Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset.

BACKGROUND: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. METHODS: We identified non-demented participants without neurodegenerative disease from the National Alzheimer's Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. RESULTS: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). CONCLUSION: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease.

BACKGROUND: Intranasal insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose uptake, reduce amyloid plaques, and improve verbal memory in cognitively impaired as well as healthy adults. Investigations have suggested rapid-acting insulins such as glulisine may result in superior cognitive benefits compared with regular insulin. OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of rapid-acting intranasal glulisine in subjects with amnestic mild cognitive impairment (MCI) or mild probable Alzheimer's disease (AD). METHODS: We performed a single-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy of intranasal glulisine 20 IU twice daily versus saline placebo in 35 memory-impaired (MCI/AD) subjects using the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), Clinical Dementia Rating (CDR) global score, and Functional Assessment Questionnaire (FAQ) were measured at baseline and 3 and 6 months. Secondary outcome measures included digit span forward/backwards, Trail Making Test Parts A/B, Controlled Oral Word Association Test (COWAT), and Weschler Memory Scale (WMS)-IV logical memory. Adverse effects (AEs) and serious adverse effects (SAEs) were measured along with blood glucose/insulin levels. RESULTS: No significant difference in ADAS-Cog13, CDR Sum of Boxes (CDR-SOB), or FAQ scores were found between treatment groups at 3 and 6 months. Subjects in the saline group were significantly older than those in the glulisine group (p = 0.022). No significant differences in sex, education, apolipoprotein E4 (ApoE4) status, and Montreal Cognitive Assessment (MoCA) score existed between treatment groups. Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24; p = 0.824), although subjects receiving intranasal glulisine had higher rates of nasal irritation (25.0% vs. 13.9%) and respiratory symptoms (15.9% vs. 8.3%) compared with placebo. There were no differences in blood sugar or rate of hypoglycemia between the treatment and placebo groups. CONCLUSIONS: Intranasal glulisine was relatively safe and well-tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of intranasal glulisine on cognition, function, or mood, but the ability to detect significance was limited by the number of subjects successfully enrolled and the study duration. CLINICALTRIALS. GOV REGISTRATION: NCT02503501.

Cognitive Effects of Aerobic Exercise in Alzheimer's Disease: A Pilot Randomized Controlled Trial.

BACKGROUND: Aerobic exercise has shown inconsistent cognitive effects in older adults with Alzheimer's disease (AD) dementia. OBJECTIVE: To examine the immediate and longitudinal effects of 6-month cycling on cognition in older adults with AD dementia. METHODS: This randomized controlled trial randomized 96 participants (64 to cycling and 32 to stretching for six months) and followed them for another six months. The intervention was supervised, moderate-intensity cycling for 20-50 minutes, 3 times a week for six months. The control was light-intensity stretching. Cognition was assessed at baseline, 3, 6, 9, and 12 months using the AD Assessment Scale-Cognition (ADAS-Cog). Discrete cognitive domains were measured using the AD Uniform Data Set battery. RESULTS: The participants were 77.4±6.8 years old with 15.6±2.9 years of education, and 55% were male. The 6-month change in ADAS-Cog was 1.0±4.6 (cycling) and 0.1±4.1 (stretching), which were both significantly less than the natural 3.2±6.3-point increase observed naturally with disease progression. The 12-month change was 2.4±5.2 (cycling) and 2.2±5.7 (control). ADAS-Cog did not differ between groups at 6 (p = 0.386) and 12 months (p = 0.856). There were no differences in the 12-month rate of change in ADAS-Cog (0.192 versus 0.197, p = 0.967), memory (-0.012 versus -0.019, p = 0.373), executive function (-0.020 versus -0.012, p = 0.383), attention (-0.035 versus -0.033, p = 0.908), or language (-0.028 versus -0.026, p = 0.756). CONCLUSION: Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia. Aerobic exercise did not show superior cognitive effects to stretching in our pilot trial, possibly due to the lack of power.

Screening Positive for Cognitive Impairment: Impact on Healthcare Utilization and Provider Action in Primary and Specialty Care Practices.

