Exercise priming with transcranial direct current stimulation: a study protocol for a randomized, parallel-design, sham-controlled trial in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive type of brain stimulation that uses electrical currents to modulate neuronal activity. A small number of studies have investigated the effects of tDCS on cognition in patients with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), and have demonstrated variable effects. Emerging evidence suggests that tDCS is most effective when applied to active brain circuits. Aerobic exercise is known to increase cortical excitability and improve brain network connectivity. Exercise may therefore be an effective, yet previously unexplored primer for tDCS to improve cognition in MCI and mild AD. METHODS: Participants with MCI or AD will be randomized to receive 10 sessions over 2 weeks of either exercise primed tDCS, exercise primed sham tDCS, or tDCS alone in a blinded, parallel-design trial. Those randomized to an exercise intervention will receive individualized 30-min aerobic exercise prescriptions to achieve a moderate-intensity dosage, equivalent to the ventilatory anaerobic threshold determined by cardiopulmonary assessment, to sufficiently increase cortical excitability. The tDCS protocol consists of 20 min sessions at 2 mA, 5 times per week for 2 weeks applied through 35 cm2 bitemporal electrodes. Our primary aim is to assess the efficacy of exercise primed tDCS for improving global cognition using the Montreal Cognitive Assessment (MoCA). Our secondary aims are to evaluate the efficacy of exercise primed tDCS for improving specific cognitive domains using various cognitive tests (n-back, Word Recall and Word Recognition Tasks from the Alzheimer's Disease Assessment Scale-Cognitive subscale) and neuropsychiatric symptoms (Neuropsychiatric Inventory). We will also explore whether exercise primed tDCS is associated with an increase in markers of neurogenesis, oxidative stress and angiogenesis, and if changes in these markers are correlated with cognitive improvement. DISCUSSION: We describe a novel clinical trial to investigate the effects of exercise priming before tDCS in patients with MCI or mild AD. This proof-of-concept study may identify a previously unexplored, non-invasive, non-pharmacological combination intervention that improves cognitive symptoms in patients. Findings from this study may also identify potential mechanistic actions of tDCS in MCI and mild AD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03670615 . Registered on September 13, 2018.

The potential roles of excitatory-inhibitory imbalances and the repressor element-1 silencing transcription factor in aging and aging-associated diseases.

Disruptions to the central excitatory-inhibitory (E/I) balance are thought to be related to aging and underlie a host of neural pathologies, including Alzheimer's disease. Aging may induce an increase in excitatory signaling, causing an E/I imbalance, which has been linked to shorter lifespans in mice, flies, and worms. In humans, extended longevity correlates to greater repression of genes involved in excitatory neurotransmission. The repressor element-1 silencing transcription factor (REST) is a master regulator in neural cells and is believed to be upregulated with senescent stimuli, whereupon it counters hyperexcitability, insulin/insulin-like signaling pathway activity, oxidative stress, and neurodegeneration. This review examines the putative mechanisms that distort the E/I balance with aging and neurodegeneration, and the putative roles of REST in maintaining neuronal homeostasis.

Efficacy of non-invasive brain stimulation on global cognition and neuropsychiatric symptoms in Alzheimer's disease and mild cognitive impairment: A meta-analysis and systematic review.

