Exercise interventions in Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials

AimsTo assess the potential multi-domain benefits of exercise interventions on patients with Alzheimer’s disease (AD), as well as to determine the specific effects of different exercise modalities (aerobic, strength, or combined training).MethodsA systematic search was conducted in PubMed and Web of Science until March 2021 for randomized controlled trials assessing the effect of exercise interventions (compared with no exercise) on patients with AD. Outcomes included cognitive function (mini-mental state examination [MMSE] test), physical function (e.g., 6-minute walking test [6MWT]), functional independence (Barthel index), and neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]). A random-effects meta-analysis was conducted.Results28 studies (total n = 1337 participants, average age 79–90 years) were included in the systematic review, of which 21 could be meta-analyzed. Although considerable heterogeneity was found, exercise interventions induced several significant benefits, including in Barthel index (n = 147 patients, mean difference [MD]=8.36 points, 95% confidence interval [CI]=0.63–16.09), 6MWT (n = 369, MD=84 m, 95% CI=44–133)), and NPI (n = 263, MD=−4.4 points, 95% CI=−8.42 to −0.38). Benefits were also found in the MMSE test, albeit significance was only reached for aerobic exercise (n = 187, MD=2.31 points, 95% CI 0.45–4.27).ConclusionsExercise interventions appear to exert multi-domain benefits in patients with AD.     

Randomised controlled trials for the prevention of cognitive decline or dementia: A systematic review

Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably for individuals with Alzheimer’s disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing the efficacy of single-domain pharmacological (n = 33, 29%), nutritional (n = 27, 24%), physical activity (n = 18, 16%) and cognitive stimulation (n = 13, 12%), or multidomain (n = 22, 20%) interventions on incident dementia, or a relevant intermediate marker (e.g. cognitive function, biomarkers or dementia risk scores) in people without dementia. The earliest trials tested pharmacological interventions or nutritional supplements, but lifestyle interventions predominated in the last decade. In total, 21 (19%) trials demonstrated a clear beneficial effect on the pre-specified primary outcome (or all co-primary outcomes), but only two (10%) were large-scale (testing blood pressure lowering (Syst-Eur) or multidomain (FINGER) interventions on incident dementia and cognitive change in cognitive function, respectively). Of the 116 ongoing trials, 40% (n = 46) are testing multidomain interventions. Recent methodological shifts concern target populations, primary outcome measures, and intervention design, but study design remains constant (parallel group randomised controlled trial). Future trials may consider using adaptive trials or interventions, and more targeted approaches, since certain interventions may be more effective in certain subgroups of the population, and at specific times in the life-course. Efforts should also be made to increase the representativeness and diversity of prevention trial populations.     

C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment

C9orf72 G₄C₂ repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G₄C₂ pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G₄C₂ repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G₄C₂ repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor.     

Motivational interviewing to support medication adherence in adults with chronic conditions: Systematic review of randomized controlled trials

ObjectivesTo systematically review published randomized controlled trials (RCTs) assessing the efficacy of MI to support medication adherence in adults with chronic conditions.MethodsA systematic review (PROSPERO-CRD42020025374) was performed by searching in Pubmed/MEDLINE, PsycINFO, The Cochrane Library and Web of Science. Studies were included for the following: RCTs assessing the impact of MI on medication adherence among adults with chronic diseases. Two reviewers conducted independent screening of records and full-text articles published until July 2020. Quality was assessed with the Risk of Bias 2 tool for RCTs.ResultsFrom 1262 records identified, 54 RCTs were included. The MI interventions were delivered alone or in combination with other interventions, and varied in mode of delivery (e.g. face-to-face, phone), exposure level (duration, number of sessions), and provider characteristics (profession, training). Most interventions were developed in infectious diseases (n = 16), cardiology (n = 14), psychiatry (n = 8), and endocrinology (n = 7). Medication adherence showed significant improvement in 23 RCTs, and other clinical outcomes were improved in 19 RCTs (e.g. risky behaviors, disease symptoms).ConclusionsMI is an approach to medication adherence support with an increasing evidence base in several clinical domains and further potential for adaptation to different settings.Practice implicationsIn further studies, particular attention should focus on methodological issues such as the populations of patients to include – patients with suboptimal adherence, the evaluation of fidelity to the MI spirit and components, and a sound measurement of medication adherence and clinical outcomes.     

