Memantine Improves Attentional Processes in Fragile X-Associated Tremor/Ataxia Syndrome: Electrophysiological Evidence from a Randomized Controlled Trial.

Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syndrome (FXTAS), with no targeted treatment yet established. In this substudy of the first randomized controlled trial for FXTAS, we examined the effects of NMDA antagonist memantine on attention and working memory. Data were analyzed for patients (24 in each arm) who completed both the primary memantine trial and two EEG recordings (at baseline and follow-up) using an auditory "oddball" task. Results demonstrated significantly improved attention/working memory performance after one year only for the memantine group. The event-related potential P2 amplitude elicited by non-targets was significantly enhanced in the treated group, indicating memantine-associated improvement in attentional processes at the stimulus identification/discrimination level. P2 amplitude increase was positively correlated with improvement on the behavioral measure of attention/working memory during target detection. Analysis also revealed that memantine treatment normalized the P2 habituation effect at the follow-up visit. These findings indicate that memantine may benefit attentional processes that represent fundamental components of executive function/dysfunction, thought to comprise the core cognitive deficit in FXTAS. The results provide evidence of target engagement of memantine, as well as therapeutically relevant information that could further the development of specific cognitive or disease-modifying therapies for FXTAS

A Clinical Trial to Validate Event-Related Potential Markers of Alzheimer\u27s Disease in Outpatient Settings

INTRODUCTION: We investigated whether event-related potentials (ERP) collected in outpatient settings and analyzed with standardized methods can provide a sensitive and reliable measure of the cognitive deficits associated with early Alzheimer\u27s disease (AD). METHODS: A total of 103 subjects with probable mild AD and 101 healthy controls were recruited at seven clinical study sites. Subjects were tested using an auditory oddball ERP paradigm. RESULTS: Subjects with mild AD showed lower amplitude and increased latency for ERP features associated with attention, working memory, and executive function. These subjects also had decreased accuracy and longer reaction time in the target detection task associated with the ERP test. DISCUSSION: Analysis of ERP data showed significant changes in subjects with mild AD that are consistent with the cognitive deficits found in this population. The use of an integrated hardware/software system for data acquisition and automated data analysis methods make administration of ERP tests practical in outpatient settings

What Electrophysiology Tells Us About Alzheimer’s Disease::A Window into the Synchronization and Connectivity of Brain Neurons

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer’s disease (AD), despite a surge in recent validated evidence. This Position Paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity reflecting thalamocortical and cortico-cortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies

Usefulness of event-related potentials in the assessment of mild cognitive impairment

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to determine if changes in latencies and amplitudes of the major waves of Auditory Event-Related Potentials (AERP), correlate with memory status of patients with mild cognitive impairment (MCI) and conversion to Alzheimer's disease (AD).</p> <p>91 patients with MCI (mean ± SD age = 66.6 ± 5.4, MMSE score = 27.7) and 30 age-matched healthy control (AMHC) subjects (mean ± SD age = 68.9 ± 9.9) were studied. 54 patients were re-examined after an average period of 14(± 5.2) months. During this time period 5 patients converted to AD. Between-group differences in latency and amplitude of the major AERP waves (N200, P300 and Slow Wave) were determined. Within each group, correlation coefficients (CC) between these characteristics of the different AERP waves were calculated. Finally, for patients, CCs were determined among each AERP wave and their age and MMSE scores. Confirmatory factor analysis (CFA) was used to examine the underlying structure of waveforms both in the control and the patient groups.</p> <p>Results</p> <p>Latencies of all major AERP components were prolonged in patients compared to controls. Patients presented with significantly higher N200 amplitudes, but no significant differences were observed in P300 amplitudes. Significant differences between follow-up and baseline measurements were found for P300 latency (p = 0.009), N200 amplitude (p < 0.001) and P300 amplitude (p = 0.05). MMSE scores of patients did not correlate with latency or amplitude of the AERP components. Moreover, the establishment of a N200 latency cut-off value of 287 ms resulted in a sensitivity of 100% and a specificity of 91% in the prediction of MCI patients that converted to AD.</p> <p>Conclusion</p> <p>Although we were not able to establish significant correlations between latencies and amplitudes of N200, P300 and SW and the patients' performance in MMSE, which is a psychometric test for classifying patients suffering from MCI, our results point out that the disorganization of the AERP waveform in MCI patients is a potential basis upon which a neurophysiologic methodology for identifying and "staging" MCI can be sought. We also found that delayed N200 latency not only identifies memory changes better than the MMSE, but also may be a potential predictor of the MCI patients who convert to AD.</p

Validity of a novel computerized cognitive battery for mild cognitive impairment

BACKGROUND: The NeuroTrax Mindstreams computerized cognitive assessment system was designed for widespread clinical and research use in detecting mild cognitive impairment (MCI). However, the capability of Mindstreams tests to discriminate elderly with MCI from those who are cognitively healthy has yet to be evaluated. Moreover, the comparability between these tests and traditional neuropsychological tests in detecting MCI has not been examined. METHODS: A 2-center study was designed to assess discriminant validity of tests in the Mindstreams Mild Impairment Battery. Participants were 30 individuals diagnosed with MCI, 29 with mild Alzheimer's disease (AD), and 39 healthy elderly. Testing was with the Mindstreams battery and traditional neuropsychological tests. Receiver operating characteristic (ROC) analysis was used to examine the ability of Mindstreams and traditional measures to discriminate those with MCI from cognitively healthy elderly. Between-group comparisons were made (Mann-Whitney U test) between MCI and healthy elderly and between MCI and mild AD groups. RESULTS: Mindstreams outcome parameters across multiple cognitive domains significantly discriminated among MCI and healthy elderly with considerable effect sizes (p < 0.05). Measures of memory, executive function, visual spatial skills, and verbal fluency discriminated best, and discriminability was at least comparable to that of traditional neuropsychological tests in these domains. CONCLUSIONS: Mindstreams tests are effective in detecting MCI, providing a comprehensive profile of cognitive function. Further, the enhanced precision and ease of use of these computerized tests make the NeuroTrax system a valuable clinical tool in the identification of elderly at high risk for dementia

Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer’s disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer’s disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs

Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer's Disease

Evidence of reduced blood-brain barrier (BBB) integrity preceding other Alzheimer's disease (AD) pathology provides a strong link between cerebrovascular angiopathy and AD. However, the “Vascular hypothesis”, holds that BBB leakiness in AD is likely due to hypoxia and neuroinflammation leading to vascular deterioration and apoptosis. We propose an alternative hypothesis: amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice that overexpress the human amyloid precursor protein (APP) containing the double missense mutations, APPsw, found in a Swedish family, that causes early-onset AD. The expression of tight junction (TJ) proteins, occludin and ZO-1, were examined in conjunction with markers of apoptosis and angiogenesis. In aged Tg2576 AD mice, a significant increase in the incidence of disrupted TJs, compared to age matched wild-type littermates and young mice of both genotypes, was directly linked to an increased microvascular density but not apoptosis, which strongly supports amyloidogenic triggered hypervascularity as the basis for BBB disruption. Hypervascularity in human patients was corroborated in a comparison of postmortem brain tissues from AD and controls. Our results demonstrate that amylodogenesis mediates BBB disruption and leakiness through promoting neoangiogenesis and hypervascularity, resulting in the redistribution of TJs that maintain the barrier and thus, provides a new paradigm for integrating vascular remodeling with the pathophysiology observed in AD. Thus the extensive angiogenesis identified in AD brain, exhibits parallels to the neovascularity evident in the pathophysiology of other diseases such as age-related macular degeneration

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele