Plasma p-tau217 concordance with amyloid PET among ethnically diverse older adults.

INTRODUCTION: Commercially available plasma p-tau217 biomarker tests are not well studied in ethnically diverse samples. METHODS: We evaluated associations between ALZPath plasma p-tau217 and amyloid-beta positron emission tomography (Aß-PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non-Hispanic/Latino older adults. One- and two-cutoff ranges were derived and evaluated to assess agreement with Aß-PET. RESULTS: A total of 239 participants underwent blood draw and Aß-PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p-tau217 showed excellent discrimination of Aß-PET positive and negative participants (visual read: AUC = 0.91 [0.87-0.95], p < 0.001; Centiloids quantification: AUC = 0.90 [0.86-0.94]). There was a greater percent agreement between low p-tau217 and negative Aß-PET (95.8%) than high p-tau217 and positive Aß-PET (86.3%). Analyses within ethnicity-specific subgroups suggested similar p-tau217 performance. DISCUSSION: Plasma p-tau217 (ALZPath) relates to brain Aß in Hispanic/Latino and non-Hispanic/Latino older adults. Independent validation and replication are necessary to establish reference ranges and inform appropriate contexts of use across ethno-racially diverse populations. HIGHLIGHTS: Plasma p-tau217 (ALZPath) and Aß-PET were measured in Hispanic/Latino and non-Hispanic/Latino older adults.Plasma p-tau217 accurately discriminated Aß-PET positive and negative participants.Applying a two-cutoff "intermediate" plasma p-tau217 approach could reduce need for more invasive and costly testing.Plasma p-tau217 associations with Aß-PET were strong within both Hispanic/Latino and non-Hispanic/Latino groups.

The computerized LASSI-BC Test versus the Standard LASSI-L Paper-and-Pencil Version in Community-Based-Samples.

Proactive Semantic Interference (PSI) and failure to recover from PSI (frPSI), are novel constructs assessed by the LASSI-L. These measures are sensitive to cognitive changes in early Mild Cognitive Impairment (MCI) and preclinical AD determined by Aß load using PET. The goal of this study was to compare a new computerized version of the LASSI-L (LASSI-Brief Computerized) to the standard paper-and-pencil version of the test. In this study, we examined 110 cognitively unimpaired (CU) older adults and 79 with amnestic MCI (aMCI) who were administered the paper-and-pencil form of the LASSI-L. Their performance was compared with 62 CU older adults and 52 aMCI participants examined using the LASSI-BC. After adjustment for covariates (degree of initial learning, sex, education, and language of evaluation) both the standard and computerized versions distinguished between aMCI and CU participants. The performance of CU and aMCI groups using either form was relatively commensurate. Importantly, an optimal combination of Cued B2 recall and Cued B1 intrusions on the LASSI-BC yielded an area under the ROC curve of .927, a sensitivity of 92.3% and specificity of 88.1%, relative to an area under the ROC curve of .815, a sensitivity of 72.5%, and a specificity of 79.1% obtained for the paper-and-pencil LASSI-L. Overall, the LASSI-BC was comparable, and in some ways, superior to the paper-and-pencil LASSI-L. Advantages of the LASSI-BC include a more standardized administration, suitability for remote assessment, and an automated scoring mechanism that can be verified by a built-in audio recording of responses.

Different aspects of failing to recover from proactive semantic interference predicts rate of progression from amnestic mild cognitive impairment to dementia.

Introduction: This study investigated the role of proactive semantic interference (frPSI) in predicting the progression of amnestic Mild Cognitive Impairment (aMCI) to dementia, taking into account various cognitive and biological factors. Methods: The research involved 89 older adults with aMCI who underwent baseline assessments, including amyloid PET and MRI scans, and were followed longitudinally over a period ranging from 12 to 55 months (average 26.05 months). Results: The findings revealed that more than 30% of the participants diagnosed with aMCI progressed to dementia during the observation period. Using Cox Proportional Hazards modeling and adjusting for demographic factors, global cognitive function, hippocampal volume, and amyloid positivity, two distinct aspects of frPSI were identified as significant predictors of a faster decline to dementia. These aspects were fewer correct responses on a frPSI trial and a higher number of semantic intrusion errors on the same trial, with 29.5% and 31.6 % increases in the likelihood of more rapid progression to dementia, respectively. Discussion: These findings after adjustment for demographic and biological markers of Alzheimer's Disease, suggest that assessing frPSI may offer valuable insights into the risk of dementia progression in individuals with aMCI.