BACKGROUND: Non-invasive brain stimulation (NIBS) techniques have shown some promise in improving cognitive and neuropsychiatric symptoms (NPS) in people with Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI). However, data from clinical trials involving NIBS have shown inconsistent results. This meta-analysis investigated the efficacy of NIBS, specifically repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) compared to sham stimulation on global cognition and NPS in people with AD and MCI. METHOD: Multi-session randomized sham-controlled clinical trials were identified through MEDLINE, PsycINFO, and Embase until June 2021. Standardized mean difference (SMD) and 95% confidence interval (CI) between the active and sham treatments were calculated using random-effects meta-analyses. Included studies reported outcome measures for global cognition and/or NPS. Heterogeneity, from different NIBS techniques, disease populations, or tests used to assess global cognition or NPS, was measured using chi-square and I2, and investigated using subgroup analyses. Possible effects of covariates were also investigated using meta-regressions. RESULT: The pooled meta-analyses included 19 studies measuring global cognition (Nactive=288, Nsham=264), and 9 studies investigating NPS (Nactive=165, Nsham=140). NIBS significantly improved global cognition (SMD=1.14; 95% CI=0.49,1.78; p = 0.001; I2 = 90.2%) and NPS (SMD=0.82; 95% CI=0.13, 1.50; p = 0.019; I2 = 86.1%) relative to sham stimulation in patients with AD and MCI. Subgroup analyses found these effects were restricted to rTMS but not tDCS, and to patients with AD but not MCI. Meta-regression showed that age was significantly associated with global cognition response (Nstudies=16, p = 0.020, I2 = 89.51%, R2 = 28.96%), with larger effects sizes in younger populations. All significant meta-analyses had large effect sizes (SMD ≥0.8), suggesting clinical utility of NIBS in the short term. There remained substantial heterogeneity across all subgroup analyses and meta-regressions (all I2 > 50%). Egger's tests showed no evidence of publication biases. CONCLUSION: rTMS improved global cognition and NPS in those with AD. Further studies in MCI and using tDCS will help to fully evaluate the specific NIBS techniques and populations most likely to benefit on global cognition and NPS measures. Additional research should investigate the long term clinical utility of NIBS in these populations.

The association between placebo arm inclusion and adverse event rates in antidepressant randomized controlled trials: An examination of the Nocebo Effect.

BACKGROUND: Antidepressant efficacy is influenced by patient expectations and, in randomized controlled trials (RCTs), the probability of receiving a placebo. It is unclear whether tolerability demonstrates a similar pattern. This study aimed to determine whether study design influences adverse event (AE) rates in antidepressant trials for subjects receiving active treatment or placebo. METHODS: RCTs comparing one antidepressant to another antidepressant, placebo, or both in major depressive disorder (MDD) (1996-2018) were retrieved from Medline and PsycINFO. Clinicaltrials.gov was searched for unpublished trials. Of 1,997 studies screened, 77 trials were included. Studies were classified as drug-drug, drug-drug-placebo, or drug-placebo based on design and overall number of subjects experiencing any AE was recorded. Subgroup meta-analysis of proportions and meta-regression techniques were used to compare AE rates across study designs in patients receiving active antidepressant treatment and placebo. RESULTS: Among the actively treated, AE rates were lower in drug-drug trials (58.5%) compared to drug-drug-placebo (75.7%) and drug-placebo (76.4%) (the model reported coefficients for percent differences between AE rates of different study designs were B=17.0, p<0.001 and B=17.8, p<0.001, respectively). AE rates in patients receiving placebo were not different between study designs. LIMITATIONS: The present study is limited by the diverse range of study populations, variability in reporting of AEs, and specific antidepressants employed in the included trials. CONCLUSIONS: The inclusion of a placebo arm in the study design was unexpectedly associated with higher rates of AEs among patients receiving active medication in antidepressant trials. This observation has important implications for interpretation of trial tolerability findings.

Evidence-based umbrella review of 162 peripheral biomarkers for major mental disorders.

The literature on non-genetic peripheral biomarkers for major mental disorders is broad, with conflicting results. An umbrella review of meta-analyses of non-genetic peripheral biomarkers for Alzheimer's disease, autism spectrum disorder, bipolar disorder (BD), major depressive disorder, and schizophrenia, including first-episode psychosis. We included meta-analyses that compared alterations in peripheral biomarkers between participants with mental disorders to controls (i.e., between-group meta-analyses) and that assessed biomarkers after treatment (i.e., within-group meta-analyses). Evidence for association was hierarchically graded using a priori defined criteria against several biases. The Assessment of Multiple Systematic Reviews (AMSTAR) instrument was used to investigate study quality. 1161 references were screened. 110 met inclusion criteria, relating to 359 meta-analytic estimates and 733,316 measurements, on 162 different biomarkers. Only two estimates met a priori defined criteria for convincing evidence (elevated awakening cortisol levels in euthymic BD participants relative to controls and decreased pyridoxal levels in participants with schizophrenia relative to controls). Of 42 estimates which met criteria for highly suggestive evidence only five biomarker aberrations occurred in more than one disorder. Only 15 meta-analyses had a power >0.8 to detect a small effect size, and most (81.9%) meta-analyses had high heterogeneity. Although some associations met criteria for either convincing or highly suggestive evidence, overall the vast literature of peripheral biomarkers for major mental disorders is affected by bias and is underpowered. No convincing evidence supported the existence of a trans-diagnostic biomarker. Adequately powered and methodologically sound future large collaborative studies are warranted.

