A Critical Review of Noninvasive Brain Stimulation Technologies in Alzheimer's Dementia and Primary Progressive Aphasia.

Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer's disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer's Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters.

Attention problems and off-topic verbosity among young adult and older adult age cohorts.

Off-topic verbosity refers to tangential discourse with excessive and irrelevant information. Previous research suggests that age-related increases in off-topic verbosity may be due to underlying changes in neurocognitive functioning. The purpose of this study was to investigate relationships between attention problems and off-topic verbosity. Young adults (n = 63) and older adults (n = 82) were administered a continuous performance test and provided speech samples, which were transcribed and rated for tangentiality, egocentrism, and quantity of speech. Overall, results found that attention problems were associated with greater tangentiality among older adults, but among young adults more attention problems were associated with lower quantity of speech. Attention problems may affect young adults' and older adult's speech in different ways, possibly reflecting differences in neurocognitive functioning or communication goals.

Mild Traumatic Brain Injury Is Related to Elevated Cerebrospinal Fluid Tau in Alzheimer's Disease Dementia.

Few studies have examined an association between mild traumatic brain injury (mTBI) and Alzheimer's disease (AD). For this reason, we compared an AD dementia group with an mTBI history (n = 10) to a matched AD control group (n = 20) on measures of cognitive function, cerebral glucose metabolism, and markers of amyloid and tau deposition. Only a trend and medium-to-large effect size for higher phosphorylated and total tau was identified for the mTBI group. A history of mTBI may be associated with greater tau in AD, indicating a potential pathway for increasing risk for AD, though further evaluation with larger samples is needed.

Who wants to live forever? Age cohort differences in attitudes toward life extension.

INTRODUCTION: Biomedical technology holds the promise of extending human life spans; however, little research has explored attitudes toward life extension. METHODS: This survey asked young adults (n = 593), younger-old adults (n = 272), and older-old adults (n = 46) whether they would take a hypothetical life extension treatment as well as the youngest and oldest age at which they would wish to live forever. RESULTS: Age cohorts did not vary in their willingness to use life extension; however, in all three age cohorts, a plurality indicated that they would not use it. Men indicated a higher level of willingness to use the life extension treatment than women. Younger-old and older-old adults indicated that they would prefer to live permanently at an older age than younger adults. DISCUSSION: If a life extension treatment were to become available that effectively stopped aging, young adults may be likely to use such a treatment to avoid reaching the ages at which older cohorts say they would prefer to live forever.

Tau pathology in cognitively normal older adults.

INTRODUCTION: Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. METHODS: Using 18F-AV-1451 (18F-flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. RESULTS: Greater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (ß = -1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (ß = -0.086, SE = 0.039, P = .029). DISCUSSION: Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease.

Apolipoprotein E ε4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

INTRODUCTION: Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS: In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.

Effects of amyloid pathology and neurodegeneration on cognitive change in cognitively normal adults.

Understanding short-term cognitive decline in relation to Alzheimer's neuroimaging biomarkers in early stages of the development of neuropathology and neurodegeneration will inform participant recruitment and monitoring strategies in clinical trials aimed at prevention of cognitive impairment and dementia. We assessed associations among neuroimaging measures of cerebral amyloid pathology, a hallmark Alzheimer's neuropathology, hippocampal atrophy, and prospective cognition among 171 cognitively normal Baltimore Longitudinal Study of Aging participants (baseline age 56-95 years, 48% female, 562 cognitive assessments, 3.7 years follow-up). We categorized each individual based on dichotomous amyloid pathology (A) and hippocampal neurodegeneration (N) status at baseline: A-N-, A+N-, A-N+, A+N+. We conducted linear mixed effects analyses to assess cross-sectional and longitudinal trends in cognitive test z-scores by amyloid and neurodegeneration group. To investigate the effects of amyloid dose and degree of hippocampal atrophy, we assessed the associations of continuous mean cortical amyloid level and hippocampal volume with cognitive performance among individuals with detectable amyloid pathology at baseline. Individuals with amyloidosis or hippocampal atrophy had steeper longitudinal declines in verbal episodic memory and learning compared to those with neither condition (A+N- versus A-N-: ß = - 0.069, P = 0.017; A-N+ versus A-N-: ß = - 0.081, P = 0.025). Among individuals with hippocampal atrophy, amyloid positivity was associated with steeper declines in verbal memory (ß = - 0.123, P = 0.015), visual memory (ß = - 0.121, P = 0.036), language (ß = - 0.144, P = 0.0004), and mental status (ß = - 0.242, P = 0.002). Similarly, among individuals with amyloidosis, hippocampal atrophy was associated with steeper declines in verbal memory (ß = - 0.135, P = 0.004), visual memory (ß = - 0.141, P = 0.010), language (ß = - 0.108, P = 0.006), and mental status (ß = - 0.165, P = 0.022). Presence of both amyloidosis and hippocampal atrophy was associated with greater declines than would be expected by their additive contributions in visual memory (ß = - 0.139, P = 0.036), language (ß = - 0.132, P = 0.005), and mental status (ß = - 0.170, P = 0.049). Neither amyloidosis nor hippocampal atrophy was predictive of declines in executive function, processing speed, or visuospatial ability. Among individuals with amyloidosis, higher baseline amyloid level was associated with lower concurrent visual memory, steeper declines in language, visuospatial ability, and mental status, whereas greater hippocampal atrophy was associated with steeper declines in category fluency. Our results suggest that both amyloid pathology and neurodegeneration have disadvantageous, in part synergistic, effects on prospective cognition. These cognitive effects are detectable early among cognitively normal individuals with amyloidosis, who are in preclinical stages of Alzheimer's disease according to research criteria. Our findings highlight the importance of early intervention to target both amyloidosis and atrophy to preserve cognitive function before further damage occurs.