Abstract Background Alzheimer’s disease (AD) is associated with increased cortical excitability, including a risk of seizures and epileptiform discharges. Transcranial magnetic stimulation (TMS) can be used to index cortical excitability non‐invasively, and previous studies have revealed increased TMS excitability measures in AD. However, it is not yet known if TMS shows increased cortical excitability in amyloid‐β positive mild cognitive impairment (Aβ+ MCI), how TMS excitability relates to other AD biomarkers, or the extent to which cortical excitability may predict disease progression. Method TMS was applied to left motor cortex in 18 participants with Aβ+ MCI (aged 70±8.9, 9 females). Resting motor threshold (RMT) was measured as the minimum TMS intensity required to elicit a motor evoked potential on 5/10 trials. The primary analyses tested if RMT differed between Aβ+ MCI participants and a cohort of 36 older healthy controls (OHC; aged 63±9.7, 17 females). Separate linear models in Aβ+ MCI tested the relationship of RMT with hippocampal volume, Aβ burden on [ 18 F]Florbetapir PET, and the Clinical Dementia Rating – Sum of Boxes (CDR‐SB). CDR‐SB was reassessed after 1‐2 years follow‐up, and a CDR‐SB Change Score was calculated to measure cognitive decline. The relationship with RMT and CDR‐SB Change Score was tested using a simple linear regression. Result The primary linear model controlling for age, gender, and scalp‐to‐cortex distance (SCD) showed a between‐group difference in RMT (B=3.62, p=0.023, Figure 1), with Aβ+ MCI showing lower RMT reflecting higher levels of cortical excitability. The covariate of SCD (B=1.92, p<0.001) was also significant. Secondary models with the same covariates showed that lower RMT was related to greater Aβ burden (B=‐0.43, p=0.016), but not hippocampal volume or CDR‐SB. In the subgroup of 10 Aβ+ MCI participants with longitudinal follow‐up, lower RMT predicted of worsening cognition on CDR‐SB Change Score (R=0.74, p=0.015, Figure 2). Conclusion Increased cortical excitability is found in Aβ+ MCI, is related to amyloid burden, and appears to predict greater longitudinal cognitive decline. TMS measures of cortical excitability may be useful as measures of target engagement for future therapies aimed at delaying disease progression in the early symptomatic stages of AD.
In the cerebellar type of multiple system atrophy (MSA-C), the burden of pathological changes involves the cerebellum and its associated brainstem structures in the basis pontis and the inferior olivary nucleus, and as a result, the clinical phenotype is dominated early on by the cerebellar dysfunction. We report our clinical and post mortem findings in a patient with MSA-C who exhibited pathological laughter in the absence of any congruent changes of mood. A review of the clinical notes of 27 other patients with MSA-C revealed a problem with pathological laughter, or crying, or both in 9 more patients. Our finding of about 36% occurrence suggests that the problem of dysregulation of emotional expression is more prevalent in MSA-C than the paucity of reports in the literature suggests. Our findings are consistent with the view that the cerebellum and its interconnected structures may be involved in the regulation of emotional expression.
Seizures occur at a higher frequency in people with Alzheimer's disease (AD) but overt, clinically obvious events are infrequent. Evidence from animal models and studies in mild cognitive impairment suggest that subclinical epileptic discharges may play a role in the clinical and pathophysiological manifestations of AD. In this feasibility study, the neurophysiological and cognitive effects of acute administration of levetiracetam (LEV) are measured in patients with mild AD to test whether it could have a therapeutic benefit. AD participants were administered low dose LEV (2.5 mg/kg), higher dose LEV (7.5 mg/kg), or placebo in a double-blind, within-subject repeated measures study with EEG recorded at rest before and after administration. After administration of higher dose of LEV, we found significant decreases in coherence in the delta band (1-3.99 Hz) and increases in the low beta (13-17.99 Hz) and the high beta band (24-29.99 Hz). Furthermore, we found trends toward increased power in the frontal and central regions in the high beta band (24-29.99 Hz). However, there were no significant changes in cognitive performance after this single dose administration. The pattern of decreased coherence in the lower frequency bands and increased coherence in the higher frequency bands suggests a beneficial effect of LEV for patients with AD. Larger longitudinal studies and studies with healthy age-matched controls are needed to determine whether this represents a relative normalization of EEG patterns, whether it is unique to AD as compared to normal aging, and whether longer term administration is associated with a beneficial clinical effect.
Patients with Alzheimer's disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD.In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD.We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n = 9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random order in three sessions. Afterwards, the participants underwent ASL-MRI.Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, and the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus.Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings.
