Effect of Targeted Transcranial Magnetic Stimulation on Hippocampal-Dependent Declarative Memory in Older Adults

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Somatosensory dysfunction is masked by variable cognitive deficits across patients on the Alzheimer’s disease spectrum

Background: Alzheimer’s disease (AD) is generally thought to spare primary sensory function; however, such interpretations have drawn from a literature that has rarely taken into account the variable cognitive declines seen in patients with AD. As these cognitive domains are now known to modulate cortical somato-sensory processing, it remains possible that abnormalities in somatosensory function in patients with AD have been suppressed by neuropsychological variability in previous research. Methods: In this study, we combine magnetoencephalographic (MEG) brain imaging during a paired-pulse somatosensory gating task with an extensive battery of neuropsychological tests to investigate the influence of cognitive variability on estimated differences in somatosensory function between biomarker-confirmed patients on the AD spectrum and cognitively-normal older adults. Findings: We show that patients on the AD spectrum exhibit largely non-significant differences in somato-sensory function when cognitive variability is not considered (p-value range: .020-.842). However, once attention and processing speed abilities are considered, robust differences in gamma-frequency somatosensory response amplitude (p \u3c .001) and gating (p = .004) emerge, accompanied by significant statistical suppression effects. Interpretation: These findings suggest that patients with AD exhibit insults to functional somatosensory processing in primary sensory cortices, but these effects are masked by variability in cognitive decline across individuals

Piecing it together: atrophy profiles of hippocampal subfields relate to cognitive impairment along the Alzheimer’s disease spectrum

IntroductionPeople with Alzheimer’s disease (AD) experience more rapid declines in their ability to form hippocampal-dependent memories than cognitively normal healthy adults. Degeneration of the whole hippocampal formation has previously been found to covary with declines in learning and memory, but the associations between subfield-specific hippocampal neurodegeneration and cognitive impairments are not well characterized in AD. To improve prognostic procedures, it is critical to establish in which hippocampal subfields atrophy relates to domain-specific cognitive declines among people along the AD spectrum. In this study, we examine high-resolution structural magnetic resonance imaging (MRI) of the medial temporal lobe and extensive neuropsychological data from 29 amyloid-positive people on the AD spectrum and 17 demographically-matched amyloid-negative healthy controls.MethodsParticipants completed a battery of neuropsychological exams including select tests of immediate recollection, delayed recollection, and general cognitive status (i.e., performance on the Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]). Hippocampal subfield volumes (CA1, CA2, CA3, dentate gyrus, and subiculum) were measured using a dedicated MRI slab sequence targeting the medial temporal lobe and used to compute distance metrics to quantify AD spectrum-specific atrophic patterns and their impact on cognitive outcomes.ResultsOur results replicate prior studies showing that CA1, dentate gyrus, and subiculum hippocampal subfield volumes were significantly reduced in AD spectrum participants compared to amyloid-negative controls, whereas CA2 and CA3 did not exhibit such patterns of atrophy. Moreover, degeneration of the subiculum along the AD spectrum was linked to a significant decline in general cognitive status measured by the MMSE, while degeneration scores of the CA1 and dentate gyrus were more widely associated with declines on the MMSE and tests of learning and memory.DiscussionThese findings provide evidence that subfield-specific patterns of hippocampal degeneration, in combination with cognitive assessments, may constitute a sensitive prognostic approach and could be used to better track disease trajectories among individuals on the AD spectrum

CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease

Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson’s disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson’s Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs

The Economic Impact of Neuropsychiatric Symptoms in Alzheimer's Disease: Can Drugs Ease the Burden?

The majority of patients with Alzheimer's disease (AD) will have clinically significant neuropsychiatric symptoms during the course of their disease. There is growing evidence that neuropsychiatric symptoms increase direct costs of care in patients with AD, especially the costs associated with formal long-term care and unpaid caregiving. For example, we have estimated that a 1-point worsening of the neuropsychiatric inventory score is associated with an incremental increase of between $US247 and$US409 per year in total direct costs of care based upon year 2001 US dollars, depending on the value of unpaid caregiving. Although data are still limited, there have been a series of well designed, controlled clinical trials that have established the efficacy of several drugs used in the treatment of neuropsychiatric symptoms in patients with AD. The economic impact of using efficacious drugs to treat neuropsychiatric symptoms in patients with AD has not been evaluated formally. To successfully complete formal economic evaluations of these drugs there is a need for more research to refine methods for determining the economic value of unpaid caregiving and to collect more data concerning the incremental effects of neuropsychiatric symptoms on QOL, costs of care and survival. The current ongoing treatment trials that are collecting economic and QOL data as a part of the trial will be able to perform cost-effectiveness and cost-utility analyses of these new efficacious drugs. These economic evaluations will provide important information for decision makers who are formulating healthcare policy for the treatment of patients with AD.Alzheimer's-disease, Antidepressants, Antipsychotics, Behavioural-disorders, Cholinesterase-inhibitors, Cost-of-illness, Depression