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

BackgroundNon-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.MethodMulti-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.ResultThe pooled meta-analyses included 19 studies measuring global cognition (N_active=288, N_sham=264), and 9 studies investigating NPS (N_active=165, N_sham=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 (N_studies=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.ConclusionrTMS 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.     

Sex differences in the prevalence and incidence of mild cognitive impairment: A meta-analysis

ObjectiveMore women have Alzheimer’s disease (AD) than men. Understanding sex differences in mild cognitive impairment (MCI) may further knowledge of AD etiology and prevention. We conducted a meta-analysis to examine sex differences in the prevalence and incidence of MCI, which included amnestic and non-amnestic subtypes.MethodSystematic searches were performed in July 2015 using MEDLINE/PubMed, Scopus, and PsycINFO for population-or community-based studies with MCI data for men and women. Random-effects model were used.ResultsFifty-six studies were included. There were no statistically significant sex differences in prevalence or incidence of amnestic MCI. There was a significantly higher prevalence (p = 0.038), but not incidence, of non-amnestic MCI among women. There were no sex differences in studies that combined both subtypes of MCI.ConclusionThe only statistically significant finding emerging from this study was that women have a higher prevalence of non-amnestic MCI. To better understand sex differences in the preclinical stages of dementia, studies must better characterize the etiology of the cognitive impairment.     

A patient-centered gout information value chain: a scoping review

ObjectiveTo examine and identify the scope of research addressing health information requirements for gout patients using value chain analysis.MethodsFive electronic databases (PubMed, CINAHL, ERIC, PsycINFO, Embase, and Scopus) and grey literature (WorldCat) were searched in accordance with a published protocol. Only English language articles were included, with no limitations for date of publication. The findings of the 33 studies included for final analysis were subsequently divided into 6 groups according to the stages of the care delivery value chain their research most closely pertained to: screening/preventing (n = 2), diagnosing (n = 1), preparing (n = 7), intervening (n = 11), recovering/rehabilitating (n = 5), and monitoring/managing (n = 13).ResultsThe 33 studies focused on one or more of the following information phenotypes: 1) pathophysiology; 2) medical treatment; and 3) nonpharmaceutical interventions. Long term treatment adherence was a popular topic amongst studies that focused on gout patient education.ConclusionBased on the identified studies, gout patients are being told what to do, but are not being adequately educated regarding why recommended interventions are important or how to accomplish them.Practice implicationsThis review provides a foundation to develop and evaluate personalized education materials using value chain analysis.     

Model-based physiomarkers of cerebral hemodynamics in patients with mild cognitive impairment

In our previous studies, we have introduced model-based “functional biomarkers” or “physiomarkers” of cerebral hemodynamics that hold promise for improved diagnosis of early-stage Alzheimer's disease (AD). The advocated methodology utilizes subject-specific data-based dynamic nonlinear models of cerebral hemodynamics to compute indices (serving as possible diagnostic physiomarkers) that quantify the state of cerebral blood flow autoregulation to pressure-changes (CFAP) and cerebral CO2 vasomotor reactivity (CVMR) in each subject. The model is estimated from beat-to-beat measurements of mean arterial blood pressure, mean cerebral blood flow velocity and end-tidal CO2, which can be made reliably and non-invasively under resting conditions. In a previous study, it was found that a CVMR index quantifying the impairment in CO2 vasomotor reactivity correlates with clinical indications of early AD, offering the prospect of a potentially useful diagnostic tool. In this paper, we explore the use of the same model-based indices for patients with amnestic Mild Cognitive Impairment (MCI), a preclinical stage of AD, relative to a control subjects and clinical cognitive assessments. It was found that the model-based CVMR values were lower for MCI patients relative to the control subjects.     