BACKGROUND: Alzheimer's disease, the most common cause of dementia, goes unrecognized in half of patients presenting to healthcare providers and is associated with increased acute care utilization. Routine cognitive screening of older adults in healthcare settings could improve rates of dementia diagnosis and patterns of healthcare utilization. OBJECTIVE: To evaluate the impact of screening positive for cognitive impairment on provider action in primary and specialty care practices and patient healthcare utilization. DESIGN: Individuals asymptomatic for cognitive impairment completed cognitive screening with the Mini-Cog (MC). Outcomes included MC screen-positive rates, provider follow-up actions, and healthcare utilization for all participants over a period of 36 months (18 months prior to and following MC screening). Data were extracted from the electronic medical record (EMR). Healthcare provider interventions and healthcare utilization for screen-positive and -negative groups, before and after screening, were compared. PARTICIPANTS: Primary and specialty care patients (n = 787) aged ≥ 65 without history of cognitive impairment seen in HealthPartners, an integrated healthcare system in Minnesota and Western Wisconsin. KEY RESULTS: In primary care and neurology practices combined, over the entire 36-month study window, individuals screening positive showed 32% higher rates of ED visits (p < 0.05) pre and post-screening compared to those screening negative. Screen positive also showed 39% higher rates of hospitalizations pre-screening (p < 0.05) and 58% higher rates post-screening (p < 0.01). While screen-detected cognitive impairment was associated with some relevant provider follow-up action in 32% of individuals, subsequent healthcare utilization did not change between the 18-month pre- and post-screening periods. CONCLUSION: Despite being associated with higher rates of healthcare utilization, screening positive on the MC led to a change in provider action in a minority of cases and did not reduce post-screening healthcare utilization. Screening for cognitive impairment alone is not sufficient to alter patterns of provider practice or patient healthcare utilization.

Executive function: Responses to aerobic exercise in Alzheimer's disease.

Executive dysfunction occurs early and is prevalent in Alzheimer's disease (AD). This study tested the ability of different measures for identifying changes in executive function and the effect of 6-months of aerobic exercise on executive function in older adults with mild to moderate AD, using a single-group, repeated-measures design (n = 28, age 78.1 ± 8.37). Factor analysis and linear mixed-effects model analyses showed that individually the Exit Interview-25 (EXIT-25), Behavioral Dyscontrol Scale (BDS), and Golden Stroop test were the preferred instruments for measuring changes in executive function in the sample. The COWAT and TMT had substantial floor effects limiting their ability to identify changes in executive function. A single latent factor was sufficient to describe the heterogeneity of executive function. Over 6 months, aerobic exercise maintained executive function (effect size = -0.11, -0.24, -0.27, and -0.21 for the EXIT-25, BDS, Stroop, and latent factor, respectively). Decline in the latent factor (effect size = -0.21, p = 0.06) was minimal and comparable to that in global cognition (effect size = -0.20, p = 0.34). Aerobic exercise may be effective on maintaining executive function in AD.

Physical Activity Interventions in Preventing Cognitive Decline and Alzheimer-Type Dementia: A Systematic Review.

Background: The prevalence of cognitive impairment and dementia is expected to increase dramatically as the population ages, creating burdens on families and health care systems. Purpose: To assess the effectiveness of physical activity interventions in slowing cognitive decline and delaying the onset of cognitive impairment and dementia in adults without diagnosed cognitive impairments. Data Sources: Several electronic databases from January 2009 to July 2017 and bibliographies of systematic reviews. Study Selection: Trials published in English that lasted 6 months or longer, enrolled adults without clinically diagnosed cognitive impairments, and compared cognitive and dementia outcomes between physical activity interventions and inactive controls. Data Extraction: Extraction by 1 reviewer and confirmed by a second; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence. Data Synthesis: Of 32 eligible trials, 16 with low to moderate risk of bias compared a physical activity intervention with an inactive control. Most trials had 6-month follow-up; a few had 1- or 2-year follow-up. Evidence was insufficient to draw conclusions about the effectiveness of aerobic training, resistance training, or tai chi for improving cognition. Low-strength evidence showed that multicomponent physical activity interventions had no effect on cognitive function. Low-strength evidence showed that a multidomain intervention comprising physical activity, diet, and cognitive training improved several cognitive outcomes. Evidence regarding effects on dementia prevention was insufficient for all physical activity interventions. Limitation: Heterogeneous interventions and cognitive test measures, small and underpowered studies, and inability to assess the clinical significance of cognitive test outcomes. Conclusion: Evidence that short-term, single-component physical activity interventions promote cognitive function and prevent cognitive decline or dementia in older adults is largely insufficient. A multidomain intervention showed a delay in cognitive decline (low-strength evidence). Primary Funding Source: Agency for Healthcare Research and Quality.