The Risk of Incident Mild Cognitive Impairment and Progression to Dementia Considering Mild Cognitive Impairment Subtypes

Background: It remains unclear how demographic and clinical characteristics are related to the risk of incident mild cognitive impairment (MCI) by its subtypes. Moreover, the contribution of the subtypes of incident MCI to the progression to dementia remains puzzling. Methods: We used data collected by the National Alzheimer Coordinating Center. Our analysis sample included cognitively normal subjects at baseline. The associations were examined using competing-risks survival regression models and Cox proportional hazards models. Results: About 16.3% of subjects developed incident MCI of whom 15.8% progressed to Alz­heimer disease (overall mean follow-up of 4.3 years). The risk of incident amnestic MCI (aMCI) was greater in subjects with 1 copy (subhazard ratio [SHR]: 1.23; 95% CI: 1.00–1.50) or 2 copies (SHR: 2.14; 95% CI: 1.49–3.05) of the APOE ε4 allele than in those who had no ε4 allele. Multiple-domain aMCI patients were more likely to progress to dementia than single-domain aMCI patients (hazard ratio: 2.14; 95% CI: 1.28–3.58). Conclusions: Cognitively normal subjects with an APOE ε4 allele had a higher likelihood of developing aMCI and the MCI subtype was associated with the dementia subtype. Our findings provide important information about practical indicators for the prediction of cognitive decline

Stimulating Memory: Reviewing Interventions Using Repetitive Transcranial Magnetic Stimulation to Enhance or Restore Memory Abilities

Human memory systems are imperfect recording devices that are affected by age and disease, but recent findings suggest that the functionality of these systems may be modifiable through interventions using non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). The translational potential of these rTMS interventions is clear: memory problems are the most common cognitive complaint associated with healthy aging, while pathological conditions such as Alzheimer’s disease are often associated with severe deficits in memory. Therapies to improve memory or treat memory loss could enhance independence while reducing costs for public health systems. Despite this promise, several important factors limit the generalizability and translational potential of rTMS interventions for memory. Heterogeneity of protocol design, rTMS parameters, and outcome measures present significant challenges to interpretation and reproducibility. However, recent advances in cognitive neuroscience, including rTMS approaches and recent insights regarding functional brain networks, may offer methodological tools necessary to design new interventional studies with enhanced experimental rigor, improved reproducibility, and greater likelihood of successful translation to clinical settings. In this review, we first discuss the current state of the literature on memory modulation with rTMS, then offer a commentary on developments in cognitive neuroscience that are relevant to rTMS interventions, and finally close by offering several recommendations for the design of future investigations using rTMS to modulate human memory performance

Sleep quality differentially modulates neural oscillations and proteinopathy in Alzheimer's diseaseResearch in context

Summary: Background: Alterations in resting-state neural activity have been reported in people with sleep disruptions and in patients with Alzheimer's disease, but the direct impact of sleep quality on Alzheimer's disease-related neurophysiological aberrations is unclear. Methods: We collected cross-sectional resting-state magnetoencephalography and extensive neuropsychological and clinical data from 38 biomarker-confirmed patients on the Alzheimer's disease spectrum and 20 cognitively normal older control participants. Sleep efficiency was quantified using the Pittsburgh Sleep Quality Index. Findings: Neural activity in the delta frequency range was differentially affected by poor sleep in patients on the Alzheimer's disease spectrum. Such neural changes were related to processing speed abilities and regional amyloid accumulation, and these associations were mediated and moderated, respectively, by sleep quality. Interpretation: Together, our results point to a mechanistic role for sleep disturbances in the widely reported neurophysiological aberrations seen in patients on the Alzheimer's disease spectrum, with implications for basic research and clinical intervention. Funding: National Institutes of Health, USA