Cerebral Perfusion Enhancing Interventions: A New Strategy for the Prevention of Alzheimer Dementia

Cardiovascular and cerebrovascular diseases are major risk factors in the development of cognitive impairment and Alzheimer's disease (AD). These cardio‐cerebral disorders promote a variety of vascular risk factors which in the presence of advancing age are prone to markedly reduce cerebral perfusion and create a neuronal energy crisis. Long‐term hypoperfusion of the brain evolves mainly from cardiac structural pathology and brain vascular insufficiency. Brain hypoperfusion in the elderly is strongly associated with the development of mild cognitive impairment (MCI) and both conditions are presumed to be precursors of Alzheimer dementia. A therapeutic target to prevent or treat MCI and consequently reduce the incidence of AD aims to elevate cerebral perfusion using novel pharmacological agents. As reviewed here, the experimental pharmaca include the use of Rho kinase inhibitors, neurometabolic energy boosters, sirtuins and vascular growth factors. In addition, a compelling new technique in laser medicine called photobiomodulation is reviewed. Photobiomodulation is based on the use of low level laser therapy to stimulate mitochondrial energy production non‐invasively in nerve cells. The use of novel pharmaca and photobiomodulation may become important tools in the treatment or prevention of cognitive decline that can lead to dementia.     

Visual contrast sensitivity in Alzheimer’s disease,mild cognitive impairment,and older adults with cognitive complaints

Deficits in contrast sensitivity (CS) have been reported in Alzheimer’s disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.     

Concurrent cardiac transthyretin and brain β amyloid accumulation among the older adults: The Hisayama study

Previous studies have revealed risk for cognitive impairment in cardiovascular diseases. We investigated the relationship between degenerative changes of the brain and heart, with reference to Alzheimer's disease (AD) pathologies, cardiac transthyretin amyloid (ATTR) deposition, and cardiac fibrosis. A total of 240 consecutive autopsy cases of a Japanese population-based study were examined. β amyloid (Aβ) of senile plaques, phosphorylated tau protein of neurofibrillary tangles, and ATTR in the hearts were immunohistochemically detected and graded according to the NIH-AA guideline for AD pathology and as Tanskanen reported, respectively. Cerebral amyloid angiopathy (CAA) was graded according to the Vonsattel scale. Cardiac fibrosis was detected by picrosirius red staining, followed by image analysis. Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner. ATTR deposition was more common, and of higher grades, in the dementia cases. We subdivided the cases into two age groups: ≤90 years old (n = 173) and >90 years old (n = 67), which was the mean and median age at death of the AD cases. When adjusted for age and sex, TTR deposition grades correlated with Aβ phase score (A2–3), the Consortium to Establish a Registry for AD score (sparse to frequent), and high Braak stage (V–VI) only in those aged ≤90 years at death. No significant correlation was observed between the cardiac ATTR deposition and CAA stages, or between cardiac fibrosis and AD pathologies. Collectively, AD brain pathology correlated with cardiac TTR deposition among the older adults ≤90 years.     

PET imaging of amyloid deposition in patients with mild cognitive impairment

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 ± 7.8 (S.D.) years) underwent PET studies with ¹¹C-PIB, and ¹⁸F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1 ± 6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps < 0.01). The PIB retention in MCI converters was comparable to AD patients (p > 0.01). Correlations were observed in the MCI patients between PIB retention and CSF Aβ_1-42, total Tau and episodic memory, respectively.     

Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis

Combined cognitive and physical exercise interventions have potential to elicit cognitive benefits in older adults with mild cognitive impairment (MCI) or dementia. This meta-analysis aims to quantify the overall effect of these interventions on global cognitive functioning in older adults with MCI or dementia. Ten randomized controlled trials that applied a combined cognitive-physical intervention with cognitive function as an outcome measure were included. For each study effect sizes were computed (i.e., post-intervention standardized mean difference (SMD) scores) and pooled, using a random-effects meta-analysis. The primary analysis showed a small-to-medium positive effect of combined cognitive-physical interventions on global cognitive function in older adults with MCI or dementia (SMD[95% confidence interval] = 0.32[0.17;0.47], p < 0.00). A combined intervention was equally beneficial in patients with dementia (SMD = 0.36[0.12;0.60], p < 0.00) and MCI (SMD = 0.39[0.15;0.63], p < 0.05). In addition, the analysis showed a moderate-to-large positive effect after combined cognitive-physical interventions for activities of daily living (ADL) (SMD = 0.65[0.09;1.21], p < 0.01)and a small-to-medium positive effect for mood (SMD = 0.27[0.04;0.50], p < 0.01). These functional benefits emphasize the clinical relevance of combined cognitive and physical training strategies.     

