Journal of Alzheimer's disease & Parkinsonism最新文献

The thalamus is a critical module in the circuit which has been associated with movement disorders including dystonia. This circuit extends from cortex to striatum to pallidum to the thalamic nucleus Ventral Lateral anterior (VLa) to cortex and can be studied by activity recorded during thalamic stereotactic surgery for the treatment of dystonia. Neuronal recordings in the VLa nucleus show low frequency modulation of firing that is correlated with and leads the low frequency modulation of EMG activity; this EMG activity is characteristic of dystonia. Immediately posterior is the Ventral Lateral posterior (VLp) nucleus which, in controls (patients with tremor or chronic pain), is characterized by deep sensory cells which fire at short latency in response to movement of a single joint or to stimulation of deep structures, such as muscles, tendons and joints. In patients with dystonia, neurons with this sensory activity are much more common than in controls and single neurons often respond to movement of multiple joints. In controls operated for the treatment of tremor or chronic pain many neurons in both nuclei are activated during active or involuntary joint movements, such as tremor or dystonia. The active joint movement related to the firing of a cell is usually in the opposite direction to the passive joint movement which causes that cell to fire. This linkage of active or involuntary and passive joint movement is unfocussed in dystonia. The involuntary dystonic joint movement best correlated with firing of a neuron may not activate the neuron when it occurs as a passive movement, while multiple other passive movements will activate the neuron. These linkages may explain the overflow of isolated voluntary activity to multiple other muscles that is seen in dystonia. The activity of either nucleus may have a critical role in dystonia since their disruption by stimulation or lesioning can decrease dystonia.

RNA sequencing, DNA microfluidic array, LED-Northern, Western immunoassay and bioinformatics analysis have uncovered a small family of up-regulated human brain enriched microRNAs (miRNAs) and down-regulated messenger RNAs (mRNAs) in short post-mortem interval (PMI) sporadic Alzheimer's disease (AD) brain. At the mRNA level, a large majority of the expression of human brain genes found to be down-regulated in sporadic AD appears to be a consequence of an up-regulation of a specific group of NF-kB-inducible microRNAs (miRNAs). This group of up-regulated miRNAs - including miRNA-34a and miRNA-146a - has strong, energetically favorable, complimentary RNA sequences in the 3' untranslated regions (3'-UTR) of their target mRNAs which ultimately drive the down-regulation in the expression of certain essential brain genes. Interestingly, just 2 significantly up-regulated miRNAs - miRNA-34a and miRNA-146a - appear to down-regulate mRNA targets involved in synaptogenesis (SHANK3), phagocytosis deficits and tau pathology (TREM2), inflammation (CFH; complement factor H) and amyloidogenesis (TSPAN12), all of which are distinguishing pathological features characteristic of middle-to-late stage AD neuropathology. This paper reports the novel finding of parallel miRNA-34a and miRNA-146a up-regulation in sporadic AD hippocampal CA1 RNA pools and proposes an altered miRNA-mRNA coupled signaling network in AD, much of which is supported by current experimental findings in the recent literature.

Objective: Parkinson's disease (PD), caused by basal ganglia dysfunction, is associated with motor disturbances including dysarthria. Stimulation of the subthalamic nucleus, a preferred treatment targeting basal ganglia function, improves features of the motor disorder, but has uncertain effects on speech.We studied speech during contrasting stimulation states to reveal subcortical effects on voice and articulation. Measures were made on selected samples of spontaneous and repeated speech.

Methods: Persons with Parkinson's disease (PWP) who had undergone bilateral deep brain stimulation of the subthalamic nucleus (DBS-STN) provided spontaneous speech samples and then repeated portions of their monologue both on and off stimulation. Excerpts were presented in a listening protocol probing intelligibility. Also analysed were a continuous phrase repetition task and a second spontaneous speech sample. Fundamental frequency (F0), harmonic-to-noise ratio (HNR), jitter, shimmer and fluency were measured in these three speech samples performed with DBS stimulation on and off.

Results: During subcortical stimulation, spontaneous excerpts were less intelligible than repeated excerpts. F0 and HNR were higher and shimmer was decreased in repetition and stimulation. Articulatory dysfluencies were increased for spontaneous speech and during stimulation in all three speech samples.

Conclusion: Deep brain stimulation disrupts fluency and improves voice in spontaneous speech, reflecting an inverse influence of subcortical systems on articulatory posturing and laryngeal mechanisms. Better voice and less dysfluency in repetition may occur because an external model reduces the speech planning burden, as seen for gait and arm reach. These orthogonal results for fluency versus phonatory competence may account for ambivalent reports from dysarthric speakers and reveal the complexity of subcortical control of motor speech.

