Unique trans-kingdom microbiome structural and functional signatures predict cognitive decline in older adults.

The prevalence of age-related cognitive disorders/dementia is increasing, and effective prevention and treatment interventions are lacking due to an incomplete understanding of aging neuropathophysiology. Emerging evidence suggests that abnormalities in gut microbiome are linked with age-related cognitive decline and getting acceptance as one of the pillars of the Geroscience hypothesis. However, the potential clinical importance of gut microbiome abnormalities in predicting the risk of cognitive decline in older adults is unclear. Till now the majority of clinical studies were done using 16S rRNA sequencing which only accounts for analyzing bacterial abundance, while lacking an understanding of other crucial microbial kingdoms, such as viruses, fungi, archaea, and the functional profiling of the microbiome community. Utilizing data and samples of older adults with mild cognitive impairment (MCI; n = 23) and cognitively healthy controls (n = 25). Our whole-genome metagenomic sequencing revealed that the gut of older adults with MCI harbors a less diverse microbiome with a specific increase in total viruses and a decrease in bacterial abundance compared with controls. The virome, bacteriome, and microbial metabolic signatures were significantly distinct in subjects with MCI versus controls. Selected bacteriome signatures show high predictive potential of cognitive dysfunction than virome signatures while combining virome and metabolic signatures with bacteriome boosts the prediction power. Altogether, the results from our pilot study indicate that trans-kingdom microbiome signatures are significantly distinct in MCI gut compared with controls and may have utility for predicting the risk of developing cognitive decline and dementia- debilitating public health problems in older adults.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Study rationale and baseline data for pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's dementia (THC-AD).

Agitation is a common complication of Alzheimer's dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

Aducanumab: evidence from clinical trial data and controversies.

Alzheimer's disease (AD) is the most common cause for dementia worldwide. Until recently, all approved treatments for AD were symptomatic and not disease modifying. On 7 June 2021, the US FDA approved aducanumab, a human IgG1 anti-Aß monoclonal antibody selective for Aß aggregates, as the first disease-modifying treatment for AD. Aducanumab is approved in the United States for the treatment of mild cognitive impairment or mild-dementia stage of AD. In this Editorial, we review the trial data for aducanumab in the treatment of AD and the controversies that its approval has generated.

Integration of Health Information Technology and Promotion of Personhood in Family-Centered Dementia Care: Intervention Trial.

Alzheimer's disease and related dementias (ADRD) often result in communication deficits that can lead to negative health outcomes as well as complications for caregiving and clinical care. Although augmentative and alternative communication (AAC) devices have demonstrated efficacy in assisting persons living with dementia (PLWD) in communicating, few devices offer customization for the person's care preferences (e.g., clothing, food, activities) or are designed for integration into clinical care and caregiving. To address this issue, our research team is developing a novel electronic AAC prototype with a touchscreen to promote communication and personhood for PLWD. The current article describes the development of this technology and uses the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement to describe the clinical trial that is planned to test its efficacy. TARGETS: PLWD and their care partners. INTERVENTION DESCRIPTION: Use of AAC Plus to promote communication and personhood for PLWD. MECHANISMS OF ACTION: AAC Plus will provide PLWD and care partners a way to communicate PLWD's daily preferences and provide clinical data for health care providers. OUTCOMES: Determine whether enhanced communication of daily preferences of PLWD will improve quality of life of PLWD and their care partners. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04571502 (Date of registration October 1, 2020). [Research in Gerontological Nursing, 14(5), 225-234.].

Cannabinoids for Agitation in Alzheimer's Disease.

Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacologic options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to preclinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

Interventions to Enhance Empathy and Person-Centered Care for Individuals With Dementia: A Systematic Review.