Relating microarray component testing and reported food allergy and food-triggered atopic dermatitis: a real-world analysis

BackgroundHigh epitope diversity has been associated with increased IgE-mediated food allergy severity.ObjectiveTo characterize associations between results from an automated microarray system and self-reported food allergy and food-triggered atopic dermatitis (AD).MethodsFamilies with food allergic children were identified from a Jewish community in Lakewood, New Jersey, with immediate family members without food allergy or food-triggered AD serving as controls for the identified children. Sets of microarray components analyzed were to milk (Bos d 4, Bos d 5, Bos d 8, Bos d lactoferrin), egg (Gal d 1, Gal d 2, Gal d 3, Gal d 5), and peanut (Ara h 1, Ara h 2, Ara h 3, Ara h 6).ResultsSeventy-three patients from 23 families were recruited. Culprit foods included milk (n = 20), egg (n = 10), and peanut (n = 6) for food allergy and milk (n = 10) and egg (n = 7) for food-triggered AD. Odds of having had a self-reported related food allergy or food-triggered AD reaction significantly increased with a higher number of detectable microarray components to that food. Ara h 1, Ara h 2, and Ara h 6 were individually associated with reported peanut allergy, and Bos d 4 was individually associated with reported milk allergy. The number of egg components significantly increased the odds of having related food-triggered AD.ConclusionHigh diversity of food allergen components relates well to self-reported history of food allergy and food-associated AD.     

Associations between sleep duration and cognitive impairment in mild cognitive impairment

The prevalence of mild cognitive impairment (MCI) increases among elderly people and is associated with a high risk of dementia. Identifying factors that may contribute to the progress of MCI to dementia is critical. The objective of this study was to examine the association of objective sleep with cognitive performance in MCI patients. A subsample of 271 participants with a diagnosis of probable Alzheimer's disease (AD; N = 50) or mild cognitive impairment (MCI; N = 121) and 100 persons who were not cognitively impaired (NI) were recruited from a large population‐based cohort in the island of Crete, Greece (3140 older adults aged >60 years). All participants underwent extensive neuropsychiatric/neuropsychological evaluation and a 3‐day 24‐hr actigraphy. Objective sleep variables and their association with neuropsychological performance were examined across the three groups, controlling for demographics, body mass index, depression, sleep apnea symptoms and psychotropic medications. Patients with AD had significantly longer 24‐hr total sleep time (TST) compared to the MCI and NI groups. Long 24‐hr TST was associated with reduced performance on tasks that placed significant demands on attention and processing speed in the MCI group and the AD group. Elderly patients with MCI have similar objective sleep duration to normal controls, whereas AD patients sleep longer. Long sleep duration in patients with multidomain subtypes of MCI is associated with critical non‐memory cognitive domains. It appears that within the MCI group those that sleep longer have more severe cognitive impairment.     

The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials

Non-pharmacological therapies, such as physical activity interventions, are an appealing alternative or add-on to current pharmacological treatment of cognitive symptoms in patients with dementia. In this meta-analysis, we investigated the effect of physical activity interventions on cognitive function in dementia patients, by synthesizing data from 802 patients included in 18 randomized control trials that applied a physical activity intervention with cognitive function as an outcome measure. Post-intervention standardized mean difference (SMD) scores were computed for each study, and combined into pooled effect sizes using random effects meta-analysis. The primary analysis yielded a positive overall effect of physical activity interventions on cognitive function (SMD[95% confidence interval] = 0.42[0.23;0.62], p < .01). Secondary analyses revealed that physical activity interventions were equally beneficial in patients with Alzheimer's disease (AD, SMD = 0.38[0.09;0.66], p < .01) and in patients with AD or a non-AD dementia diagnosis (SMD = 0.47[0.14;0.80], p < .01). Combined (i.e. aerobic and non-aerobic) exercise interventions (SMD = 0.59[0.32;0.86], p < .01) and aerobic-only exercise interventions (SMD = 0.41[0.05;0.76], p < .05) had a positive effect on cognition, while this association was absent for non-aerobic exercise interventions (SMD = -0.10[−0.38;0.19], p = .51). Finally, we found that interventions offered at both high frequency (SMD = 0.33[0.03;0.63], p < .05) and at low frequency (SMD = 0.64[0.39;0.89], p < .01) had a positive effect on cognitive function. This meta-analysis suggests that physical activity interventions positively influence cognitive function in patients with dementia. This beneficial effect was independent of the clinical diagnosis and the frequency of the intervention, and was driven by interventions that included aerobic exercise.     