Does Cognitive Training Prevent Cognitive Decline?: A Systematic Review.

Background: Structured activities to stimulate brain function-that is, cognitive training exercises-are promoted to slow or prevent cognitive decline, including dementia, but their effectiveness is highly debated. Purpose: To summarize evidence on the effects of cognitive training on cognitive performance and incident dementia outcomes for adults with normal cognition or mild cognitive impairment (MCI). Data Sources: Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and PsycINFO through July 2017, supplemented by hand-searches. Study Selection: Trials (published in English) lasting at least 6 months that compared cognitive training with usual care, waitlist, information, or attention controls in adults without dementia. Data Extraction: Single-reviewer extraction of study characteristics confirmed by a second reviewer; dual-reviewer risk-of-bias assessment; consensus determination of strength of evidence. Only studies with low or medium risk of bias were analyzed. Data Synthesis: Of 11 trials with low or medium risk of bias, 6 enrolled healthy adults with normal cognition and 5 enrolled adults with MCI. Trainings for healthy older adults were mostly computer based; those for adults with MCI were mostly held in group sessions. The MCI trials used attention controls more often than trials with healthy populations. For healthy older adults, training improved cognitive performance in the domain trained but not in other domains (moderate-strength evidence). Results for populations with MCI suggested no effect of training on performance (low-strength and insufficient evidence). Evidence for prevention of cognitive decline or dementia was insufficient. Adverse events were not reported. Limitation: Heterogeneous interventions and outcome measures; outcomes that mostly assessed test performance rather than global function or dementia diagnosis; potential publication bias. Conclusion: In older adults with normal cognition, training improves cognitive performance in the domain trained. Evidence regarding prevention or delay of cognitive decline or dementia is insufficient. Primary Funding Source: Agency for Healthcare Research and Quality.

Pharmacologic Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review.

Background: Optimal treatment to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia is uncertain. Purpose: To summarize current evidence on the efficacy and harms of pharmacologic interventions to prevent or delay cognitive decline, MCI, or dementia in adults with normal cognition or MCI. Data Sources: Several electronic databases from January 2009 to July 2017, bibliographies, and expert recommendations. Study Selection: English-language trials of at least 6 months' duration enrolling adults without dementia and comparing pharmacologic interventions with placebo, usual care, or active control on cognitive outcomes. Data Extraction: Two reviewers independently rated risk of bias and strength of evidence; 1 extracted data, and a second checked accuracy. Data Synthesis: Fifty-one unique trials were rated as having low to moderate risk of bias (including 3 that studied dementia medications, 16 antihypertensives, 4 diabetes medications, 2 nonsteroidal anti-inflammatory drugs [NSAIDs] or aspirin, 17 hormones, and 7 lipid-lowering agents). In persons with normal cognition, estrogen and estrogen-progestin increased risk for dementia or a combined outcome of MCI or dementia (1 trial, low strength of evidence); high-dose raloxifene decreased risk for MCI but not for dementia (1 trial, low strength of evidence); and antihypertensives (4 trials), NSAIDs (1 trial), and statins (1 trial) did not alter dementia risk (low to insufficient strength of evidence). In persons with MCI, cholinesterase inhibitors did not reduce dementia risk (1 trial, low strength of evidence). In persons with normal cognition and those with MCI, these pharmacologic treatments neither improved nor slowed decline in cognitive test performance (low to insufficient strength of evidence). Adverse events were inconsistently reported but were increased for estrogen (stroke), estrogen-progestin (stroke, coronary heart disease, invasive breast cancer, and pulmonary embolism), and raloxifene (venous thromboembolism). Limitation: High attrition, short follow-up, inconsistent cognitive outcomes, and possible selective reporting and publication. Conclusion: Evidence does not support use of the studied pharmacologic treatments for cognitive protection in persons with normal cognition or MCI. Primary Funding Source: Agency for Healthcare Research and Quality.