Abstract Background Alzheimer’s disease (AD) is associated with increased cortical excitability, including an elevated risk of seizures. Transcranial magnetic stimulation with electromyography (TMS‐EMG‐EEG) can be used to index intracortical excitability. Prior work has shown that TMS‐based excitability measures are altered in AD and are related to disease severity. However, it is not yet known how TMS‐EMG measures are related to neurodegeneration within brain regions affected by AD. Method TMS‐EMG was applied to left motor cortex (M1) in 22 participants with biomarker‐confirmed mild cognitive impairment due to AD (early AD, aged 70.5±8.4, 11 females). Single pulse TMS was preformed to measure resting motor threshold (RMT) and motor evoked potential amplitude (MEP Amplitude). Paired‐pulse TMS was preformed to measure short interval intracortical inhibition (SICI, GABA‐ergic) and intracortical facilitation (ICF, glutamatergic). In 5 participants, TMS‐evoked responses on EEG were also obtained during single‐pulse stimulation to M1 and the inferior parietal lobe (IPL), and the local mean field amplitude (LMFA) was computed from 15 to 40 msec after the TMS pulse. Structural MRI scans for each participant were processed using Freesurfer to obtain cortical thickness measurements within the distributed Alzheimer‐signature brain regions (AD‐signature atrophy). The primary analyses tested the relationship between each TMS measure and AD‐signature atrophy using separate linear models, controlling for age. For TMS‐EEG analysis, effect sizes were reported in lieu of p‐values given the small sample sizes. Result In early AD, SICI was related to AD‐signature atrophy (R 2 adj = 0.40, B = ‐0.13, p = 0.018; Fig1), with less intracortical inhibition related to greater atrophy. RMT, MEP Amplitude, and ICF were not related to AD‐signature atrophy ( p ‐values>0.105). There was a large effect size of IPL LMFA on AD‐signature atrophy (R 2 adj = 0.70), while the effect size of M1 was small (R 2 adj = ‐0.19). Conclusion Decreased intracortical inhibition is related to increased AD‐signature atrophy in early AD. Decreased function of GABA‐A circuitry related to cortical atrophy may play a role in the development of cortical hyperexcitability in AD. Our preliminary results further suggests that TEPs from stimulation of IPL, a node of the default mode network and an area commonly showing AD pathology, may also be related to AD‐signature atrophy.
High levels of chronic stress negatively impact the hippocampus and are associated with increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease. While mindfulness meditation may mitigate the effects of chronic stress, it is uncertain if adults with MCI have the capacity to learn mindfulness meditation. 14 adults with MCI were randomized 2:1 to Mindfulness Based Stress Reduction (MBSR) or a wait-list control group. We conducted qualitative interviews with those who completed MBSR. Transcribed interviews were: a) coded using an emergent themes inductive approach informed by grounded theory; b) rated 0-10, with higher scores reflecting greater perceived benefit from, and understanding of, mindfulness meditation. Ratings were correlated with daily home practice times and baseline level of cognitive function. Seven themes emerged from the interviews: positive perceptions of class; development of mindfulness skills, including meta-cognition; importance of the group experience; enhanced well-being; shift in MCI perspective; decreased stress reactivity and increased relaxation; improvement in interpersonal skills. Ratings of perceived benefit and understanding ranged from 2-10 (mean = 7) and of 0-9.5 (mean = 6), respectively. Many participants experienced substantial benefit/understanding, some had moderate, and a few had minimal benefit/understanding. Understanding the key concepts of mindfulness was highly positively correlated with ≥20 minutes/day of home practice (r = 0.90) but not with baseline cognitive function (r = 0.13). Most adults with MCI were able to learn mindfulness meditation and had improved MCI acceptance, self-efficacy, and social engagement. Cognitive reserve may be enhanced through a mindfulness meditation program even in patients with MCI.
To investigate the effect of postoperative delirium on longitudinal brain microstructural changes, as measured by diffusion tensor imaging.We studied a subset of the larger Successful Aging after Elective Surgery (SAGES) study cohort of older adults (≥70 years) without dementia undergoing elective surgery: 113 participants who had diffusion tensor imaging before and 1 year after surgery. Postoperative delirium severity and occurrence were assessed during the hospital stay using the Confusion Assessment Method and a validated chart review method. We investigated the association of delirium severity and occurrence with longitudinal diffusion changes across 1 year, adjusting for age, sex, vascular comorbidity, and baseline cognitive performance. We also assessed the association between changes in diffusion and cognitive performance across the 1-year follow-up period, adjusting for age, sex, education, and baseline cognitive performance.Postoperative delirium occurred in 25 participants (22%). Delirium severity and occurrence were associated with longitudinal diffusion changes in the periventricular, frontal, and temporal white matter. Diffusion changes were also associated with changes in cognitive performance across 1 year, although the cognitive changes did not show significant association with delirium severity or occurrence.Our study raises the possibility that delirium has an effect on the development of brain microstructural abnormalities, which may reflect brain changes underlying cognitive trajectories. Future studies are warranted to clarify whether delirium is the driving factor of the observed changes or rather a correlate of a vulnerable brain that is at high risk for neurodegenerative processes.
Abstract Background The choroid plexus is a major contributor to the generation of cerebrospinal fluid (CSF) and the maintenance of its electrolyte and metabolite balance. Here, we sought to characterize the blood flow dynamics of the choroid plexus using arterial spin labeling (ASL) MRI to establish ASL as a non-invasive tool for choroid plexus function and disease studies. Methods Seven healthy volunteers were imaged on a 3T MR scanner. ASL images were acquired with 12 labeling durations and post labeling delays. Regions of the choroid plexus were manually segmented on high-resolution T 1 weighted images. Choroid plexus perfusion was characterized with a dynamic ASL perfusion model. Cerebral gray matter perfusion was also quantified for comparison. Results Kinetics of the ASL signal were clearly different in the choroid plexus than in gray matter. The choroid plexus has a significantly longer T 1 than the gray matter (2.33 ± 0.30 s vs. 1.85 ± 0.10 s, p < 0.02). The arterial transit time was 1.24 ± 0.20 s at the choroid plexus. The apparent blood flow to the choroid plexus was measured to be 39.5 ± 10.1 ml/100 g/min and 0.80 ± 0.31 ml/min integrated over the posterior lateral ventricles in both hemispheres. Correction with the choroid plexus weight yielded a blood flow of 80 ml/100 g/min. Conclusions Our findings suggest that ASL can provide a clinically feasible option to quantify the dynamic characteristics of choroid plexus blood flow. It also provides useful reference values of the choroid plexus perfusion. The long T 1 of the choroid plexus may suggest the transport of water from arterial blood to the CSF, potentially providing a method to quantify CSF generation.
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