Effects of lithium on serum Brain-Derived Neurotrophic Factor in Alzheimer's patients with agitation.

BACKGROUND: There is ample evidence in animal models that lithium increases Brain-Derived Neurotrophic Factor (BDNF) with supporting evidence in human studies. Little is known, however, about the effects of lithium on BDNF in Alzheimer's Dementia (AD). In one study of patients with Mild Cognitive Impairment, serum BDNF increased after treatment with lithium. These patients also showed mild improvement in cognitive function. OBJECTIVES: To evaluate low-dose lithium treatment of agitation in Alzheimer's disease (AD). METHOD: We measured levels of BDNF in patients treated with lithium prior to and after a 12-week randomized placebo-controlled trial. RESULTS: BDNF levels did not change significantly and were not associated with improvement in overall neuropsychiatric symptoms or in cognitive function. CONCLUSIONS: More research is needed to understand the potential effects of lithium on BDNF in AD including whether its use might be dependent on the stage of cognitive decline and dementia.

Semantic intrusion errors are associated with plasma Ptau-181 among persons with amnestic mild cognitive impairment who are amyloid positive.

Introduction: Semantic intrusion errors (SI) have distinguished between those with amnestic Mild Cognitive Impairment (aMCI) who are amyloid positive (A+) versus negative (A-) on positron emission tomography (PET). Method: This study examines the association between SI and plasma - based biomarkers. One hundred and twenty-eight participants received SiMoA derived measures of plasma pTau-181, ratio of two amyloid-ß peptide fragments (Aß42/Aß40), Neurofilament Light protein (NfL), Glial Fibrillary Acidic Protein (GFAP), ApoE genotyping, and amyloid PET imaging. Results: The aMCI A+ (n = 42) group had a higher percentage of ApoE ɛ4 carriers, and greater levels of pTau-181 and SI, than Cognitively Unimpaired (CU) A- participants (n = 25). CU controls did not differ from aMCI A- (n = 61) on plasma biomarkers or ApoE genotype. Logistic regression indicated that ApoE ɛ4 positivity, pTau-181, and SI were independent differentiating predictors (Correct classification = 82.0%; Sensitivity = 71.4%; Specificity = 90.2%) in identifying A+ from A- aMCI cases. Discussion: A combination of plasma biomarkers, ApoE positivity and SI had high specificity in identifying A+ from A- aMCI cases.

A Novel Computerized Cognitive Test for the Detection of Mild Cognitive Impairment and Its Association with Neurodegeneration in Alzheimer's Disease Prone Brain Regions.

During the prodromal stage of Alzheimer's disease (AD), neurodegenerative changes can be identified by measuring volumetric loss in AD-prone brain regions on MRI. Cognitive assessments that are sensitive enough to measure the early brain-behavior manifestations of AD and that correlate with biomarkers of neurodegeneration are needed to identify and monitor individuals at risk for dementia. Weak sensitivity to early cognitive change has been a major limitation of traditional cognitive assessments. In this study, we focused on expanding our previous work by determining whether a digitized cognitive stress test, the Loewenstein-Acevedo Scales for Semantic Interference and Learning, Brief Computerized Version (LASSI-BC) could differentiate between Cognitively Unimpaired (CU) and amnestic Mild Cognitive Impairment (aMCI) groups. A second focus was to correlate LASSI-BC performance to volumetric reductions in AD-prone brain regions. Data was gathered from 111 older adults who were comprehensively evaluated and administered the LASSI-BC. Eighty-seven of these participants (51 CU; 36 aMCI) underwent MR imaging. The volumes of 12 AD-prone brain regions were related to LASSI-BC and other memory tests correcting for False Discovery Rate (FDR). Results indicated that, even after adjusting for initial learning ability, the failure to recover from proactive semantic interference (frPSI) on the LASSI-BC differentiated between CU and aMCI groups. An optimal combination of frPSI and initial learning strength on the LASSI-BC yielded an area under the ROC curve of 0.876 (76.1% sensitivity, 82.7% specificity). Further, frPSI on the LASSI-BC was associated with volumetric reductions in the hippocampus, amygdala, inferior temporal lobes, precuneus, and posterior cingulate.