Objective: Years of education are the most common proxy for measuring cognitive reserve (CR) when assessing the relationship between Alzheimer's disease (AD) neuropathology and cognition. However, years of education may be limited as a CR proxy given that it represents a specific timeframe in early life and is static. Studies suggest that measures of intellectual function provide a dynamic estimate of CR that is superior to years of education since it captures the effect of continued learning over time. The present study determined whether dynamic measures of CR were better predictors of episodic memory and executive function in the presence of AD pathology than a static measure of CR.

Methods: Subjects examined died with a pre-mortem clinical diagnosis of no cognitive impaired, mild cognitive impairment and mild to moderate AD. CERAD and Braak stage were used to stratify the sample by AD pathology severity. Linear regression analyses using CR by CERAD and CR by Braak stage interaction terms were used to determine whether Extended Range Vocabulary Test (ERVT) scores or years of education were significantly associated with episodic memory composite (EMC) and executive function composite (EFC) performance. All models were adjusted for clinical diagnosis, age at death, gender, APOE e4 carrier status and Braak stage.

Results: For episodic memory, years of education by CERAD interaction were not statistically significant (β=-0.01, SE=0.01, p=0.53). By contrast, ERVT interaction with CERAD diagnosis was statistically significant (β=-0.03, SE=0.01, p=0.004). Among the models using Braak stages, none of the CR by pathology interactions were associated with EMC or EFC.

Conclusion: Results suggest that a dynamic rather than a static measure is a better indicator of CR and that the relationship between CR and cognition is dependent upon the severity of select AD criteria.

A number of experimental investigations utilizing different murine species have previously reported: (i) that standard mouse-diets supplemented with physiologically realistic amounts of neurotoxic metal salts substantially induce pro-inflammatory signaling in a number of murine tissues; (ii) that these diet-stimulated changes may contribute to a systemic inflammation (SI), a potential precursor to neurodegenerative events in both the central and the peripheral nervous system (CNS, PNS); and (iii) that these events may ultimately contribute to a chronic and progressive inflammatory neurodegeneration, such as that which is observed in Alzheimer's disease (AD) brain. In these experiments we assayed for markers of SI in the blood serum of C57BL/6J mice after 0, 1, 3 and 5 months of exposure to a standard mouse diet that included aluminum-sulfate in the food and drinking water, compared to age-matched controls receiving magnesium-sulfate or no additions. The data indicate that the SI markers that include the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), the acute phase reactive protein C-reactive protein (CRP) production and a triad of pro-inflammatory microRNAs (miRNA-9, miRNA-125b and miRNA-146a) all increase in the serum after aluminum-sulfate exposure. For the first time these results suggest that ad libitum exposure to aluminum-sulfate at physiologically realistic concentrations, as would be found in the human diet over the long term, may predispose to SI and the potential development of chronic, progressive, inflammatory neurodegeneration with downstream pathogenic consequences.

Objective: Alzheimer's disease and related dementias (ADRD) affect more than five million Americans and their family caregivers. Caregiving creates challenges, may contribute to decreased caregiver health and is associated with $9.7 billion of caregiver health care costs. The purpose of this 12 month randomized clinical trial (RCT) was to examine if the Enhancing Physical Activity Intervention (EPAI), a moderate to vigorous physical activity (MVPA) treatment group, versus the Caregiver Skill Building Intervention (CSBI) control, would have greater: (1) MVPA adherence; and (2) physical function.

Methods: Caregivers were randomly assigned to EPAI or CSBI (N=211). MVPA was assessed using a self-report measure; and physical function was objectively assessed using two measures. Intention-to-treat analyses used descriptive, categorical and generalized estimating equations (GEE), with an exchangeable working correlation matrix and a log link, to examine main effects and interactions in change of MVPA and physical function over time.

Results: At 12 months, EPAI significantly increased MVPA (p=<0.001) and number of steps (p=< .01); maintained stable caregiving hours and use of formal services; while CSBI increased hours of caregiving (p=<0.001) and used more formal services (p=<0.02). Qualitative physical function data indicated that approximately 50% of caregivers had difficulties completing physical function tests.

Conclusion: The EPAI had a stronger 12 month effect on caregiver MVPA and physical function, as well as maintaining stability of caregiving hours and formal service use; while CSBI increased caregiving hours and use of formal services. A study limitation included greater EPAI versus CSBI attrition. Future directions are proposed for dementia family caregiver physical activity research.