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INTRODUCTION: This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early‐stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well‐established measures. METHODS: For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. RESULTS: Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test‐retest reliability) and stronger associations with AD‐related demographic, genetic, and brain risk markers than well‐established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early‐stage AD clinical trials. Highlights: Well‐established cognitive tests may not accurately detect subtle cognitive changes.No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties.NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains.Novel measures had better psychometric properties compared to established measures.Significant associations with Alzheimer's disease biomarkers were found with novel measures. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The effects of sleep–wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR). METHODS: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis. RESULTS: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep‐related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93). DISCUSSION: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below‐mean CR. Therefore, improving sleep–wake regulation and leisure activities may protect against fatigability and cognitive decline. Highlights: Clinical fatigue and fatigability cannot be alleviated by rest.Clinical fatigability disrupts daily activities during preclinical Alzheimer's.High cognitive reserve mitigates sleep–wake disturbance effects.High cognitive reserve attenuates clinical fatigability effects on daily functioning.Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain. [ABSTRACT FROM AUTHOR]

Background: The pathology of Alzheimer's disease (AD) is characterized by two types of proteins: intracellular neurofibrillary tau tangles and extracellular β‐amyloid (Aβ) plaques. In the present observational studies, spatial discrepancies between these two proteins across the brain regions are well‐documented. However, the association between these two proteins remains elusive in different stages of depositions. Methods: We aimed to investigate the remote association between tau and Aβ uptakes by using 572 elderlies 67.11 ± 6.08 (476 healthy control (HC) and 96 mild cognitive impairments (MCI)) Aβ and tau positron emission tomography (PET) scans. We leveraged 47 tau‐PET and 97 Aβ‐PET scans of healthy young individuals (aged 20‐40) to find the regional cut‐points for 68 cortical regions in the brain. Then by using these cut‐points and tau PET scans of all elderly individuals, we identified four groups of individuals (no tau phase, pre‐acceleration phase, acceleration phase, and post‐acceleration phase) (Table 1). Finally, a regional multiple linear regression model is performed for each group to detect the hubs region based on the remote association between each target region of tau and all other regions Aβ in the different phases of tau accumulations (controlling for gender, age, intracranial volume, and each target region Aβ). Results: First, we show that the left and right entorhinal cortex, and right parahippocampal tau are the hubs of remote association with Aβ in several cortical regions (especially temporal regions) in the early stage of aggregation (Figure 1). Second, we identify tau in the same regions, continuing to demonstrate the highest remote associations with cortical Aβ (Figure 2) in the acceleration phase. Conclusion: The remote association appears in medial temporal lobe (MTL) tau during the early stage, as well as the later stage of tau accumulation (pre‐acceleration and acceleration phases). While the cellular mechanism of remote association is still elusive, in vivo studies have demonstrated that the Aβ triggers tau deposition indirectly in distal regions. Understanding the association between tau and Aβ at the preclinical stage of AD is critically important for a better consideration of tau spreading, especially in disease‐related brain regions. [ABSTRACT FROM AUTHOR]

Introduction: Mild to moderate exercise may decrease Alzheimer's disease (AD) risk, but the effects of vigorous, regular physical exercise remain unclear. Methods: Two patients with initial diagnoses of amnestic mild cognitive impairment (MCI) demonstrated positive AD biomarkers throughout 16 and 8 years of follow‐up, with final diagnoses of mild AD and amnestic MCI, respectively. Results: Patient 1 was diagnosed with amnestic MCI at age 64. Neuropsychological testing, magnetic resonance imaging (MRI), fluorodeoxyglucose–positron emission tomography (FDG‐PET), amyloid imaging PET, and cerebrospinal fluid (CSF) biomarkers during follow‐ups remained consistent with AD. By age 80, progression was minimal with Montreal Cognitive Assessment (MoCA) 26 of 30. Patient 2 was diagnosed with amnestic MCI at age 72. Neuropsychological testing, MRI, FDG‐PET, and amyloid imaging PET during follow‐ups remained consistent with AD. At age 80, MoCA was 27 of 30 with no clinical progression. Both patients regularly performed vigorous, regular exercise that increased after retirement/work reduction. Discussion: Vigorous, regular exercise may slow disease progression in biomarker‐positive amnestic MCI and mild AD. [ABSTRACT FROM AUTHOR]

Background: Odor identification deficits predict transition to dementia, whereas intact odor identification and global cognition may identify lack of transition. The purpose of this study is to examine intact odor identification and global cognitive functioning as prognostic indicators of lack of transition to dementia in a well‐characterized biracial (Black and White) cohort. Method: In a community‐dwelling sample of 2,270 older adults without dementia participating in the Health, Aging, and Body Composition (Health ABC) study, odor identification was measured using the Cross‐Cultural Smell Identification Test (BSIT) and global cognition was measured using the Teng Modified Mini‐Mental Status Examination (3MS), both in Year 3. Incident dementia was defined by diagnosis in medical/hospital records or prescription of anti‐Alzheimer's disease medications. Survival analyses for dementia transition over 4 years and 8 years were conducted using Cox proportional‐hazards models. Result: Survival analyses adjusted for demographic and medical covariates indicated that impaired odor identification (hazard ratio [HR] = 2.17, 95% confidence interval [CI] = 1.5‐3.1) and global cognition (HR = 2.75, 95% CI = 1.8‐4.3) each independently predicted transition to dementia (n = 287). Odor identification interacted with ApoE genotype, such that the effect of impaired odor identification on dementia transition risk was significantly greater in ApoE e4 carriers (HR = 4.0) than noncarriers (HR = 1.6). This interaction was significant for White participants, though not for Black participants. Among participants with intact odor identification (BSIT ≥ 11/12 correct) and global cognition (3MS ≥ 77/100 correct), 6.4% (49/765) transitioned to dementia over 8 years of follow‐up. Only 0.9% (4/451) of participants aged 70–75 with intact performance on both measures transitioned to dementia over 4 years of follow‐up. Conclusion: Odor identification testing paired with global cognitive screening identified individuals at low risk for transition to dementia in a biracial community cohort with this decrease in risk being pronounced in the seventh to eighth decade of life. Identification of such individuals can obviate the need for extensive investigation to establish a diagnosis and has potential for screening participants for clinical trials. [ABSTRACT FROM AUTHOR]

