in vitro. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E2 production in rat primary microglia.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).

The role of genetic risk markers for Alzheimer's disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (n = 811), and non-amnestic MCI (naMCI) (n = 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI (n = 262), Pr-naMCI (n = 76), possible (Pss)-aMCI (n = 549), and Pss-naMCI (n = 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample, APOE-ε4 was significantly associated with the memory function NEs "delayed recall (DR)" (β = -0.76, p = 4.1 × 10-10), "learning" (β = -1.35, p = 2.91 × 10-6), and "recognition memory" (β = -0.58, p = 9.67 × 10-5); and with "DR" in the aMCI group (β = -0.36, p = 2.96 × 10-5). These results were confirmed by validation in the AgeCoDe (n = 503) and DCN (n = 583) datasets. APOE-ε4 was also significantly associated with the NE "learning" in individuals classified as having Pss-aMCI (β = -1.37, p = 5.82 × 10-5). Moreover, there was a near study-wide significant association between the HS3ST1 locus (rs6448799) and the "backward digits" working memory NE (β = 0.52, p = 7.57 × 10-5) among individuals with Pr-aMCI, while the AP2A2 locus (rs10751667) was significantly associated with the language NE "repetition" (β = -0.19, p = 5.34 × 10-6). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.

Restorative therapy concepts, such as cell based therapies aim to restitute impaired neurotransmission in neurodegenerative diseases. New strategies to enhance grafted cell survival and integration are still needed to improve functional recovery. Anodal direct current stimulation (DCS) promotes neuronal activity and secretion of the trophic factor BDNF in the motor cortex. Transcranial DCS applied to the motor cortex transiently improves motor symptoms in Parkinson's disease (PD) patients. In this proof-of-concept study, we combine cell based therapy and noninvasive neuromodulation to assess whether neurotrophic support via transcranial DCS would enhance the restitution of striatal neurotransmission by fetal dopaminergic transplants in a rat Parkinson model. Transcranial DCS was applied daily for 20 min on 14 consecutive days following striatal transplantation of fetal ventral mesencephalic (fVM) cells derived from transgenic rat embryos ubiquitously expressing GFP. Anodal but not cathodal transcranial DCS significantly enhanced graft survival and dopaminergic reinnervation of the surrounding striatal tissue relative to sham stimulation. Behavioral recovery was more pronounced following anodal transcranial DCS, and behavioral effects correlated with the degree of striatal innervation. Our results suggest anodal transcranial DCS may help advance cell-based restorative therapies in neurodegenerative diseases. In particular, such an assistive approach may be beneficial for the already established cell transplantation therapy in PD.

The exploration and retrieval of words during category fluency involves different strategies to improve or maintain performance. Deficits in that task, which are common in patients with amnestic mild cognitive impairment (aMCI), mirror either impaired semantic memory or dysfunctional executive control mechanisms. Relating category fluency to tasks that place greater demands on either semantic knowledge or executive functions might help to determine the underlying cognitive process. The aims of this study were to compare performance and strategy use of 20 patients with aMCI to 30 healthy elderly controls (HC) and to identify the dominant component (either executive or semantic) for better task performance in category fluency. Thus, the relationship between category fluency, design fluency and naming was examined. As fluency tasks have been associated with the superior frontal gyrus (SFG), the inferior frontal gyrus (IFG), and the temporal pole, we further explored the relationship between gray matter volume in these areas and both performance and strategy use. Patients with aMCI showed significantly lower performance and significantly less strategy use during fluency tasks compared to HC. However, both groups equally improved their performance when repeatedly confronted with the same task. In aMCI, performance during category fluency was significantly predicted by design fluency performance, while in HC, it was significantly predicted by naming performance. In HC, volume of the SFG significantly predicted both category and design fluency performance, and strategy use during design fluency. In aMCI, the SFG and the IFG predicted performance during both category and design fluency. The IFG significantly predicted strategy use during category fluency in both groups. The reduced category fluency performance in aMCI seems to be primarily due to dysfunctional executive control mechanisms rather than impaired semantic knowledge. This finding is directly relevant to patients in the different stages of Alzheimer's disease as it links the known semantic fluency deficit in this population to executive functions. Although patients with aMCI are impaired in both performance and strategy use compared to HC, they are able to increase performance over time. However, only HC were able to significantly improve the utilization of fluency strategies in both category and design fluency over time. HC seem to rely more heavily on the SFG during fluency tasks, while in patients with aMCI additional frontal brain areas are involved, possibly reflecting compensational processes.

