6,933 research outputs found
Focal Spot, Fall/Winter 2001
https://digitalcommons.wustl.edu/focal_spot_archives/1089/thumbnail.jp
Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice
BACKGROUND: The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss. RESULTS: We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Aβ. CONCLUSIONS: The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression
The physiologic correlates of learning in the classroom environment
This study served to further investigate learning and memory, and to offer a potential tool to support educational interventions. More specifically, this was accomplished by an investigation of the physiologic changes in the brain that occurred while students learned medical anatomy. A group of 29 students taking the Gross Anatomy course at Boston University School of Medicine participated in the study. Testing occurred in two sessions: prior to the course and at the completion of the course. For each session, scalp EEG was recorded while participants were shown 176 anatomical terms (132 relevant to the course and 44 obscure) and asked to respond with "Can Define", "Familiar", or "Don't Know". Behavioral results indicated a positive correlation between participants' course grades and performance on the experimental tasks. EEG results were analyzed for event-related potential (ERP) components related to two memory components: familiarity and recollection. Results had a number of indications. For Don't Know responses, a stronger early frontal, late parietal, and late frontal effect occurred more so for terms of Session 1 compared to Session 2. For an analysis of just Session 2 data, results indicated increased activity of the early frontal, late parietal, and late frontal effects for Can Define responses only. Session 2 Can Define responses elicited a stronger early frontal ERP, occurring between 300 and 500 milliseconds yet, the most post-retrieval processing and monitoring appeared for Can Define terms of Session 2. Ultimately, we focused on investigating two points: 1) the effect of classroom learning on memory, and 2) the examination of ERPs as a tool to guide education interventions. Specifically, ERPs would potentially indicate markers to predict whether students would retain materials long before behavioral measures indicate these results. This has potential to determine whether long-lasting or transient learning will occur; as well as the potential to support early intervention strategies for not just students, but also individuals with learning disabilities or memory impairments
Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset
OBJECTIVE
Alzheimer's disease (AD) is considered an age-related disorder. However, it is unclear whether AD induces the same pathological and neurophysiological modifications in synaptic functions independently from age of disease onset. We used transcranial magnetic stimulation tools to investigate the mechanisms of cortical plasticity and sensory-motor integration in AD patients with a wide range of disease onset.
METHODS
We evaluated newly diagnosed sporadic AD (n = 54) in comparison with healthy age-matched controls (HS; n = 24). Cortical plasticity mechanisms of long-term potentiation (LTP) or of long-term depression (LTD) were assessed using respectively intermittent (iTBS) or continuous theta burst stimulation (cTBS) protocols. Sensory-motor integration was evaluated by means of short afferent inhibition (SAI) protocol.
RESULTS
AD patients show after iTBS an impairment of LTP-like cortical plasticity forming a paradoxical LTD in comparison to HS. LTD-like cortical plasticity is similar between AD and HS. LTP-like cortical plasticity is not associated with age, but AD patients presenting with more altered LTP-like cortical plasticity have more-severe cognitive decline at 18 months. SAI is impaired in AD and shows a strong association with the individual age of subjects rather than with disease age of onset.
INTERPRETATION
Cortical LTP disruption is a central mechanism of AD that is independent from age of onset. AD can be described primarily as a disorder of LTP-like cortical plasticity not influenced by physiological aging and associated with a more-severe cognitive decline. Ann Neurol 2016;80:202-210
Probing the secrets of Alzheimer's disease using human-induced pluripotent stem cell technology.
Our understanding of Alzheimer's disease (AD) is still incomplete and, as a result, we lack effective therapies. Reprogramming to generate human-induced pluripotent stem cells provides a new approach to the generation of human neurons that carry the genomes of people with familial or sporadic AD. Differentiation of such stem cells to human neurons is already providing new insights into AD and molecular pathways that may provide new targets for effective therapy. These pathways include typical amyloid response pathways, as well as pathways leading from altered behavior of amyloid precursor protein to the elevated phosphorylation of tau protein. There is also a need for standardization of models so that isogenic lines differing only in the familial AD mutation can be compared
Focal Spot, Spring 2009
https://digitalcommons.wustl.edu/focal_spot_archives/1111/thumbnail.jp
Multimodal phenotyping of synaptic damage in Alzheimer’s disease : translational perspective with focus on quantitative EEG
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common
form of dementia. Accumulation of AD-associated pathology in the brain may begin a decade
or more before the appearance of the first symptoms of the disease. The pathological-clinical
“continuum of AD” therefore encompasses time between the initial neuropathological changes
and symptoms of advanced disease. Besides cognitively healthy individuals at risk, it includes
subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and
eventually dementia when the severity of cognitive impairment affects patients’ ability to carry
out everyday activities. Timely detection of the disease would therefore recognize patients that
are at risk for future cognitive deterioration and provide time window for the prevention and
novel therapeutical interventions. Accumulating evidence suggests that degeneration and
dysfunction of brain neuronal connections, i.e. synapses, is one of the earliest and best proxies
of cognitive deficits in patients along AD continuum. Human electroencephalography (EEG)
is a non-invasive and widely available diagnostic method that records real-time large-scale
synaptic activity. The commonly used method in research settings is quantitative EEG (qEEG)
analysis that provides objective information on EEG recorded at the level of the scalp.
Quantitative EEG analysis unravels complex EEG signal and adds relevant information on its
spectral components (frequency domain), temporal dynamics (time domain) and topographic
estimates (space domain) of brain cortical activity. The general aim of the present thesis was
to characterize different aspects of synaptic degeneration in AD, with the focus on qEEG and
its relationship to both conventional and novel synaptic markers. In study I, global qEEG
measures of power and synchronization were found to correlate with conventional
cerebrospinal fluid (CSF) biomarkers of Aβ and tau pathology in patients diagnosed with SCD,
MCI and AD, linking the markers of AD pathology to the generalized EEG slowing and
reduced brain connectivity in fast frequency bands. In study II, qEEG analysis in the time
domain (EEG microstates) revealed alterations in the organization and dynamics of large-scale
brain networks in memory clinic patients compared to healthy elderly controls. In study III,
topographical qEEG analysis of brain functional connectivity was associated with regionspecific
cortical glucose hypometabolism ([18F]Fluorodeoxyglucose positron-emission
tomography) in MCI and AD patients. Study IV provided evidence that qEEG measures of
global power and synchronization correlate with CSF levels of synaptic marker neurogranin,
both modalities being in combination independent predictors of progression to AD dementia
in MCI patients. Study V and associated preliminary study introduced in the thesis assessed the
translational potential of CSF neurogranin and qEEG as well as their direct relationship to AD
neuropathology in App knock-in mouse models of AD. In study V, changes in CSF neurogranin
levels and their relationship to conventional CSF markers in App knock-in mice corresponded
to the pattern observed in clinical AD cohorts. These findings highlighted the potential use of
mouse CSF biomarkers as well as App knock-in mouse models for translational investigation
of synaptic dysfunction due to AD. In general, the results of the thesis invite for further clinical
validation of multimodal synaptic markers in the context of early AD diagnosis, prognosis, and
treatment monitoring in individual patients
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