Antidepressant-placebo differences for specific adverse events in major depressive disorder: A systematic review.

BACKGROUND: Adverse events (AEs) are known to occur while patients are treated with placebos, part of the so-called nocebo effect. Yet evidence is limited regarding the likelihood that specific AEs occurring with antidepressant treatment are or are not due to nocebo effects. METHODS: This study identified 56 placebo-controlled, randomized controlled trials (RCTs) of antidepressant monotherapy for adults with major depressive disorder that reported AE rates in sufficient detail for comparison. Poisson regression analyses compared rates of AEs according to antidepressant class weighted by study population to determine which separated from placebo. A "nocebo index" was also calculated (with 0 defined as the lowest rate and 1 or higher indicating the same or greater rate of an AE in the placebo group). RESULTS: Numerous AEs did not differ statistically between antidepressant classes and placebo including worsening psychiatric symptoms, all forms of pain, weight gain and respiratory symptoms. Nevertheless, a number of AEs were significantly more common in antidepressants than placebos across multiple antidepressant classes. These were predominantly neurological, sexual and anticholinergic effects. Several AEs that separated statistically between antidepressants and placebos nevertheless had moderate nocebo indices (≥0.5). For example, dizziness in SSRIs separated significantly from placebo (OR 1.50, 95%CI 1.13-1.99) but had a nocebo index of 0.67. LIMITATIONS: This study relied on multiple RCTs with subtle design differences. CONCLUSIONS: This study identified several AEs that are likely the physiological result of antidepressants and many that likely represent nocebo effects. These results should inform clinical decision making and discussions with patients.

A Pilot Study Comparing Effects of Bifrontal Versus Bitemporal Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Mild Alzheimer Disease.

OBJECTIVE: While transcranial direct current stimulation (tDCS) can enhance aspects of memory in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), there has been wide variability in both the placement of tDCS electrodes and treatment response. This study compared the effects of bifrontal (anodal stimulation over the dorsolateral prefrontal cortices), bitemporal (anodal stimulation over the temporal cortices), and sham tDCS on cognitive performance in MCI and AD. METHODS: Seventeen patients diagnosed with MCI or mild AD received 3 sessions of anodal tDCS (bifrontal, bitemporal, 2 mA for 20 minutes; and sham) in random order. Sessions were separated by 1 week. The Alzheimer's Disease Assessment Scale-Cognitive Word Recognition Task, Alzheimer's Disease Assessment Scale-Cognitive Word Recall Task, 2-back, and Montreal Cognitive Assessment were used to assess cognition. RESULTS: There was a significant effect of stimulation condition on 2-back accuracy (F2,28 = 5.28 P = 0.01, ηp = 0.27), with greater improvements following bitemporal tDCS compared with both bifrontal and sham stimulations. There were no significant changes on other outcome measures following any stimulation. Adverse effects from stimulation were mild and temporary. CONCLUSIONS: These findings demonstrate that improvements in specific memory tasks can be safely achieved after a single session of bitemporal tDCS in MCI and mild AD patients.

Sleep and Attention in Alzheimer's Disease.

Individuals with Alzheimer's disease (AD) present with a wide variety of symptoms, including sleep disruption and sleep disorders. Conversely, disordered sleep has been associated with an increased risk of developing AD. Both conditions individually have adverse effects on attention, which can be further divided into selective, sustained, divided, and alternating attention. The neural mechanisms underpinning sleep problems in AD involve the disruption of the circadian system. This review comprehensively discusses the types of attention impairments, the relationship between AD pathology and sleep disruption, and the effect of sleep issues on attention in AD. Recommendations for future research include addressing the lack of consistency among study designs and outcomes, and the need to continue exploring the biology of sleep and attention in AD.

Prevalence, neurobiology, and treatments for apathy in prodromal dementia.