Persistent Failure to Recover from Proactive Semantic Interference on the Cognitive Stress Test Differentiates Between Amnestic Mild Cognitive Impairment, Pre-Mild Cognitive Impairment, and Cognitively Unimpaired Older Adults.

BACKGROUND: Susceptibility to proactive semantic interference (PSI) and the inability to ameliorate these difficulties with one additional learning trial have repeatedly been implicated as early features of incipient Alzheimer's disease (AD). Unfortunately, persistent failure to recover from PSI (frPSI) after repeated learning trials, are not captured by existing memory measures, or been examined in pre-mild cognitive impairment (PreMCI). OBJECTIVE: A novel Cognitive Stress Test (CST) was employed to measure the impact of PSI, initial failure to recover from PSI and persistent effects of PSI, despite multiple learning trials of the new to-be-remembered material (pfrPSI). We hypothesized that PSI deficits on the CST would persist in both PreMCI and amnestic MCI (aMCI) groups over repeated learning trials when compared to cognitively unimpaired (CU) older adults. METHODS: One hundred fifty older adults (69 CU, 31 PreMCI, and 50 aMCI) underwent a standardized clinical and neuropsychological evaluation. The CST was independent of diagnostic classification. RESULTS: Even after adjusting for strength of initial learning, aMCI and PreMCI groups demonstrated greater persistent PSI (pfrPSI) relative to the CU group despite repeated learning trials of List B. Further, the aMCI group made a higher number of semantic intrusion errors relative to the PreMCI and CU groups on all List B Cued Recall trials. CONCLUSION: Persistent PSI appears to be a common feature of aMCI and PreMCI. The possible theoretical mechanisms and empirical implications of these new findings are discussed.

Semantic intrusion errors as a function of age, amyloid, and volumetric loss: a confirmatory path analysis.

OBJECTIVE: To examine the direct and indirect effects of age, APOE ϵ4 genotype, amyloid positivity, and volumetric reductions in AD-prone brain regions as it relates to semantic intrusion errors reflecting proactive semantic interference (PSI) and the failure to recover from proactive semantic interference (frPSI) on the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L), a cognitive stress test that has been consistently more predictive of preclinical and prodromal Alzheimer's disease (AD) than traditional list-learning tests. DESIGN: Cross-sectional study. SETTING: 1Florida Alzheimer's Disease Research Center baseline study. PARTICIPANTS: Two-hundred and twelve participants with Mini-Mental State Examination (MMSE) score above 16 and a broad array of cognitive diagnoses ranging from cognitively normal (CN) to dementia, of whom 58% were female, mean age of 72.1 (SD 7.9). MEASURES: Participants underwent extensive clinical and neuropsychological evaluations, MR and amyloid Positron Emission Tomography/Computer/Computer Tomography (PET/CT) imaging, and analyses of APOE ϵ4 genotype. Confirmatory path analyses were conducted in the structural equation modeling framework that estimated multiple equations simultaneously while controlling for important covariates such as sex, education, language of evaluation, and global cognitive impairment. RESULTS: Both amyloid positivity and decreased brain volumes in AD-prone regions were directly related to LASSI-L Cued B1 and Cued B2 intrusions (sensitive to PSI and frPSI effects) even after controlling for covariates. APOE ϵ4 status did not evidence direct effects on these LASSI-L cognitive markers, but rather exerted their effects on amyloid positivity, which in turn related to PSI and frPSI. Similarly, age did not have a direct relationship with LASSI-L scores, but exerted its effects indirectly through amyloid positivity and volumes of AD-prone brain regions. CONCLUSIONS: Our study provides insight into the relationships among age, APOE ϵ4, amyloid, and brain volumetric reductions as it relates to semantic intrusion errors. The investigation expands our understanding of the underpinnings of PSI and frPSI intrusions in a large cohort.