Importance: Understanding associations of Alzheimer disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) may have implications for diagnosis and management.Objective: To evaluate ADRD neuropathological diagnoses and NPS without consideration of clinical diagnosis.Design, Setting, and Participants: This retrospective cohort study evaluated 1808 brains from 39 sites in the US National Alzheimer Coordinating Center v. 10 collection for participants among whom the Neuropsychiatric Inventory Questionnaire (NPIQ) was administered annually. Brain autopsy diagnoses of AD, Lewy body disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration, cerebrovascular disease, hippocampal sclerosis, and no known pathology were examined. Autopsy data collected from January 2012 to January 2018 were deidentified and compiled into the publicly available v. 10 database. Data were analyzed from February 2021 to August 2021.Main Outcomes and Measures: The primary outcome was NPIQ domain score, if present at any time point, and mean NPIQ domain score during follow-up was secondary. Associations of ADRD diagnoses with 12 NPIQ symptom domains were examined in regression analyses, correcting for multiple comparisons.Results: The study sample of 1808 adults had a mean (SD) age of 80.0 (11.0) years, and 987 participants (54.6%) were male. Apathy was the most prevalent NPS, reaching 80% (203 of 254 individuals) in those with hippocampal sclerosis. Cerebrovascular disease showed few NPS associations. Frontotemporal lobar degeneration was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared with AD. Hippocampal sclerosis was associated with increased apathy (odds ratio, 2.60; 95% CI; 1.86-3.66, false discovery rate controlled P < .001) and disinhibition (odds ratio, 2.15; 95% CI, 1.63-2.84; false discovery rate controlled P < .001). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was consistently associated with increased NPS (eg, LBD was associated with an increase in hallucinations from brain stem [β, 0.23; 95% CI, 0.07-0.76; P = .02] to limbic [β, 1.69; 95% CI, 1.27-2.27; P < .001] to neocortical [β, 4.49; 95% CI, 3.27-6.16; P < .001] pathology). Hallucinations were more common in participants with AD and LBD (168 of 534 [31.5%]) compared with those with AD without LBD (152 of 704 [21.6%]) and those with LBD without AD (23 of 119 [19.6%]).Conclusions and Relevance: In this cohort study of 1808 brains from the US National Alzheimer Coordinating Center, patients with LBD and AD showed a higher prevalence of hallucinations compared with those with LBD without AD. Neuropsychiatric symptom criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported in this study. In hippocampal sclerosis, the findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was associated with NPS severity, indicating that NPS may reflect underlying ADRD pathology and highlighting the importance of diagnosing and treating NPS. [ABSTRACT FROM AUTHOR]

Patients with dementia can experience hallucinations and delusions because of their underlying neurodegenerative condition, a syndrome known as dementia-related psychosis. Dementia-related psychosis contributes to morbidity and mortality among patients with dementia and increases the burden on caregivers and the health care system. With no pharmacological treatment currently approved in the United States for this condition, patients are often treated off-label with antipsychotics. Though typical and atypical antipsychotics have demonstrated variable to modest efficacy in dementia-related psychosis, serious safety concerns arise with their use. Accordingly, clinical and Centers for Medicare & Medicaid Services guidelines recommend trying antipsychotics only when other therapies have failed and encourage treatment discontinuation of antipsychotics after 4 months to assess whether ongoing therapy is needed. Discontinuation of effective antipsychotic treatment, however, may increase the risk for relapse of symptoms and the associated morbidities that accompany relapse. A randomized medication withdrawal clinical trial design allows assessment of relapse risk after discontinuation and can provide initial information on longer-term safety of therapy for dementia-related psychosis. Given the substantial unmet need in this condition, new, well-tolerated therapies that offer acute and sustained reduction of symptoms while also preventing recurrence of symptoms of psychosis are critically needed. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in MCI is unclear. Method: In a two‐site, single‐blinded, 78‐week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home‐based, computerized training with Web‐based cognitive games or Web‐based crossword puzzles, followed by six booster sessions. In mixed‐model analyses, the primary outcome was change from baseline in the 11‐item Alzheimer's Disease Assessment Scale‐Cognitive (ADAS‐Cog) score, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score and Functional Activities Questionnaire score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed. Result: Among 107 participants (n = 51 [games]; n = 56 [crosswords]), ADAS‐Cog11 score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, 21.44; 95% CI 22.83 to 20.06; P = 0.04). From baseline to week 78, mean ADAS‐Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, 22.45; SE, 0.89; 95% CI 24.21 to 20.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, 21.08; 95% CI 21.97 to 20.18, p = 0.02). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI 0.51 to 67.63, p <.05 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04, p =.02 [cortical thickness]). Conclusion: Home‐based computerized training with crosswords demonstrated superior efficacy to games at 78 weeks. Common directionality was observed in the primary outcome of ADAS‐Cog (cognition) and the secondary outcomes of FAQ (function) score and changes in MRI hippocampal volume and cortical thickness (neurodegeneration). If these effects are replicated and expanded in future trials with the inclusion of a control group that does not receive cognitive training, crossword puzzles training could become a home‐based, scalable, cognitive enhancement tool for individuals with MCI. [ABSTRACT FROM AUTHOR]

Background: Human neuroimaging efforts to understand the pathophysiology of Alzheimer's disease (AD) have solely focused on the amyloid‐beta (Aβ) deposition and tau neurofibrillary tangle formation. Until recently, the idea of a connectivity‐based molecular functional framework for understanding AD pathophysiology was missing, which eluded researchers from connecting functional connectivity (FC) with Aβ/Tau deposition. Method: The initial dataset includes 631 older (67.44 ± 6.48 years) adults (521 healthy controls and 110 mild cognitive impairment (MCI)) who have been imaged for Tau pathology as well as resting‐state functional magnetic resonance imaging (rsfMRI) and structural MRI scans. Using Schaefer's 200 parcellation atlas and a regional cutoff (SUVR = 1.25), we identified four groups of tau staging based on the number of regions having higher than cutoff tau SUVR (no tau stage (N = 193), pre‐acceleration stage (N = 222), acceleration stage (N = 149), and post‐acceleration stage (N = 67)). Since the entorhinal cortex (EC) is widely regarded as the epi‐center for tau accumulation, the left and right EC time series were derived from rsfMRI data using the Desikan‐Killiany atlas and used as seed regions for our Pearson correlation coefficient based functional connectivity analysis with all 200 regions in the Schaefer atlas. Finally, linear regression models were run to predict the mean regional accumulation of tau based on the strength of mean FC between that region and EC. Result: As shown in Fig. 1, left/right EC functional connectivity is strongly associated with the accumulation of tau in that region during the pre‐acceleration phase (left: t = 3.586, p < 0.0004; right: t = 4.404, p < 0.0001) and in the acceleration phase (left: t = 6.229, p < 0.0001; right: t = 7.577, p < 0.0001) (results not shown). The functional connectivity values from left/right EC for the pre‐acceleration phase are plotted on the surface of the brain, as shown in Fig. 2. Conclusion: Our results provide evidence of the role of functional connectivity in tau spreading from EC to the rest of the brain and can help throw light on the dynamic patterns of tau spreading in MCI/AD subjects in different disease stages. [ABSTRACT FROM AUTHOR]