BACKGROUND: Apathy, characterized by diminished motivation, is a highly prevalent neuropsychiatric symptom in dementia. However, there is a substantial knowledge gap with regard to prevalence rates, neurobiological underpinnings, and effective treatments for apathy in pre-dementia states, including mild cognitive impairment (MCI) and mild behavioral impairment (MBI). METHODS: We conducted a comprehensive literature search using MEDLINE, Embase, and PsycINFO databases to identify available research on apathy in prodromal dementia. RESULTS: Apathy has consistently been detected in individuals with MCI with varying prevalence rates, and only recently has literature discussed the prevalence of apathy in MBI. Few pharmacological treatments have been utilized for apathy, with galantamine and risperidone showing mild reductions in apathetic behaviors. Non-pharmacological interventions in prodromal dementia are beginning to be explored and show promise, but few studies have replicated those results. DISCUSSION: More comprehensive guidelines for diagnosing apathy and further research investigating neurobiological mechanisms of apathy in MCI and MBI are required in order to effectively treat apathetic patients in prodromal dementia.

Using transcranial direct current stimulation to treat symptoms in mild cognitive impairment and Alzheimer's disease.

Transcranial direct current stimulation (tDCS) has recently been investigated as a potential nonpharmacological treatment for individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). A comprehensive literature search was performed on tDCS studies published until March 2017 using MEDLINE, Embase and PsychINFO databases. 12 articles with a total of 202 MCI or AD participants were included. Although ten of the 12 studies demonstrated positive findings with tDCS, two studies reported no effect on cognition. There was a wide range of methodological approaches used and in the cognitive functions measured. The variability in treatment response may be related to the heterogeneity in stimulation parameters including the site of stimulation, and cognitive assessments used. Patient-related factors including individual psychological, biological, and physiological status at the time of stimulation may also influence treatment response. We recommend that more comparative studies using similar patient factors and study parameters are needed in order to better understand the efficacy of tDCS in MCI and AD.

Peripheral inflammatory markers in Alzheimer's disease: a systematic review and meta-analysis of 175 studies.

OBJECTIVES: Increasing evidence suggests that inflammation is involved in Alzheimer's disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC). METHODS: Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type. RESULTS: A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1ß, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores. CONCLUSIONS: These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers.

Evidence for Inflammation-Associated Depression.

This chapter explores the evidence supporting inflammation-associated depression. Data to date suggest a bidirectional relationship between inflammation and depression wherein one process can drive the other. A wealth of animal and clinical studies have demonstrated an association between concentrations of pro-inflammatory cytokines - specifically interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α - and depressive symptoms. There is also evidence that this pro-inflammatory state is accompanied by aberrant inflammation-related processes including platelet activation factor hyperactivity, oxidative and nitrosative stress, and damage to mitochondria. These complex and interrelated mechanisms can collectively contribute to negative neurobiological outcomes that may, in part, underlie the etiopathology of depression. Mounting evidence has shown a concomitant reduction in both depressive symptoms and pro-inflammatory cytokine concentrations following treatment with pharmacological anti-inflammatory interventions. Taken together, the reviewed preclinical and clinical findings may suggest the existence of a distinct inflammatory subtype of depression in which these patients exhibit unique biochemical and clinical features and may potentially experience improved clinical outcomes with inflammation-targeted pharmacotherapy.

The Effect of Exercise Training on Resting Concentrations of Peripheral Brain-Derived Neurotrophic Factor (BDNF): A Meta-Analysis.

BACKGROUND: The mechanisms through which physical activity supports healthy brain function remain to be elucidated. One hypothesis suggests that increased brain-derived neurotrophic factor (BDNF) mediates some cognitive and mood benefits. This meta-analysis sought to determine the effect of exercise training on resting concentrations of BDNF in peripheral blood. METHODS: MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after exercise interventions ≥ 2 weeks. Risk of bias was assessed using standardized criteria. Standardized mean differences (SMDs) were generated from random effects models. Risk of publication bias was assessed using funnel plots and Egger's test. Potential sources of heterogeneity were explored in subgroup analyses. RESULTS: In 29 studies that met inclusion criteria, resting concentrations of peripheral blood BDNF were higher after intervention (SMD = 0.39, 95% CI: 0.17-0.60, p < 0.001). Subgroup analyses suggested a significant effect in aerobic (SMD = 0.66, 95% CI: 0.33-0.99, p < 0.001) but not resistance training (SMD = 0.07, 95% CI: -0.15-0.30, p = 0.52) interventions. No significant difference in effect was observed between males and females, nor in serum vs plasma. CONCLUSION: Aerobic but not resistance training interventions increased resting BDNF concentrations in peripheral blood.