Low Dose Lithium Treatment of Behavioral Complications in Alzheimer's Disease: Lit-AD Randomized Clinical Trial.

BACKGROUND: A case series suggested efficacy for lithium to treat agitation in dementia, but no placebo-controlled trials have been conducted. OBJECTIVES: 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 score ≥4 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 (30% reduction in NPI score for agitation/aggression plus psychosis and a Clinical Global Impression (CGI) score of much or very much improved). Safety profile of lithium was assessed. RESULTS: Fifty-eight of 77 patients (75.3%) completed the trial. In linear mixed effects model analyses, lithium was not significantly superior to placebo for agitation/aggression. Proportion of responders was 31.6% on lithium and 17.9% on placebo (χ2=1.26, p = 0.26). Moderate or marked improvement (CGI) 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 (ß=5.06; 95%CI,1.18 to 8.94, p = 0.01). Oral dose and serum levels demonstrated similar associations with efficacy outcomes. Lithium did not differ significantly from placebo on safety outcomes. CONCLUSIONS: 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 of likely lithium-responsive behavioral symptoms that overlap with mania.

Changes in LASSI-L performance over time among older adults with amnestic MCI and amyloid positivity: A preliminary study.

There is a pressing need to develop measures that are sensitive to the earliest subtle cognitive changes of Alzheimer's disease (AD) to improve early detection and track disease progression. The Loewenstein-Acevedo Scales of Semantic Interference (LASSI-L) has been shown to successfully discriminate between cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (MCI) and to correlate with total and regional brain amyloid load. The present study investigated how the LASSI-L scores change over time among three distinct diagnostic groups. Eighty-six community-dwelling older adults underwent a baseline evaluation including: a clinical interview, a neuropsychological evaluation, Magnetic Resonance Imaging (MRI), and amyloid Positron Emission Tomography (PET). A follow up evaluation was conducted 12 months later. Initial mean values were calculated using one-way ANOVAs and chi-square analyses. Post-hoc comparisons were conducted using Tukey's Honestly Significant Difference (HSD). A 3 × 2 repeated measures analysis was utilized to examine differences in LASSI-L performance over time. The MCI amyloid positive group demonstrated a significantly greater decline in LASSI-L performance than the MCI amyloid negative and CU groups respectively. The scales that best differentiated the three groups included the Cued A2, which taps into maximum learning capacity, and Cued B2, which assesses the failure to recover from proactive semantic interference. Our findings further support the LASSI-L's discriminative validity.

The relationship of semantic intrusions to different etiological subtypes of MCI and cognitively healthy older adults.

INTRODUCTION: There is increasing evidence that susceptibility to proactive semantic interference (PSI) and the failure to recover from PSI (frPSI) as evidenced by intrusion errors may be early cognitive markers of both preclinical and prodromal Alzheimer's disease (AD). METHODS: One hundred forty-five participants were administered extensive clinical and neuropsychological evaluations including the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive cognitive stress test measuring PSI and frPSI. Participants also underwent structural magnetic resonance imaging (MRI) and amyloid positron emission tomography/computed tomography (PET/CT) imaging. RESULTS: PSI and frPSI errors were much more prevalent in the mild cognitive impairment (MCI)-AD (amyloid positive) group than the other diagnostic groups. The number of intrusion errors observed across the other MCI groups without amyloid pathology and those with normal cognition were comparable. DISCUSSION: Semantic intrusion errors on the LASSI-L occur much less frequently in persons who have different types of non-AD-related MCI and may be used as an early cognitive marker of prodromal AD.

Intrusion Errors and Progression of Cognitive Deficits in Older Adults with Mild Cognitive Impairment and PreMCI States.