Calcium/Calmodulin-dependent kinase alpha (αCaMKII) has been shown to play an essential role in synaptic plasticity and in learning and memory in animal models. However, there is little evidence for an involvement in specific memories in humans. Here we tested the potential involvement of the αCaMKII coding gene CAMK2A in verbal logical memory in two Caucasian populations from Germany, in a sample of 209 elderly people with cognitive impairments and a sample of 142 healthy adults. The association of single nucleotide polymorphisms (SNPs) located within the genomic region of CAMK2A with verbal logical memory learning and retrieval from the Wechsler Memory Scale was measured and hippocampal volume was assessed by structural MRI. In the elderly people, we found the minor allele of CAMK2A intronic SNP rs919741 to predict a higher hippocampal volume and better logical memory retrieval. This association was not found in healthy adults. The present study may provide evidence for an association of a genetic variant of the CAMK2A gene specifically with retrieval of logical memory in elderly humans. This effect is possibly mediated by a higher hippocampal volume.

Transcranial direct current stimulation [(t)DCS], modulates cortical excitability and promotes neuroplasticity. Microglia has been identified to respond to electrical currents as well as neuronal activity, but its response to DCS is mostly unknown.

Several studies have demonstrated that fully automated pattern recognition methods applied to structural magnetic resonance imaging (MRI) aid in the diagnosis of dementia, but these conclusions are based on highly preselected samples that significantly differ from that seen in a dementia clinic. At a single dementia clinic, we evaluated the ability of a linear support vector machine trained with completely unrelated data to differentiate between Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia, and healthy aging based on 3D-T1 weighted MRI data sets. Furthermore, we predicted progression to AD in subjects with mild cognitive impairment (MCI) at baseline and automatically quantified white matter hyperintensities from FLAIR-images. Separating additionally recruited healthy elderly from those with dementia was accurate with an area under the curve (AUC) of 0.97 (according to Fig. 4). Multi-class separation of patients with either AD or FTD from other included groups was good on the training set (AUC >  0.9) but substantially less accurate (AUC = 0.76 for AD, AUC = 0.78 for FTD) on 134 cases from the local clinic. Longitudinal data from 28 cases with MCI at baseline and appropriate follow-up data were available. The computer tool discriminated progressive from stable MCI with AUC = 0.73, compared to AUC = 0.80 for the training set. A relatively low accuracy by clinicians (AUC = 0.81) illustrates the difficulties of predicting conversion in this heterogeneous cohort. This first application of a MRI-based pattern recognition method to a routine sample demonstrates feasibility, but also illustrates that automated multi-class differential diagnoses have to be the focus of future methodological developments and application studies.

Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer's disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.

Statins exert beneficial effects in brain diseases including stroke. Here, we investigated whether oral prophylactic atorvastatin provides long-term neuroprotection and functional recovery in permanent middle cerebral artery occlusion (pMCAO), and whether cerebral hemodynamics are affected. Male Long-Evans rats were treated with 10 mg/kg oral atorvastatin for 14 days and subjected to pMCAO. Cerebral hemodynamics were measured by bolus tracking MRI and laser Doppler flowmetry (LDF). Infarct volume was quantified at 1 week by T2-MRI and at 3 weeks by histology. Rats were also subjected to neuroscoring and cylinder test. The number of animals per group was 10. The infarct volumes were 100.8 +/- 8.2 and 47.3 +/- 5.5 mm(3) in vehicle, and 68.7 +/- 11.0 and 28.6 +/- 3.82 mm(3) in atorvastatin group at 7 and 21 days post-ischemia, respectively (mean +/- SEM). Atorvastatin significantly reduced infarct volume both at 7 and 21 days (P = 0.04 and 0.03, respectively, 1-way ANOVA). Interestingly, no improvement in cerebral hemodynamic parameters was observed in atorvastatin treated animals. The vehicle group recovered normal neuroscore at day 13, whereas atorvastatin group recovered already at day 10 after pMCAO. All treatment groups preferred to use the unaffected forelimb for rearing in Cylinder test, whereas the defected forelimb use was minimal in all groups. These results suggest that oral atorvastatin protects cerebral tissue against the subsequent pMCAO without influencing cerebral hemodynamic parameters, and it may well be that persons with ongoing atorvastatin treatment benefit in the incidence of stroke.

Neuroinflammatory responses are triggered by diverse ethiologies and can provide either beneficial or harmful results. Microglial cells are the major cell type involved in neuroinflammation, releasing several mediators, which contribute to the neuronal demise in several diseases including cerebral ischemia and neurodegenerative disorders. Attenuation of microglial activation has been shown to confer protection against different types of brain injury. Recent evidence suggests that resveratrol has anti-inflammatory and potent antioxidant properties. It has been also shown that resveratrol is a potent inhibitor of cyclooxygenase (COX)-1 activity. Previous findings have demonstrated that this compound is able to reduce neuronal injury in different models, both in vitro and in vivo. The aim of this study was to examine whether resveratrol is able to reduce prostaglandin E2 (PGE2) and 8-iso-prostaglandin F2alpha (8-iso-PGF2 alpha) production by lipopolysaccharide (LPS)-activated primary rat microglia.