Importance: People with schizophrenia are at high risk of receiving a diagnosis of dementia. Understanding the magnitude and timing of this increased risk has important implications for practice and policy.Objective: To estimate the age-specific incidence and prevalence of dementia diagnoses among older US adults with schizophrenia and in a comparison group without serious mental illness (SMI).Design, Setting, and Participants: This retrospective cohort study used a 50% random national sample of Medicare beneficiaries 66 years or older with fee-for-service plans and Part D prescription drug coverage from January 1, 2007, to December 31, 2017. The cohort with schizophrenia included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying years. The comparison group included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Data were analyzed from January 1 to July 31, 2020.Main Outcomes and Measures: Dementia was defined using the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse diagnosis codes for Alzheimer disease and related disorders or senile dementia. Incident diagnoses were defined by at least 12 consecutive eligible months without a qualifying code before meeting dementia criteria.Results: The study population of 8 011 773 adults 66 years or older (63.4% women; mean [SD] age, 74.0 [8.2] years) included 74 170 individuals with a diagnosis of schizophrenia (56.6% women) and 7 937 603 without an SMI diagnosis (63.5% women) who contributed 336 814 and 55 499 543 person-years of follow-up, respectively. At 66 years of age, the prevalence of diagnosed dementia was 27.9% (17 640 of 63 287) among individuals with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI. The annual incidence of dementia diagnoses per 1000 person-years at 66 years of age was 52.5 (95% CI, 50.1-54.9) among individuals with schizophrenia and 4.5 (95% CI, 4.4-4.6) among individuals without SMI and increased to 216.2 (95% CI, 179.9-252.6) and 32.3 (95% CI, 32.0-32.6), respectively, by 80 years of age.Conclusions and Relevance: In this cohort study, compared with older adults without SMI, those with schizophrenia had increased risk of receiving a diagnosis of dementia across a wide age range, possibly because of cognitive and functional deterioration related to schizophrenia or factors contributing to other types of dementia. High rates of dementia among adults with schizophrenia have implications for the course of illness, treatment, and service use. [ABSTRACT FROM AUTHOR]

Background: Neural networks are increasingly being applied towards neuroimaging problems in AD, but performance is often limited by lack of adequate numbers of samples. This is commonly alleviated by pre‐training the model on a related task beforehand (i.e. 'transfer learning'). To our knowledge, there exists no set/standard of widely available pretrained model weights for 3D medical images. Tau PET radiotracers such as AV‐1451 and MK‐6240 have highly similar binding patterns, and so may be well suited to transfer learning tasks. Method: Subjects with AV‐1451 scans (n=446) were downloaded from ADNI, while subjects with MK‐6240 scans (n= 320) were pooled from multiple studies recruiting at CUIMC. We trained multiple 3D neural networks (all with the same modified InceptionV3 architecture) to differentiate patients (i.e. MCI/AD) from controls based on their tau PET scan, both with and without pretraining information from prior training iterations of our models. We compare performance on holdout sets for each validation fold (n= 64 for MK‐6240 and n=89 for AV‐1451) using DeLong's test for ROC curves and analyze features learned by models with t‐SNE plots. Result: The AV‐1451 Model pretrained on MK‐6240 scans had superior performance to the AV‐1451 model not using pretraining (AUC = 0.74 vs. 0.91, Z = ‐5.5, p < 0.0001), whereas there was no significant difference with pretraining for MK‐6240 models (AUC = 0.84 vs. 0.83, Z = 0.47 ,p = 0.6). Visually, there appears to be greater separation in model learned features following pretraining in the AV‐1451 model. Conclusion: 3D pretraining for neural networks involving PET imaging could be accomplished with related but structurally different radioligands, though more work is needed into determining why certain pretraining experiments are successful. This procedure can enable better training of complex models with fewer constraints due to sample size. [ABSTRACT FROM AUTHOR]

Introduction: Odor identification deficits characterize Alzheimer's disease and other dementias. We examined if intact performance on brief cognitive and odor identification tests predicts lack of transition to dementia. Methods: In an urban community, 1037 older adults without dementia completed the 40‐item University of Pennsylvania Smell Identification Test, which includes the 12‐item Brief Smell Identification Test (B‐SIT). Data from 749 participants followed up for 4 years were analyzed. Results: In covariate‐adjusted survival analyses, impairment on the Blessed Orientation Memory Concentration Test and B‐SIT each predicted dementia (n = 109), primarily Alzheimer's disease (n = 101). Among participants with intact olfactory (B‐SIT ≥ 11/12 correct) and cognitive (Blessed Orientation Memory Concentration Test ≤ 5/28 incorrect) ability, 3.4% (4/117) transitioned to dementia during follow‐up with no transitions in the 70‐75 and 81‐83 years age group quartiles. Discussion: Odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S‐CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. Methods: S‐CitAD is a NIH‐funded, investigator‐initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study ‐ Clinical Global Impression of Change (mADCS‐CGIC). Discussion: S‐CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S‐CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846). [ABSTRACT FROM AUTHOR]

Background: The association between sleep quality and cognition is widely established but the role of aging in this relationship has been unclear due to inconsistent findings with heterogeneous methods and a lack of studies in wide age ranges. The current study examined how age impacts the sleep‐cognition relationship using a large‐scale dataset with adults from young adulthood to older adulthood. Furthermore, we tested non‐linear effect of age to investigate the presence of age ranges in which the association between sleep and cognition is modified. Method: Sample included 711 individuals (ages 36.00‐89.83, 59.66 ± 14.91, 55.7% female) from the Human Connectome Project‐Aging (HCP‐A). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI), and cognitive outcome measures included the NIH Toolbox fluid cognition (Dimensional change Card Sort Test, List Sorting Working Memory Test, Picture Sequence Memory Test, Pattern comparison Processing Speed Test, Flanker Inhibitory Control and Attention Test) and crystallized cognition composite scores (Oral Reading Recognition Test and Picture Vocabulary Test), the Trail Making Test (TMT) A and B, and the Rey Auditory Verbal Learning Test (RAVLT). The association between sleep quality and cognitive performance was measured using linear regression models, with sex, race, use of sleep medication, and years of education as covariates. Age moderation was tested via the interaction between sleep and age on cognition, with age as linear and non‐linear (quadratic) terms. Result: There was a significant interaction term between the PSQI and non‐linear age term (age2) on TMT‐B (p = 0.02) and NIH Toolbox crystallized cognition (p = 0.02), indicating that the association between poor sleep quality and cognitive performance was moderated by age. Further analyses indicated that there were "critical age ranges" in which the sleep‐cognition association was more salient (ages 50‐75 for TMT‐B and 66‐70 for crystallized cognition). Conclusion: The association between sleep quality and cognitive performance may be modified by age. Individuals of the middle‐age to early older adulthood may be more vulnerable to sleep‐related cognitive impairment, indicating the clinical importance of detection and treatment of sleep disturbance in this particular age group. [ABSTRACT FROM AUTHOR]

Objective: Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment.Methods: A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire).Results: Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo.Conclusion: The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses. [ABSTRACT FROM AUTHOR]

Background: Pimavanserin was investigated for the treatment of dementia‐related psychosis (DRP) in HARMONY (NCT03325556), a phase 3 randomized discontinuation study. As the study met the primary endpoint (one‐sided P = 0.0023), we evaluated the consistency of the efficacy for reducing the risk of relapse in the largest dementia patient subgroup (ie, Alzheimer's dementia psychosis [ADP] patients) treated with pimavanserin 34mg. Method: Enrolled DRP patients (N = 392) entered the 12‐week open‐label (OL) period and received pimavanserin 34mg daily. During weeks 1‐4, dose could be adjusted to 20mg at investigator discretion. Patients meeting prespecified response criteria at weeks 8 and 12 were randomized to continue pimavanserin or receive placebo for up to 26 weeks in the double‐blind (DB) period. The primary endpoint was time from randomization to adjudicated relapse. Efficacy analyses included patients at the interim analysis (IA); safety analyses included all dosed patients. Result: Of 260 ADP patients, 243 stayed on pimavanserin 34mg throughout the OL period; 17 patients received pimavanserin 20mg beyond OL week 4. At baseline, mean age in the pimavanserin 34mg group was 75.7 years; mean MMSE score was 16.0. Twenty‐nine patients were terminated with sponsor termination of the study; of the remaining 214 patients, 130 (60.7%) met response criteria at weeks 8 and 12 and were randomized. At the IA, 116 ADP patients were randomized to pimavanserin 34mg (N = 57) or placebo (N = 59). Hazard ratio for psychosis relapse risk with pimavanserin 34mg versus placebo was 0.466 (95% CI: 0.179, 1.214); 6/57 (10.5%) pimavanserin‐treated and 14/59 (23.7%) placebo‐treated patients met relapse criteria. Treatment‐emergent adverse events incidence rates were: OL, 29.6% (72/243); DB‐pimavanserin 34mg, 39.7% (25/63); DB‐placebo, 34.3% (23/67). Pimavanserin did not have a negative effect on Mini‐Mental State Examination or Extrapyramidal Symptom Rating Scale‐Abbreviated score change from baseline versus placebo in the DB period. Conclusion: In a study that met its primary endpoint, a post‐hoc subgroup analysis in ADP, although not statistically significant, demonstrated a clinically meaningful reduction in the risk of relapse was observed in patients treated with pimavanserin 34mg versus placebo. Pimavanserin was not associated with an adverse impact on cognition or motor function. [ABSTRACT FROM AUTHOR]

Background: The No Practice Effects (NPE) battery is a novel set of neuropsychological measures designed to assess important cognitive domains and have robust psychometric properties for use in preclinical and early‐stage Alzheimer's disease clinical trials. The current study used exploratory factor analysis to examine cognitive domains in the NPE battery. We further examined the association between identified cognitive domains with demographic characteristics, brain imaging metrics, and genetic risk markers for Alzheimer's disease. Methods: A total of 116 older adults who are cognitively healthy or have early mild cognitive impairment (eMCI) (mean age 70.35 ± 6.53, 62.9% women) and have baseline cognitive assessments were included. The NPE battery contains seven primarily computerized tests of memory and attention. We conducted an exploratory factor analysis using an oblique rotation to identify different cognitive domains within the NPE, then composite scores were calculated for each domain. Simple correlation analyses were conducted to examine the association between these composite scores and demographic characteristics. The multiple regression analyses were performed to examine the association between composite scores and AD risk markers. Results: The exploratory factor analysis produced three factors within the NPE battery corresponding to 1) Cognitive Control/Executive Functions (including Letter and Category Verbal Fluency, Brown‐Peterson Paradigm, Digit Symbol Substitution Test, Letter‐Number Span, and N‐Back); 2) Response Monitoring (Recognition Memory Test [RMT] learning and correctly rejected recognition items) reflecting encoding process and post‐recollection cognitive monitoring; and 3) Recall/Retention (RMT total recall and hits on recognition items) that may be considered a "memory consolidation" factor. Greater performance on Response Monitoring was associated with younger age (r2 = ‐0.27, P = 0.004), higher education level (r2 = 0.29, P = 0.002), and APOE4 genotype (B = ‐0.27, SE = 0.13, P = 0.04). Recall/Retention was positively associated with the thickness of the entorhinal cortex (B = 0.58, SE = 0.28, P = 0.04), but not hippocampal or parahippocampal volumes. The general composite score encompassing all tests was associated with age (r2 = ‐0.29, P = 0.002), education (0.28, P = 0.003), and APOE4 (B = ‐0.25, SE = 0.10, P = 0.01). Conclusion: These results provide preliminary evidence that the NPE battery identifies domains characteristic of cognition. These cognitive domains were associated with demographic factors, such as age and education, along with APOE4 genotype, and brain structural measures. [ABSTRACT FROM AUTHOR]

Background: There is no consensus in the field regarding the relationship between AD pathologies (Aβ, and Tau) and neurodegeneration. One reason that may contribute to this disagreement is the definition of cut‐point to categorize participants with or without significant pathologies. This approach overlooks an important early stage of pathological accumulation. In this study, we take advantage of Florbetaben/MK6240 PET scans from 61/21 young (<40) and healthy participants to redefined the cut‐point of Aβ/Tau uptake and investigate their association with cortical thickness as a measurement of neurodegeneration. Method: To capture the early effect of pathologies, we quantify global pathologies by averaging AD‐related regions uptake; global Aβ: frontal, parietal, temporal, anterior and posterior cingulate, and precuneus, global Tau: fusiform, amygdala, parahippocampal, entorhinal, inferior temporal, middle temporal, and medial temporal lobe (MTL) Tau: entorhinal and parahippocampal. We redefied the cut‐point of AD pathologies using 95% percentile of the fitted normal distribution to the young subject's uptakes. Using newly defined cut‐points (1.01

Background: The utility of functional deficits in patients with mild cognitive impairment is not established.Materials and Methods: In 3886 individuals with mild cognitive impairment evaluated and followed at 34 National Alzheimer Coordinating Center sites, informant-reported Pfeffer Functional Activities Questionnaire (FAQ) items associated with progression to dementia were derived in a training set (n=1943) and tested in the validation set (n=1943).Results: In the training set, the optimal combination comprised 6 FAQ items (FAQ6): difficulties with finances (2 items), remembering events/appointments, playing games of skill, current events, and travel. In the validation set, hazard ratio for dementia increased from 2.00 for 1 FAQ6 deficit to 5.56 for 6 FAQ6 deficits. In patients 50 to 67 years old with high Mini Mental State Exam scores, dementia risk rose from 12.06% for no FAQ6 deficits to 56.75% for 6 functional deficits. Likelihood of progression to dementia reached 80% to 89% in older age groups with low Mini Mental State Exam and severe FAQ6 deficits.Conclusions: Specific functional deficits increased dementia risk and, with age and global cognition, constituted a validated clinical algorithm to estimate dementia risk. Clinicians can use this clinically important algorithm to personalize decision-making about further investigation and identify high-risk patients for early treatment or inclusion in clinical trials. [ABSTRACT FROM AUTHOR]

Background: The associations of Alzheimer's disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) is not well‐established. Method: This retrospective cohort study used 1,808 brains from 39 sites in the National Alzheimer's Coordinating Center (NACC) V.10 collection for participants with the Neuropsychiatric Interview‐Questionnaire (NPI‐Q) administered annually and without consideration of clinical diagnosis. Brain autopsy diagnoses of AD, Lewy Body Disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration (FTLD), cerebrovascular disease (CVD), hippocampal sclerosis, and "no known pathology" were examined. NPI‐Q domain score if present at any timepoint was the primary outcome and average NPI‐Q domain score during follow‐up was secondary. The associations of ADRD diagnoses with twelve NPI‐Q symptom domains were examined in regression analyses, correcting for multiple comparisons. Result: The study sample of 1,808 adults had a mean [SD] age 80.0 [11.0] years and 54.6% were male. Apathy was the most prevalent NPS, reaching 80% in hippocampal sclerosis. CVD showed few NPS associations. FTLD was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared to AD. Hippocampal sclerosis was associated with increased apathy (OR 2.60, 95%CI 1.86‐3.66, pfdr<.05) and disinhibition (OR 2.15, 95% CI 1.63‐2.84, pfdr<.05). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was associated consistently with increased NPS, e.g., LBD showed increase in hallucinations from brainstem (β=0.23, 95% CI 0.07‐0.76, p<.05) to limbic (β=1.69, 95% CI 1.27‐2.27, p<.01) to neocortical (β=4.49, 95% CI 3.27‐6.16, p<.001) pathology. Hallucinations were more common in participants with AD+LBD (168/534=31.5%) compared to AD without LBD (152/704=21.6%) and LBD without AD (23/119=19.6%). Conclusion: Visual hallucinations may characterize LBD with AD more than LBD without AD. NPS criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported. In hippocampal sclerosis, the novel findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was related to NPS severity, indicating that NPS reflect underlying ADRD pathology and highlight the importance of diagnosing and treating NPS. [ABSTRACT FROM AUTHOR]

Background: We examined the association between sleep health consequences and perceived fatigability within the context of carrying out everyday activities in non‐demented older adults and investigated whether cognitive reserve (CR; individual differences in susceptibility to cognitive decline due to brain aging, pathology, or insult) moderated this relationship. Method: This was a cross‐sectional study. We prospectively screened adults age 55‐90 years at a Memory Research Clinic. An IRB approved the study protocol, and informed consent was obtained. Patients with cognitive concerns underwent neurocognitive testing to determine cognitive status based on the ADNI criteria. Inclusion criteria: the ADNI criteria for cognitively normal or MCI. Exclusion criteria: 1) depression assessed with the Geriatric Depression Scale (GDS>5) and DSM‐5 criteria, 2) history of primary psychiatric illnesses, 3) medical conditions associated with fatigue, and 4) a history of obstructive sleep apnea diagnosed by a clinical sleep physician. Measures included the PROMIS Sleep‐related Impairment (SRI); the Neuro‐QOL Cognitive function (CogF) and Fatigue measure, which yields "fatigue symptom severity (Fat_Sx)" and "perceived fatigability (Fatiga)" subscales. CR was assessed with the CR Index questionnaire (CRIq). Linear regression models were fit to the fatigue outcomes and included the SRI, CR, and their interaction as predictors. If the interaction was significant, SRI slopes were assessed at CR=mean and mean ±1SD. All analyses were adjusted for age, sex, and education. Result: There were 37 subjects in this study; mean age of 70.8 years (SD=9.3); 70.3% subjects were female; 86.5% white, 10.8% Hispanic, and 2.7% others. CR significantly moderated the relationship between SRI and perceived fatigability (F (1,32)=18.64, p=0.011). A higher SRI score was associated with a higher perceived fatigability severity with a low CR (CRIq mean‐1SD)=108.6; b(se)=.493(.089), p<0.001) and a mean CR (CRIq mean=128.0; b(se)=.274(.076); p=0.001), but not a high CR (CRIg mean+1SD=147.4; b(se)=0.1278; p=0.636). Moreover, higher perceived fatigability was associated with lower cognitive function (b(se)=‐.24 2(0.077), p=0.004), controlling for age, gender, and education. Conclusion: Poorer cognitive function was significantly associated with greater fatigability within the context of managing everyday activities. Greater cognitive reserve may reduce the detrimental influence of poor sleep health on perceived fatigability in managing daily function during the preclinical stages of dementia. [ABSTRACT FROM AUTHOR]

Background: There is limited information on the impact of specific neuropathologies on neuropsychiatric symptoms (NPS). We evaluated the impact of neuropathologically defined subtypes of Alzheimer's Disease and Related Dementias (ADRD) on neuropsychiatric symptoms (NPS) during life. Method: The study design used a direct and unbiased approach that did not consider clinical diagnoses and included all brains with neuropathological diagnoses in the V.10 collection of the National Alzheimer's Coordinating Center (NACC) database that also had Neuropsychiatric Interview‐Questionnaire (NPI‐Q) data collected during life. Data from 1,808 patients from 39 sites were examined. We utilized pairwise, ordinal and multiple logistic regression analyses to assess the effects of 8 neuropathological diagnoses on 12 domains in the Neuropsychiatric Inventory Questionnaire (NPI‐Q), correcting for multiple statistical comparisons. For NPS, average NPI‐Q domain scores during annual follow‐ups was the primary measure and NPI‐Q domain ever present/always absent was the secondary measure. Result: The neuropathological diagnosis of Alzheimer's disease (AD) using ABC criteria showed moderate associations with increased delusions, agitation/aggression and hallucinations. Cerebral amyloid angiopathy showed associations with NPS that were similar to AD. Lewy Body Disease (LBD) showed increased hallucinations. Infarcts/lacunes and microinfarcts showed weak associations with mood and motivational symptoms. Frontotemporal Dementia (FTD) was associated with marked increase in apathy and significantly decreased psychotic features and agitation. Hippocampal sclerosis was associated with less depression and increased apathy and disinhibition; these associations persisted after controlling for vascular neuropathology and FTD. In multiple regression analyses that controlled for other neuropathologies, the main findings were not altered. Conclusion: The associations of ADRD neuropathologies with specific NPS support current diagnostic criteria for behavioral symptoms in specific disorders. The findings on apathy and disinhibition in hippocampal sclerosis are novel and unique, and may explain inconsistent findings for depression treatment in dementia. Further investigation is needed to clarify the impact of hippocampal sclerosis on medial temporal lobe function and NPS, which may help eventually with diagnosis and clinical management. [ABSTRACT FROM AUTHOR]

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled “Sensory and Motor Dysfunctions in Aging and AD.” The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses. [ABSTRACT FROM AUTHOR]

Jennifer Gatchel (Symposium Co-chair) will introduce the speakers and then present data from the Harvard Aging Brain Study and screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. Mood, cognition, and PET data from 4,486 participants will be presented from the A4 Study and from 135 participants from the Harvard Aging Brain Study. These unpublished data show associations among neuropsychiatric symptoms, cognition, and in vivo neuroimaging biomarkers—amyloid and tau—in cognitively unimpaired individuals. Findings support cortical amyloid and regional cerebral tau as risk factors for cognitive decline in older adults. Davangere Devanand will review the evidence that olfactory identification deficits predict the development of Alzheimer's dementia, and show that olfactory impairments are superior to episodic verbal memory deficits in predicting cognitive decline. He will present data from a large community sample showing that intact performance on brief global cognitive and olfactory tests is associated with lack of transition to dementia during follow-up. These unique data will show that in 711 subjects, intact olfactory and cognitive abilities were protective with few transitions to dementia and none in the 70-75 and 81-83 years age groups. Terry Goldberg will review the apolipoprotein E e4 allele (APOE e4) as a risk factor for Alzheimer's dementia, and present unpublished data from the National Alzheimer's Consortium database showing that the apolipoprotein E e2 (APOE e2) genotype is protective against amyloid and tau pathologies of Alzheimer's disease but not Lewy body pathology, fronto-temporal or related tauopathy dementias as identified by gold standard neuropathological diagnosis. He will describe unpublished genetic and pathologic results from the Alzheimer's NACC consortium (N=1557) showing that APOE e2 protects against Alzheimer's and APOE e4 promotes Lewy body pathology in limbic and cortical regions but not midbrain. Gary Small (Symposium Chair) will moderate the audience questions and panel responses after presenting new data from randomized controlled trials indicating the cognitive benefits of pomegranate juice, bioavailable curcumin, or physical exercise – all strategies that reduce inflammation. These findings, as well as previous research on medications, physical activity, diet, obesity, and other risk/protective factors, suggest that several anti-inflammatory interventions may protect brain health and lower the risk for Alzheimer's dementia. He will describe data from placebo-controlled trials of memory effects of pomegranate juice (N=260) and curcumin (N=40), and a trial of memory training/aerobic exercise (N=55). [ABSTRACT FROM AUTHOR]

The article presents several case studies of patients with Alzheimer disease (AD) and frontotemporal dementia (FTD) who are treated with low-dose lithium for agitation and psychosis symptoms.

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is associated with an elevated risk of progressing to Alzheimer's disease. Much less is known about the course of dysexecutive mild cognitive impairment (dMCI). The goals of this study were to determine how the profile of cognitive deficits differs over time between patients with dMCI and aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with stroke and white matter hyperintensity on magnetic resonance imaging (MRI) than aMCI. Methods: The authors undertook a prospective evaluation of an inception cohort of 1167 ethnically diverse elders recruited from an urban community-based sample monitored with clinical and neuropsychological testing for an average of 4.5 years (standard deviation, 0.8 year). A subset of the subjects underwent MRI. We compared four groups of MCI patients: single-domain amnestic and dysexecutive MCI, and multiple-domain MCI with and without executive dysfunction. Results: Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single-domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple-domain MCI did not increase risk of progression to dementia. Patients with multiple-domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer's–type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to experience stroke, but not white matter hyperintensity, detected via MRI than patients with aMCI. Conclusions: dMCI appears to follow a different course, and is less associated with Alzheimer's disease and more associated with stroke than aMCI. [Copyright &y& Elsevier]

Background: Dementia‐related psychosis (DRP) is common in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), vascular dementia (VaD), and frontotemporal dementia (FTD). However, no therapies have been approved. Current guidelines and real‐world practice involve a trial of off‐label antipsychotics when other interventions fail, with assessment of response in an individual patient and taper within 4 months in patients who have responded. Pimavanserin is an inverse agonist/antagonist at the 5‐HT2A receptor and is approved in the U.S. for treating hallucinations and delusions associated with Parkinson's disease psychosis. The objective of this analysis was to examine the response (≥30% reduction on the SAPS‐H+D Total Score AND a CGI‐I score of 1=very much improved or 2=much improved) to pimavanserin during open‐label treatment of patients with DRP. Method: HARMONY was a placebo‐controlled, randomized, Phase 3, relapse prevention study in patients with dementia (NIA‐AA criteria) and moderate to severe psychosis associated with PDD, DLB, AD, FTD or VaD. Eligible patients who failed brief psychosocial therapy during screening entered into a 12‐week open‐label (OL) period where they received pimavanserin 34 mg once daily. Patients were assessed for response at Weeks 8 and 12. Only patients who demonstrated sustained response (response at both Weeks 8 and 12) were eligible to randomize into the double‐blind portion of the trial. OL response rates and changes in psychotic symptoms were assessed in various subgroups within the study population Result: 392 patients were enrolled into the open‐label period; 41 patients were ongoing at the time of early study termination. Overall, 61.8% of patients demonstrated sustained response (59.8% AD, 71.2% PDD, 71.4% VaD, 45.5% DLB, and 50.0% FTD). Mean change in the SAPS scores across the OL period was similar regardless of dementia subtype or baseline characteristics. The response rate was similar regardless of age, dementia severity, or previous drug therapy, with more than 50% patients meeting response criteria at Week 4 across most factors. Conclusion: In this Phase 3 study, during the OL treatment phase, pimavanserin produced a robust reduction in psychosis symptoms, irrespective of most likely clinical diagnosis of dementia subtype or baseline MMSE/dementia severity. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether there is differential response to placebo or citalopram among older patients with and without deficient response inhibition (DRI). Design: This is an 8-week, double-blind, placebo-controlled trial. Setting: Outpatient psychiatry. Participants: Unipolar depressed patients aged 75 years and older. Intervention: Citalopram (20-40 mg/day) or placebo pill. Measurements: Baseline Stroop Color-Word Test and weekly 24-item Hamilton Rating Scale for Depression assessments. Results: Citalopram-treated patients with DRI did significantly worse than placebo-treated patients with DRI. Conversely, citalopram-treated patients without DRI did significantly better than placebo-treated patients without DRI. Conclusion: Patients with late-life depression and DRI respond worse to selective serotonin reuptake inhibitor (SSRI) than placebo. These findings suggest that there may be a deleterious interaction between DRI and antidepressant medication in late-life depression and that the mechanism of SSRI and placebo response is different. [ABSTRACT FROM AUTHOR]

The article focuses on a research related to high risks of dementia due to depression in cognitive impairment (CI) patients. Topics discussed include improved episodic verbal memory by using antidepressants like cholinesterase inhibitor (CheI) donepezil; role of muscarinic cholinergic transmission in odor identification; and contribution of CheIs in increasing muscarinic cholinergic neurotransmission in the brain.

Background: To evaluate low‐dose lithium treatment of agitation in Alzheimer's disease (AD). Method: In a four‐site trial, patients with AD and agitation/aggression on the Neuropsychiatric Inventory (NPI) were randomized, double‐blind, to lithium carbonate 150‐600 mg daily or placebo for 12 weeks. Primary efficacy outcome was change in NPI agitation/aggression; secondary efficacy outcome was treatment response defined by 30% reduction in NPI combined score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved. Somatic, cognitive, metabolic, and neurological side effects were assessed. Result: Fifty‐eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium did not differ from placebo in agitation/aggression change scores. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p=0.26). Moderate or marked improvement on global CGI change, which incorporated behavior, cognition, and function, was greater on lithium (10/38=36.8%) than placebo (0/39=0%, Fisher's exact test p<0.001). In exploratory analyses, improvement on lithium was greater than placebo on NPI delusions and irritability/lability (p's<0.05). Lithium showed greater reduction than placebo in patients with high Young Mania Rating Scale scores (β=5.06; 95%CI, 1.18 to 8.94, p=0.01). Oral dose and serum lithium levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on any safety outcome. Conclusion: Low dose lithium was not efficacious in treating agitation but was associated with global clinical improvement and excellent safety. A larger trial may be warranted with precision pharmacological targeting of likely lithium‐responsive behavioral symptoms that overlap with mania. [ABSTRACT FROM AUTHOR]

Background: Olfactory dysfunction consistently occurs in patients with Alzheimer's disease (AD), beyond the mild and gradual decline in olfactory ability found in normal aging. This dysfunction begins early in the disease course, typically before clinical diagnosis, and progresses with disease severity. While odor identification and detection deficits clearly differentiate AD from controls, there remains uncertainty as to whether these are determined by olfactory threshold. The primary purpose of the current fMRI study was to examine the neural correlates of olfactory processing in healthy young and old adults and compare them with AD patients. Method: Health young adults (n=10), healthy old adults (n=10), and AD patients (n=12) participated in psychophysical olfactory testing and an fMRI odorant detection paradigm. We analyzed the interplay between age and disease‐related psychophysical olfactory declines and odorant‐induced brain activation. This tested whether odor threshold deficits reflect disease progression and explain group differences in detection, identification and brain activity. Result: AD patients had decreased odor detection task‐related signal in all regions of the primary olfactory cortex, with activity in the entorhinal cortex best differentiating the groups. Within the secondary olfactory regions, AD patients showed decreased activity in orbitofrontal cortex compared to healthy age matched individuals. Moderated‐mediation analyses on neuro‐psychophysical relationships found that increased brain activation in the entorhinal cortex moderated the negative effect of disease‐related threshold decline on olfactory detection. Conclusion: Even in the face of declining olfactory thresholds, older adults compensated for this effect with increased brain activation in a primary olfactory brain region. This was the case for odor detection but not odor identification. fMRI activation induced by an olfactory identification task may eventually be useful in improving early detection of AD and may, eventually, facilitate early treatment interventions in subjects at risk for AD. [ABSTRACT FROM AUTHOR]

Background: Fatigue is associated with neuroinflammation of the brain, one of the signatures of neurodegenerative disorders across preclinical and clinical stages. Substantial research evidence demonstrates a bidirectional link between Alzheimer's neuropathology and poor sleep. Whether neuroinflammation mediates the association between sleep disturbances and cognitive decline remains to be determined. In this pilot study, we examined whether fatigue impacts the relationship between sleep quality and cognitive function ability. Method: We prospectively recruited adults aged 55‐90 years with mild cognitive impairment to evaluate their symptoms of Fatigue, Sleep, and Cognitive Function Abilities (CFA), using the NIH PROMIS Fatigue short form (v1.0), Sleep Disturbances (SD, v2.0) and Sleep‐related Impairment short form (SRI v2.0), as well as the NIH Neuro‐QOL Cognitive Function Abilities short form (v1.0). The Poor‐sleep group was defined as a T‐score of >50 on either SD or SRI scale. Depression was defined as a Geriatric Depression Scale score of 5 or greater and was a study exclusion criterion. Result: Twenty‐seven patients enrolled in the study, including 14 women and 13 men. The mean age was 67.37+/‐ 9.00 years. The Poor‐sleep group had significantly lower CFA compared to the Good‐sleep group (b=‐6.28, p=0.019). Greater Fatigue scores were significantly associated with lower Cognitive Function Abilities scores (r=.49, p=0.010). These results remained significant after controlling for age. Further, total scale SRI score was significantly associated with total scale Fatigue score (r=.72, p<0.001). Conclusion: Both fatigue and sleep disturbances were significantly associated with low CFA independently, along with a significant correlation between fatigue and poor sleep. The mechanisms by which fatigue and sleep disturbances contribute to cognitive test performance need to be elucidated in future research. [ABSTRACT FROM AUTHOR]