INTRODUCTION: Among persons with amnestic mild cognitive impairment (aMCI), intrusion errors on subscales that measure proactive semantic interference (PSI) may be among the earliest behavioral markers of elevated Alzheimer's disease brain pathology. While there has been considerable cross-sectional work in the area, it is presently unknown whether semantic intrusion errors are predictive of progression of cognitive impairment in aMCI or PreMCI (not cognitively normal but not meeting full criteria for MCI). METHODS: This study examined the extent to which the percentage of semantic intrusion errors (PIE) based on total responses on a novel cognitive stress test, the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), could predict clinical/cognitive outcomes over an average 26-month period in older adults initially diagnosed with aMCI, PreMCI, and normal cognition. RESULTS: On the LASSI-L subscale sensitive to PSI, a PIE cut point of 44% intrusion errors distinguished between those at-risk individuals with PreMCI who progressed to MCI over time compared to individuals with PreMCI who reverted to normal on longitudinal follow-up. Importantly, PIE was able to accurately predict 83.3% of aMCI individuals who later progressed to dementia. DISCUSSION: These preliminary findings indicate that PIE on LASSI-L subscales that measure PSI may be a useful predictor of clinical progression overtime in at-risk older adults.

A Teleneuropsychology Protocol for the Cognitive Assessment of Older Adults During COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic prompted the need for a teleneuropsychology protocol for the cognitive assessment of older adults, who are at increased risk for both COVID-19 and dementia. Prior recommendations for teleneuropsychological assessment did not consider many of the unique challenges posed by COVID-19. The field is still in need of clear guidelines and standards of care for the assessment of older adults under the current circumstances. Advantages of teleneuropsychological assessment during the COVID-19 pandemic include reduced risk of contracting the virus, eliminating travel time and reducing cost, and more rapid access to needed services. Challenges include disparities in technology access among patients, reduced control over the testing environment, impeded ability to make behavioral observations, and limited research on valid and reliable cognitive assessment measures. The aim of this perspective review is to propose a teleneuropsychological protocol to facilitate neuropsychological assessment utilizing a virtual platform. The proposed protocol has been successful with our clinical and research populations and may help neuropsychologists implement teleneuropsychology services without compromising validity or reliability. However, there is increasing need for research on teleneuropsychological assessment options for both clinical and research purposes.

A Brief Version of the LASSI-L Detects Prodromal Alzheimer's Disease States.

BACKGROUND: The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) is an increasingly utilized cognitive stress test designed to identify early cognitive changes associated with incipient neurodegenerative disease. OBJECTIVE: To examine previously derived cut-points for cognitively unimpaired older adults that were suggestive of performance impairment on multiple subscales of the LASSI-L. These cut-points were applied to a new sample of older adults who were cognitive healthy controls (HC: n = 26) and those on the Alzheimer's disease (AD) continuum from early stage mild cognitive impairment (EMCI: n = 28), late stage MCI (LMCI: n = 18) to mild AD (AD: n = 27). METHODS: All participants were administered the LASSI-L. All cognitively impaired participants were PET amyloid positive which likely reflects underlying AD neuropathology, while cognitively normal counterparts were deemed to have amyloid negative scans. RESULTS: There was a monotonic relationship between the number of deficits on LASSI-L subscales and independent classification of study groups with greater severity of cognitive impairment. Importantly, taken together, impairment on maximum learning ability and measures of proactive semantic interference (both reflected by cued recall and intrusion errors) correctly classified 74.1% of EMCI, 94.4% of LMCI, and 96.3% of AD. Only 7.7% of HC were incorrectly classified as having impairments. CONCLUSION: A modest number of LASSI-L subscales taking approximately 8 minutes to administer, had excellent discriminative ability using established cut-offs among individuals with presumptive stages of AD. This has potential implications for both clinical practice and clinical research settings targeting AD during early prodromal stages.

A novel method of evaluating semantic intrusion errors to distinguish between amyloid positive and negative groups on the Alzheimer's disease continuum.