Empathy, or the ability to imagine what someone else may be feeling or thinking, is a crucial component of meaningful care provision, including person-centered care (PCC), and has been shown to enhance care provider and patient well-being. The purpose of the current review was to examine the impact of interventions focused on improving the ability of health care providers or students to experience and/or communicate with empathy. Of 1,427 publications reviewed, 18 articles met inclusion criteria. All studies incorporated empathy or empathic communication competencies in their training or intended variables of change. PCC concepts were used in guiding the development of most interventions. Some interventions significantly improved participant empathy, attitudes toward patients with dementia, and certain verbal and nonverbal communication skills. Current study reports on improved positive interpersonal communication skills by nursing assistants are promising. Future study to improve therapeutic communication and delivery of dementia care with empathy using enhanced study design and measurement are needed. [Research in Gerontological Nursing, 13(3), 158-168.].

Effects of a combined transcranial magnetic stimulation (TMS) and cognitive training intervention in patients with Alzheimer's disease.

INTRODUCTION: This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy. METHODS: 131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini-Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double-blind, sham-controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale-cognitive (ADAS-Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC. RESULTS: Subjects with baseline ADAS-Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ -4 point improvement on ADAS-Cog versus 15.4% in the sham group. DISCUSSION: neuroAD™ Therapy System provides a low-risk therapeutic benefit for patients with milder AD (baseline ADAS-Cog ≤30) beyond pharmacologic SOC.

Use of Flutemetamol F 18-Labeled Positron Emission Tomography and Other Biomarkers to Assess Risk of Clinical Progression in Patients With Amnestic Mild Cognitive Impairment.

Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were ß-amyloid positive vs those who were ß-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Main Outcomes and Measures: Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive ß-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model. Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease.

INTRODUCTION: Performance of the amyloid tracer [18F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines). METHODS: After [18F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures. RESULTS: By SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with "original CERAD," 90.8% and 90.0% with "modified CERAD," and 85.7% and 100% with the 2012 NIA-AA criteria. DISCUSSION: The high accuracy of either CERAD criteria suggests that [18F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria.

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.

IMPORTANCE: Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE: To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS: In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS: A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. CONCLUSIONS AND RELEVANCE: In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01584440.

Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density.

IMPORTANCE: In vivo imaging of brain ß-amyloid, a hallmark of Alzheimer disease, may assist in the clinical assessment of suspected Alzheimer disease. OBJECTIVE: To determine the sensitivity and specificity of positron emission tomography imaging with flutemetamol injection labeled with radioactive fluorine 18 to detect ß-amyloid in the brain using neuropathologically determined neuritic plaque levels as the standard of truth. DESIGN, SETTING, AND PARTICIPANTS: Open-label multicenter imaging study that took place at dementia clinics, memory centers, and hospice centers in the United States and England from June 22, 2010, to November 23, 2011. Participants included terminally ill patients who were 55 years or older with a life expectancy of less than 1 year. INTERVENTIONS: Flutemetamol injection labeled with radioactive fluorine 18 (Vizamyl; GE Healthcare) administration followed by positron emission tomography imaging and subsequent brain donation. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of flutemetamol injection labeled with radioactive fluorine 18 positron emission tomography imaging for brain ß-amyloid. Images were reviewed without and with computed tomography scans and classified as positive or negative for ß-amyloid by 5 readers who were blind to patient information. In patients who died, neuropathologically determined neuritic plaque levels were used to confirm scan interpretations and determine sensitivity and specificity. RESULTS: Of 176 patients with evaluable images, 68 patients (38%) died during the study, were autopsied, and had neuritic plaque levels determined; 25 brains (37%) were ß-amyloid negative; and 43 brains (63%) were ß-amyloid positive. Imaging was performed a mean of 3.5 months (range, 0 to 13 months) before death. Sensitivity without computed tomography was 81% to 93% (median, 88%). Median specificity was 88%, with 4 of 5 of the readers having specificity greater than 80%. When scans were interpreted with computed tomography images, sensitivity and specificity improved for most readers but the differences were not significant. The area under the receiver operating curve was 0.90. There were no clinically meaningful findings in safety parameters. CONCLUSIONS AND RELEVANCE: This study showed that flutemetamol injection labeled with radioactive fluorine 18 was safe and had high sensitivity and specificity in an end-of-life population. In vivo detection of brain ß-amyloid plaque density may increase diagnostic accuracy in cognitively impaired patients.