Over-the-Counter Supplement Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review.

Background: Optimal interventions to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia are uncertain. Purpose: To summarize the evidence on efficacy and harms of over-the-counter (OTC) supplements to prevent or delay cognitive decline, MCI, or clinical Alzheimer-type dementia in adults with normal cognition or MCI but no dementia diagnosis. Data Sources: Multiple electronic databases from 2009 to July 2017 and bibliographies of systematic reviews. Study Selection: English-language trials of at least 6 months' duration that enrolled adults without dementia and compared cognitive outcomes with an OTC supplement versus placebo or active controls. Data Extraction: Extraction performed by a single reviewer and confirmed by a second reviewer; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence. Data Synthesis: Thirty-eight trials with low to medium risk of bias compared ω-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C or ß-carotene, multi-ingredient supplements, or other OTC interventions with placebo or other supplements. Few studies examined effects on clinical Alzheimer-type dementia or MCI, and those that did suggested no benefit. Daily folic acid plus vitamin B12 was associated with improvements in performance on some objectively measured memory tests that were statistically significant but of questionable clinical significance. Moderate-strength evidence showed that vitamin E had no benefit on cognition. Evidence about effects of ω-3 fatty acids, soy, ginkgo biloba, folic acid alone or with other B vitamins, ß-carotene, vitamin C, vitamin D plus calcium, and multivitamins or multi-ingredient supplements was either insufficient or low-strength, suggesting that these supplements did not reduce risk for cognitive decline. Adverse events were rarely reported. Limitation: Studies had high attrition and short follow-up and used a highly variable set of cognitive outcome measures. Conclusion: Evidence is insufficient to recommend any OTC supplement for cognitive protection in adults with normal cognition or MCI. Primary Funding Source: Agency for Healthcare Research and Quality.

A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer's disease.

INTRODUCTION: Intranasal (IN) insulin acutely improves verbal memory in mild cognitive impairment (MCI)/Alzheimer's disease (AD), but its therapeutic effects may be attenuated in apolipoprotein E4 (ApoE4) carriers. Furthermore, rapid-acting (RA) insulins may have superior therapeutic effects compared with regular insulin types. OBJECTIVES: To measure the safety and efficacy of intranasally delivered RA glulisine in ApoE4 carriers with mild-moderate AD. METHODS: We performed a double-blinded, randomized, cross-over study of RA insulin glulisine in nine mild-moderate AD subjects to better understand the relationship between RA insulin, ApoE4 carrier status and memory performance. RESULTS: IN glulisine was well tolerated but failed to have an acute impact on cognition in ApoE4 carriers with AD. Serum insulin levels acutely dropped following treatment, but peripheral glucose levels remained unchanged. CONCLUSION: Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.

Neurocognition in individuals co-infected with HIV and hepatitis C.

Due to similar routes of viral transmission, many individuals infected with the human immunodeficiency virus (HIV) are also infected with the hepatitis C virus (HCV). Each virus can cause cognitive compromise among mono-infected individuals; evidence is accumulating that HIV/HCV co-infection may have a particularly deleterious impact on cognition. We present neuropsychological data obtained from 118 HIV+ adults with advanced HIV disease, 35 of whom were co-infected with HCV, who completed a comprehensive neurocognitive evaluation. Rates of global cognitive impairment were higher among co-infected patients than among those with HIV alone (63% vs. 43%). Within the specific domains of learning and memory, co-infected individuals were significantly more likely to be impaired than were the HIV mono-infected participants. Finally, we discuss implications of these findings and potential future directions for research in this area.