BACKGROUND: The development and validation of clinical outcome measures to detect early cognitive decline associated with Alzheimer's disease (AD) biomarkers is imperative. Semantic intrusions on the Loewenstein Acevedo Scales of Semantic Interference and Learning (LASSI-L) has outperformed widely used cognitive measures as an early correlate of elevated brain amyloid in prodromal AD and has distinguished those with amnestic mild cognitive impairment (aMCI) and high amyloid load from aMCI attributable to other non-AD conditions. METHODS: Since intrusion errors on memory tasks vary widely, we employed a novel method that accounts for the percentage of intrusion errors (PIE) in relation to total responses. Individuals with either high or low amyloid load across the spectrum of aMCI and dementia and amyloid negative cognitively normal older adults (CN) were studied. RESULTS: Mean PIE on indices sensitive to proactive semantic interference (PSI) and failure to recover from proactive semantic interference (frPSI) could distinguish amyloid positive from amyloid negative aMCI and dementia groups. Number of correct responses alone, while able to differentiate the different diagnostic groups, did not differentiate amyloid positive aMCI from their counterparts without amyloid pathology. CONCLUSIONS: PIE, a novel and sensitive index of early memory dysfunction, demonstrated high levels of sensitivity and specificity in differentiating CN from amyloid positive persons with preclinical AD. Mean levels of PIE are higher for amyloid positive aMCI and dementia participants relative to their amyloid negative counterparts.

Semantic Intrusion Error Ratio Distinguishes Between Cognitively Impaired and Cognitively Intact African American Older Adults.

BACKGROUND: Semantic intrusion errors on memory tests may represent very early cognitive changes associated with elevated Alzheimer's disease pathology within the brain, including amyloid-ß (Aß). Subscales that measure proactive semantic interference (PSI) and intrusions related to PSI on the Loewenstein Acevedo Scales of Semantic Interference and Learning (LASSI-L) have been associated with high levels of brain amyloid load, structural changes on brain MRI in Hispanic and non-Hispanic groups. It is presently unknown whether intrusion errors or other measures of the LASSI-L can differentiate between African-American (AA) older adults diagnosed with amnestic mild cognitive impairment (aMCI) or classified as cognitively normal (CN). OBJECTIVE: This study examined the extent to which a high percentage of semantic intrusion errors on LASSI-L subscales susceptible to PSI and other LASSI-L measures could differentiate between AA aMCI and CN groups. METHODS: Forty-eight AA older adults were recruited (27 CN and 21 aMCI) and received a through clinical and neuropsychological evaluation. The LASSI-L was administered independent of diagnostic classification. RESULTS: With and without statistical adjustment for literacy, AA aMCI participants scored lower on all LASSI-L measures. ROC analyses revealed an area under the curve exceeding 90% and correctly classified 86% of AA aMCI with 82% specificity for AA CN participants. CONCLUSIONS: Percentage of intrusion errors on the LASSI-L subscales susceptible to PSI differentiated AA aMCI from AA CN. This adds to emerging evidence indicating that the LASSI-L may be culturally appropriate and can differentiate between aMCI and CN in diverse ethnic/cultural groups.

Lithium Treatment for Agitation in Alzheimer's disease (Lit-AD): Clinical rationale and study design.

Symptoms of agitation, aggression, and psychosis frequently occur in patients with Alzheimer's disease (AD). These symptoms are distressing to patients and caregivers, often lead to institutionalization, are associated with increased mortality, and are very difficult to treat. Lithium is an established treatment for bipolar and other psychotic disorders in which agitation can occur. The Lit-AD study is the first randomized, double-blind, placebo-controlled trial to assess the efficacy of lithium treatment for symptoms of agitation or aggression, with or without psychosis, in older adults diagnosed with AD. Patients are randomly assigned to low dose (150-600 mg) lithium or placebo, targeting a blood level of 0.2-0.6 mmol/L, stratified by the presence/absence of psychotic symptoms. The study duration for each patient is 12 weeks. The primary study outcome is change in the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) over the study period. The secondary outcome is improvement in neuropsychiatric symptoms defined as a 30% decrease in a NPI core score that combines agitation/aggression and psychosis domain scores. The Treatment Emergent Symptom Scale (TESS) is used to assess somatic side effects. Other exploratory analyses examine the associations between improvement on lithium and indices shown to be associated with response to lithium in bipolar disorder: serum brain-derived neurotrophic factor (BDNF) levels, a SNP in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus. If lithium demonstrates efficacy in this Phase II pilot trial, a Phase III study will be developed to establish its clinical utility in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02129348.