体外反搏对脑动脉血流量影响的建模和仿真研究

目的　研究体外反搏对脑动脉血流量的影响。方法　将实际测量的正常的颈动脉血压和进行体外反搏时的颈动脉血压作用于正常情况下和缺血情况下脑血流动力学数学模型，模拟上述情况下脑动脉血流的变化。结果　缺血和体外反搏都引起脑动脉血流的变化。结论　体外反搏可以明显增加大脑的血流灌注和改变脑动脉血流变化的时相模式。     

The state of frailty in research: A mapping review of its clinical applicability to practice

Research on frailty has expanded in the last decade, but direct evidence supporting its implementation in clinical practice may be limited. This mapping review synthesizes the contexts-of-use and overall clinical applicability of recent pre-COVID frailty research. We sampled 476 articles from articles published on frailty in PubMed and EMBASE in 2017–2018, of which 150 articles were fully appraised for the contexts-of-use, definitions, and interventions. A clinical applicability framework was used to classify articles as practice-changing, practice-informing, or not practice-informing. Of the 476 sampled articles, 31% (n = 150) used frailty in functions that could inform a clinical indication: predictor or mediator (26%, n = 125), selection criterion (3%, n = 15), and effect modifier (2%, n = 10). Articles spanned all health disciplines, and cohort studies comprised 91% (n = 137) of studies and trials 9% (n = 13). Thirty-eight frailty definitions using varied cut-offs and a wide range of interventions were identified. Among all articles, 13% (n = 63) of articles were practice-informing, 2% (n = 11) potentially practice-changing, and 0.2% (n = 1) clearly practice-changing. Lack of well-defined intervention and identifiable effect (96%) or originality (83%) were predominant reasons reducing applicability. Only a minority of recent frailty research provides direct evidence of applicability to practice. Future research on frailty should focus on translating frailty, as a risk factor, into a clinical indication and address definition ambiguity.     

The prognostic utility of CSF neurogranin in predicting future cognitive decline in the Alzheimer’s disease continuum: A systematic review and meta-analysis with narrative synthesis

Core cerebrospinal fluid (CSF) biomarkers (Aβ42, T-tau, P-tau) were included as supporting diagnostic criteria for Alzheimer’s Disease (AD), but they lack the power to predict AD progression. On the other hand, a new biomarker CSF Neurogranin (Ng) has been shown to predict cognitive decline. This systematic review aims to synthesise the prognostic utility of CSF Ng in predicting cognitive decline in the AD continuum. Seven databases were searched systematically from inception to 30 September 2020. Participants were 55 years or older, who had baseline and at least one follow-up cognitive assessments. Risk of bias was assessed using the Quality in Prognosis Studies tool. Meta-analysis was conducted by pooling standardised beta coefficients and adjusted hazard ratios. Thirteen studies were included and high-quality evidence suggests that CSF Ng predicts Mini-Mental State Examination (MMSE) decline in Aβ⁺ mild cognitive impairment (MCI). Moderate quality evidence showed that CSF Ng could predict the decline of memory and executive function in MCI. Narrative synthesis found that CSF Ng/Aβ42 was also likely to predict cognitive decline. More studies are required to validate the use of CSF Ng as an AD prognostic marker and its application in future development of drug treatment and diagnosis.     

Perfusion abnormalities in prodromal AD

Cerebral perfusion abnormalities in patients with established Alzheimer's disease (AD) are most commonly seen in the temporoparietal cortex. As the disease progresses, this perfusion pattern is increasingly prevalent. Recently, investigators have begun to examine the patterns of perfusion among individuals at risk for AD. To date, such studies have been conducted either in individuals who have a progressive memory difficulty but do not yet meet clinical criteria for AD, or in individuals with a genetic risk factor or family history of AD, either with or without a memory problem. These latter studies suggest that a set of brain regions show decreased perfusion during the prodromal phase of AD, and that a brain network or networks with multiple nodes is affected early in the course of AD. These perfusion abnormalities may also shed light on how AD progresses during the prodromal phase of disease and may ultimately lead to improved diagnosis or methods of monitoring response to treatment.