Elements of attention in HIV-infected adults: evaluation of an existing model.

Because of the multifactorial nature of neuropsychological tests, attention remains poorly defined from a neuropsychological perspective, and conclusions made regarding attention across studies may be limited due to the different nature of the measures used. Thus, a more definitive schema for this neurocognitive domain is needed. We assessed the applicability of Mirsky and Duncan's (2001) neuropsychological model of attention to a cohort of 104 HIV+ adults. Our analysis resulted in a five-factor structure similar to that of previous studies, which explained 74.5% of the variance. However, based on the psychometric characteristics of the measures comprising each factor, we offer an alternative interpretation of the factors. Findings also indicate that one factor, which is generally not assessed in clinical neuropsychology settings, may be more predictive of real-world behaviors (such as medication adherence) than those composed of traditional measures. Suggestions for further research in this important area are discussed.

Relationship between psychiatric status and frontal-subcortical systems in HIV-infected individuals.

Human immunodeficiency virus (HIV)-infected adults frequently evidence both neurocognitive and psychiatric dysfunction. It was hypothesized that apathy and irritability, but not anxiety and depression, are related to HIV effects on frontal-subcortical systems. This hypothesis was evaluated by determining the degree to which these psychiatric features are associated with neurocognitive functioning that is dependent upon frontal-subcortical circuitry and, therefore, thought to be sensitive to the central nervous system effects of HIV. Rating scales assessing irritability, apathy, depression, and anxiety and a dual-task paradigm were administered to 189 HIV-seropositive (HIV+) and 53 HIV-seronegative participants. Deficits in dual-task performance and greater anxiety, depression, apathy, and irritability were observed in HIV+ participants. Simultaneous multivariate regression and communality analyses revealed that only apathy and irritability were associated with dual-task performance in HIV+ participants. Thus, these findings suggest that apathy and irritability, but not depression and anxiety, are likely associated with the effects of HIV on frontal-subcortical circuitry.

Age-associated predictors of medication adherence in HIV-positive adults: health beliefs, self-efficacy, and neurocognitive status.

OBJECTIVE: Although most agree that poor adherence to antiretrovirals is a common problem, relatively few factors have been shown to consistently predict treatment failure. In this study, a theoretical framework encompassing demographic characteristics, health beliefs/attitudes, treatment self-efficacy, and neurocognitive status was examined in relationship to highly active antiretroviral therapy adherence. DESIGN: Prospective, cross-sectional observational design. MAIN OUTCOME MEASURES: Neuropsychological test performance, health beliefs and attitudes, and medication adherence tracked over a 1-month period using electronic monitoring technology (Medication Event Monitoring System caps). RESULTS: The rate of poor adherence was twice as high among younger participants than with older participants (68% and 33%, respectively). Results of binary logistic regression revealed that low self-efficacy and lack of perceived treatment utility predicted poor adherence among younger individuals, whereas decreased levels of neurocognitive functioning remained the sole predictor of poor adherence among older participants. CONCLUSION: These data support components of the health beliefs model in predicting medication adherence among younger HIV-positive individuals. However, risk of adherence failure in those ages 50 years and older appears most related to neurocognitive status.

Drug use and medication adherence among HIV-1 infected individuals.

This longitudinal study examined the impact of drug use and abuse on medication adherence among 150 HIV-infected individuals, 102 who tested urinalysis positive for recent illicit drug use. Medication adherence was tracked over a 6-month period using an electronic monitoring device (MEMS caps). Over the 6-month study drug-positive participants demonstrated significantly worse medication adherence than did drug-negative participants (63 vs. 79%, respectively). Logistic regression revealed that drug use was associated with over a fourfold greater risk of adherence failure. Stimulant users were at greatest risk for poor adherence. Based upon within-participants analyses comparing 3-day adherence rates when actively using versus not using drugs, this appears to be more a function of state rather than trait. These data suggest that it is the acute effects of intoxication, rather than stable features that may be characteristic of the drug-using populace, which leads to difficulties with medication adherence.