Background: Fatigue is associated with neuroinflammation of the brain, one of the signatures of neurodegenerative disorders across preclinical and clinical stages. Substantial research evidence demonstrates a bidirectional link between Alzheimer's neuropathology and poor sleep. Whether neuroinflammation mediates the association between sleep disturbances and cognitive decline remains to be determined. In this pilot study, we examined whether fatigue impacts the relationship between sleep quality and cognitive function ability. Method: We prospectively recruited adults aged 55‐90 years with mild cognitive impairment to evaluate their symptoms of Fatigue, Sleep, and Cognitive Function Abilities (CFA), using the NIH PROMIS Fatigue short form (v1.0), Sleep Disturbances (SD, v2.0) and Sleep‐related Impairment short form (SRI v2.0), as well as the NIH Neuro‐QOL Cognitive Function Abilities short form (v1.0). The Poor‐sleep group was defined as a T‐score of >50 on either SD or SRI scale. Depression was defined as a Geriatric Depression Scale score of 5 or greater and was a study exclusion criterion. Result: Twenty‐seven patients enrolled in the study, including 14 women and 13 men. The mean age was 67.37+/‐ 9.00 years. The Poor‐sleep group had significantly lower CFA compared to the Good‐sleep group (b=‐6.28, p=0.019). Greater Fatigue scores were significantly associated with lower Cognitive Function Abilities scores (r=.49, p=0.010). These results remained significant after controlling for age. Further, total scale SRI score was significantly associated with total scale Fatigue score (r=.72, p<0.001). Conclusion: Both fatigue and sleep disturbances were significantly associated with low CFA independently, along with a significant correlation between fatigue and poor sleep. The mechanisms by which fatigue and sleep disturbances contribute to cognitive test performance need to be elucidated in future research. [ABSTRACT FROM AUTHOR]

Background: Olfactory dysfunction consistently occurs in patients with Alzheimer's disease (AD), beyond the mild and gradual decline in olfactory ability found in normal aging. This dysfunction begins early in the disease course, typically before clinical diagnosis, and progresses with disease severity. While odor identification and detection deficits clearly differentiate AD from controls, there remains uncertainty as to whether these are determined by olfactory threshold. The primary purpose of the current fMRI study was to examine the neural correlates of olfactory processing in healthy young and old adults and compare them with AD patients. Method: Health young adults (n=10), healthy old adults (n=10), and AD patients (n=12) participated in psychophysical olfactory testing and an fMRI odorant detection paradigm. We analyzed the interplay between age and disease‐related psychophysical olfactory declines and odorant‐induced brain activation. This tested whether odor threshold deficits reflect disease progression and explain group differences in detection, identification and brain activity. Result: AD patients had decreased odor detection task‐related signal in all regions of the primary olfactory cortex, with activity in the entorhinal cortex best differentiating the groups. Within the secondary olfactory regions, AD patients showed decreased activity in orbitofrontal cortex compared to healthy age matched individuals. Moderated‐mediation analyses on neuro‐psychophysical relationships found that increased brain activation in the entorhinal cortex moderated the negative effect of disease‐related threshold decline on olfactory detection. Conclusion: Even in the face of declining olfactory thresholds, older adults compensated for this effect with increased brain activation in a primary olfactory brain region. This was the case for odor detection but not odor identification. fMRI activation induced by an olfactory identification task may eventually be useful in improving early detection of AD and may, eventually, facilitate early treatment interventions in subjects at risk for AD. [ABSTRACT FROM AUTHOR]

Jennifer Gatchel (Symposium Co-chair) will introduce the speakers and then present data from the Harvard Aging Brain Study and screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. Mood, cognition, and PET data from 4,486 participants will be presented from the A4 Study and from 135 participants from the Harvard Aging Brain Study. These unpublished data show associations among neuropsychiatric symptoms, cognition, and in vivo neuroimaging biomarkers—amyloid and tau—in cognitively unimpaired individuals. Findings support cortical amyloid and regional cerebral tau as risk factors for cognitive decline in older adults. Davangere Devanand will review the evidence that olfactory identification deficits predict the development of Alzheimer's dementia, and show that olfactory impairments are superior to episodic verbal memory deficits in predicting cognitive decline. He will present data from a large community sample showing that intact performance on brief global cognitive and olfactory tests is associated with lack of transition to dementia during follow-up. These unique data will show that in 711 subjects, intact olfactory and cognitive abilities were protective with few transitions to dementia and none in the 70-75 and 81-83 years age groups. Terry Goldberg will review the apolipoprotein E e4 allele (APOE e4) as a risk factor for Alzheimer's dementia, and present unpublished data from the National Alzheimer's Consortium database showing that the apolipoprotein E e2 (APOE e2) genotype is protective against amyloid and tau pathologies of Alzheimer's disease but not Lewy body pathology, fronto-temporal or related tauopathy dementias as identified by gold standard neuropathological diagnosis. He will describe unpublished genetic and pathologic results from the Alzheimer's NACC consortium (N=1557) showing that APOE e2 protects against Alzheimer's and APOE e4 promotes Lewy body pathology in limbic and cortical regions but not midbrain. Gary Small (Symposium Chair) will moderate the audience questions and panel responses after presenting new data from randomized controlled trials indicating the cognitive benefits of pomegranate juice, bioavailable curcumin, or physical exercise – all strategies that reduce inflammation. These findings, as well as previous research on medications, physical activity, diet, obesity, and other risk/protective factors, suggest that several anti-inflammatory interventions may protect brain health and lower the risk for Alzheimer's dementia. He will describe data from placebo-controlled trials of memory effects of pomegranate juice (N=260) and curcumin (N=40), and a trial of memory training/aerobic exercise (N=55). [ABSTRACT FROM AUTHOR]