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing huge emotional and economic burden to our societies. An effective therapy has not been implicated yet, which is in part also due to the fact that pathological changes occur years before clinical symptoms manifest. Thus, there is a great need for the development of a translatable biomarker. Recent evidence highlights microRNAs as candidate biomarkers. In this study, we use next-generation sequencing to study the small noncoding RNAome (sncRNAome) in exosomes derived from human cerebrospinal fluid (CSF). We show that the sncRNAome from CSF-derived exosomes is dominated not only by microRNAs (miRNAs) but also by PIWI-interacting RNAs (piRNAs). We define a combined signature consisting of three miRNAs and three piRNAs that are suitable to detect AD with an AUC of 0.83 in a replication cohort and furthermore predict the conversion of mild-cognitive impaired (MCI) patients to AD dementia with an AUC of 0.86 for the piRNA signature. When combining the smallRNA signature with pTau and Aβ 42/40 ratio the AUC reaches 0.98. Our study reports a novel exosomal small noncoding RNA signature to detect AD pathology and provides the first evidence that in addition to miRNAs, piRNAs should also be considered as a candidate biomarker for AD.

Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD-MCI) compared to Parkinson's disease (PD-MCI) are rare.

Microglia are essential contributors to synaptic transmission and stability and communicate with neurons via the fractalkine pathway. Transcranial direct current stimulation [(t)DCS], a form of non-invasive electrical brain stimulation, modulates cortical excitability and promotes neuroplasticity, which has been extensively demonstrated in the motor cortex and for motor learning. The role of microglia and their fractalkine receptor CX3CR1 in motor cortical neuroplasticity mediated by DCS or motor learning requires further elucidation. We demonstrate the effects of pharmacological microglial depletion and genetic Cx3cr1 deficiency on the induction of DCS-induced long-term potentiation (DCS-LTP) ex vivo. The relevance of microglia-neuron communication for DCS response and structural neuroplasticity underlying motor learning are assessed via 2-photon in vivo imaging. The behavioural consequences of impaired CX3CR1 signalling are investigated for both gross and fine motor learning. We show that DCS-mediated neuroplasticity in the motor cortex depends on the presence of microglia and is driven in part by CX3CR1 signalling ex vivo and provide the first evidence of microglia interacting with neurons during DCS in vivo. Furthermore, CX3CR1 signalling is required for motor learning and underlying structural neuroplasticity in concert with microglia interaction. Although we have recently demonstrated the microglial response to DCS in vivo, we now provide a link between microglial integrity and neuronal activity for the expression of DCS-dependent neuroplasticity. In addition, we extend the knowledge on the relevance of CX3CR1 signalling for motor learning and structural neuroplasticity. The underlying molecular mechanisms and the potential impact of DCS in rescuing CX3CR1 deficits remain to be addressed in the future.

ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aβ) and tau pathology, with the strongest evidence for effects on Aβ, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aβ42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aβ42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aβ42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aβ 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aβ42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-β burden and tau aggregation at specific time points in AD pathogenesis.

Early rehabilitation in the acute phase of stroke, that bears unique neuroplastic properties, is the current standard to reduce disability. Anodal transcranial direct current stimulation can augment neurorehabilitation in chronic stroke. Studies in the acute phase are sparse and held back by inconclusive preclinical data pointing towards potential negative interaction of the excitability increasing tDCS modality with stroke-induced glutamate toxicity. In this present study, we aimed to evaluate structural and behavioral safety of anodal tDCS applied in the acute phase of stroke. Photothrombotic stroke including the right primary motor cortex was induced in rats. 24 h after stroke anodal tDCS was applied for 20 min ipsilesionally at one of four different current densities in freely moving animals. Effects on the infarct volume and on stroke induced neuroinflammation were assessed. Behavioral consequences were monitored. Infarct volume and the modified Neurological Severity Score were not affected by anodal tDCS. Pasta handling, a more sensitive task for sensorimotor deficits, and microglia reactivity indicated potentially harmful effects at the highest tDCS current density tested (47.8 A/m2), which is more than 60 times higher than intensities commonly used in humans. Compared to published safety limits of anodal tDCS in healthy rats, recent stroke does not increase the sensitivity of the brain to anodal tDCS, as assessed by lesion size and neuroinflammatory response. Behavioral deficits only occurred at the highest intensity, which was associated with increased neuroinflammation. When safety limits of commonly used clinical tDCS are met, augmentation of early neurorehabilitation after stroke by anodal tDCS appears to be feasible.

The progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1-42 (Aβ42), amyloid-beta1-40 (Aβ40) levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia.

White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer's disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD.

To compare the benefits and harms of a Dutch 10-session Community Occupational Therapy programme for patients with Alzheimer's disease with the impact of a one session consultation at home in German routine healthcare.