Detection of Amyloid ß Signature in the Lens and Its Correlation in the Brain to Aid in the Diagnosis of Alzheimer's Disease.

We report the findings from a clinical trial in which a group of patients clinically diagnosed with probable Alzheimer's disease (AD) were discriminated from an age-matched group of healthy volunteers (HVs) with statistical significance (P<.001). The results from 20 patients with AD and 20 HVs were obtained by a Fluorescent Ligand Eye Scanning (FLES) technique that measures a fluorescent signature specific to an exogenous ligand bound to amyloid-ß in the lens of the eye. Sensitivity and specificity of 85% and 95%, respectively, have been achieved in predicting clinical diagnosis. Additionally, amyloid brain imaging using florbetapir F18 positron emission tomography shows significant correlation with the results obtained in the eye. Results of the study demonstrate the safety of the FLES system.

From Cicero to Cohen: developmental theories of aging, from antiquity to the present.

Cicero's famous essay "On Old Age," written in ancient Rome, was one of the first detailed depictions of the challenges and opportunities posed by the aging process. Several modern developmental theories of the life cycle have echoed many of the themes of Cicero, including the existence of unfolding life stages with specific tasks and transitions. Freud's psychoanalytic theory of infantile sexuality provided a limited starting point, as well as a theoretical base for Erik Erikson's proposed eight stages of the life cycle. Unlike Freud, however, Erikson and others including Daniel Levinson, George Vaillant, and Carol Gilligan elaborated on forces in adult development that were distinct from early life experiences. Gene Cohen's theory of human potential phases took middle age as a starting point and proposed an extensive structure for late-life development based on emergent strengths including wisdom and creativity.

The effect of an aloe polymannose multinutrient complex on cognitive and immune functioning in Alzheimer's disease.

Alzheimer's disease (AD) is a leading killer of Americans, imparts a significant toll on the quality of life of the patient and primary caregiver, and results in inordinate costs in an already overburdened medical system. Prior studies on cholinesterase inhibitors among AD patients have shown minimal amelioration of disease symptoms and/or restoration of lost cognitive functioning. The effect of improved nutrition, particularly with dietary supplements, on cognitive functioning may offer an alternative strategy compared to standard treatment. The present pilot study investigated the effect of an aloe polymannose multinutrient complex (APMC) formula on cognitive and immune functioning over 12 months among adults diagnosed with AD. Subjects participated in an open-label trial and consumed 4 teaspoons per day of the APMC. The ADAS-cog, MMSE, ADCS-ADL, and SIB were administered at baseline and 3, 6, 9, and 12 months follow-up. Cytokines and lymphocyte and monocyte subsets were assessed at baseline and 12 months. The mean ADAS-cog cognition score significantly improved at 9 and 12 months from baseline, and 46% of our sample showed clinically-significant improvement (≥4-point change) from baseline to 12 months. Participants showed significant decreases in tumor necrosis factor-α, vascular endothelial growth factor, and interleukins-2 and-4. CD90+, CD95+CD3+, CD95+CD34+, CD95+CD90+, CD14+CD34+, CD14+CD90+, and CD14+CD95+ decreased significantly, whereas CD14+ significantly increased. Participants tolerated the APMC supplement with few, temporary adverse reactions. Our results showed improvements in both clinical and physiological outcomes for a disease that otherwise has no standard ameliorative remedy.

Group therapy in older adults.

Group therapy is a well-established therapeutic modality for older individuals often conducted in combination with individual psychotherapy and pharmacotherapy. Group leaders must be aware of age-specific factors when working with older cohorts, including the presence of cognitive impairment, physical disability, and loss of independence. A limited number of outcome studies have found that various forms of group therapy in late life are generally efficacious for depression and other symptoms and compare favorably with individual psychotherapy.