Pharmacological Management of Agitation and Aggression in Alzheimer's Disease: A Review of Current and Novel Treatments.

Agitation and aggression are common neuropsychiatric symptoms of Alzheimer's disease and are highly prevalent in people with dementia. When pharmacological intervention becomes necessary, current clinical practice guidelines recommend antipsychotics, cholinesterase inhibitors, and some antidepressants. However, those interventions have modest to low efficacy, and those with the highest demonstrated efficacy have significant safety concerns. As a result, current research is focusing on novel compounds that have different mechanisms of action and that may have a better balance of efficacy over safety. The purpose of this review is to evaluate novel pharmacological therapies for the management of agitation and aggression in AD patients. We performed a comprehensive literature search to identify recent novel drugs that are not included in most clinical practice guidelines or are currently undergoing clinical trials for the treatment of agitation and/or aggression in AD. This review suggests that novel treatments, such as cannabinoids, lithium, non-steroidal anti-inflammatory drugs, analgesics, narcotics, and newer antiepileptic drugs, may provide a safer alternative treatment option for the management of agitation and aggression in AD and requires further study in order to clarify their risks and benefits.

Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer's Disease.

Alzheimer's disease (AD) is frequently associated with neuropsychiatric symptoms (NPS) such as agitation and aggression, especially in the moderate to severe stages of the illness. The limited efficacy and high-risk profiles of current pharmacotherapies for the management of agitation and aggression in AD have driven the search for safer pharmacological alternatives. Over the past few years, there has been a growing interest in the therapeutic potential of medications that target the endocannabinoid system (ECS). The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD. This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD. Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids­dronabinol or nabilone­on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.

Towards a "metabolic" subtype of major depressive disorder: shared pathophysiological mechanisms may contribute to cognitive dysfunction.

Major depressive disorder (MDD) is frequently associated with significant cognitive dysfunction. Furthermore, MDD is often co-morbid with obesity and metabolic disorders. The aim of this review is to evaluate the pathophysiological role obesity and co-morbid metabolic disorders may play in cognitive dysfunction associated with MDD. We conducted a PubMed search from December 1(st) 2013 to May 31(st) 2014 of all English language publications including the following keywords: cognition, working memory, attention, executive functioning, inflammation, insulin, brain-derived neurotrophic factor, neurotrophins, incretins, glucagon-like peptide-1, adipokines, diabetes, oxidative stress and glucocorticoids, cross- referenced with MDD and obesity, metabolic disorders, or metabolic syndrome. Clinical and epidemiological studies indicate that metabolic disturbances may contribute to cognitive dysfunction in MDD. There are several overlapping pathophysiological mechanisms linking obesity and metabolic abnormalities to MDD including disturbances in the hypothalamic pituitary adrenal axis, abnormalities in brain-derived neurotrophic factor signaling, adipose-derived hormones, insulin signalling, inflammatory cytokines, as well as oxidative and nitrosative stress pathways. Based on current research results, this article presents several putative mechanisms underlying the effects of obesity and metabolic abnormalities on cognitive dysfunction in MDD. Metabolic MDD may represent a depression subtype with unique patho-etiological mechanisms. The diverse shared pathophysiological mechanisms elucidated in this review may provide novel targets for the prevention and/or treatment of cognitive deficits in MDD.

Obesity and bipolar disorder: synergistic neurotoxic effects?

Bipolar disorder (BD) is a disabling and chronic neuropsychiatric disorder that is typified by a complex illness presentation, episode recurrence and by its frequent association with psychiatric and medical comorbidities. Over the past decade, obesity has emerged as one of many comorbidities generating substantial concern in the BD population due to important prognostic implications. This comprehensive review details the bidirectional relationship between obesity and BD as evidenced by alterations in the structure and function of the central nervous system, in addition to greater depressive recurrence, cognitive dysfunction and risk of suicidality. Drawing on current research results, this article presents several putative mechanisms underlying the synergistic toxic effects and provides a framework for future treatment options for the obesity-BD comorbidity. There is a need for more large-scale prospective studies to investigate the bidirectional relationships between obesity and BD.