A novel cognitive assessment paradigm to detect Pre-mild cognitive impairment (PreMCI) and the relationship to biological markers of Alzheimer's disease.

OBJECTIVE: A number of older adults obtain normal scores on formal cognitive tests, but present clinical concerns that raise suspicion of cognitive decline. Despite not meeting full criteria for Mild Cognitive Impairment (MCI), these PreMCI states confer risk for progression to Alzheimer's disease (AD). This investigation addressed a pressing need to identify cognitive measures that are sensitive to PreMCI and are associated with brain biomarkers of neurodegeneration. METHOD: Participants included 49 older adults with a clinical history suggestive of cognitive decline but normal scores on an array of neuropsychological measures, thus not meeting formal criteria for MCI. The performance of these PreMCI participants were compared to 117 cognitively normal (CN) elders on the LASSI-L, a cognitive stress test that uniquely assesses the failure to recover from proactive semantic interference effects (frPSI). Finally, a subset of these individuals had volumetric analyses based on MRI scans. RESULTS: PreMCI participants evidenced greater LASSI- L deficits, particularly with regards to frPSI and delayed recall, relative to the CN group. No differences on MRI measures were observed. Controlling for false discovery rate (FDR), frPSI was uniquely related to increased dilatation of the inferior lateral ventricle and decreased MRI volumes in the hippocampus, precuneus, superior parietal region, and other AD prone areas. In contrast, other LASSI-L indices and standard memory tests were not related to volumetric findings. CONCLUSIONS: Despite equivalent performance on traditional memory measures, the frPSI distinguished between PreMCI and CN elders and was associated with reductions in brain volume in numerous AD-relevant brain regions.

Pharmacological Management of Anxiety Disorders in the Elderly.

Anxiety disorders are common in the elderly. Additionally, anxiety symptoms often accompany co-morbid psychiatric, medical, as well as neurodegenerative diseases in the older population. Anxiety in the elderly, often accompanied by depression, can lead to worsening physical, cognitive and functional impairments in this vulnerable population. Antidepressants are considered first line treatment. Both SSRIs and SNRIs are efficacious and well-tolerated in the elderly. Some SSRIs are strong inhibitors of the cytochrome P450 hepatic pathway whereas others have less potential for drug interaction. Those antidepressants with more favorable pharmacokinetic profiles should be considered first-line in the treatment of anxiety. Mirtazapine and vortioxetine are also considered safe treatment options. Buspirone may have benefit, but lacks studies in elderly populations. Although tricyclic/tetracyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) may be effective in the elderly, their side effect and safety profiles are suboptimal and thus are not recommended in late-life. Benzodiazepines and beta blockers should generally be avoided when treating anxiety in the elderly. There is not enough evidence to support the use of antipsychotics or mood stabilizers given their risk of problems in both the long and short term. In addition, antipsychotics have a black box warning for increased mortality in elderly patients with dementia.

A Novel Method for Direct Assessment of Everyday Competence Among Older Adults.

BACKGROUND: Recent findings indicate that impairments in functional performance do occur among individuals diagnosed with mild cognitive impairment (MCI). Most assessment strategies for everyday competence are associated with challenges with reliability, are typically in paper and pencil format, or require in-person administration by a trained professional. OBJECTIVE: This paper reports on a novel technology-based assessment battery of everyday competence that includes ecologically valid simulations of daily activities important to independence. METHODS: The sample included 85 non-cognitively impaired older adults aged 65+ and 62 older adults diagnosed with amnestic MCI (aMCI). Participants completed standard measures of cognitive abilities and the computerized battery of everyday tasks, which included simulations of a doctor's visit; and medication and financial management tasks. RESULTS: The older adults with aMCI performed significantly poorer on all three tasks in the everyday task battery. Performance on these measures were also moderately correlated with standard measures of cognitive abilities and showed good test-retest reliability. CONCLUSIONS: The results show that it is feasible to use a technology-based assessment battery of everyday tasks with both non-cognitively impaired older adults and older adults with MCI. The use of this type of battery can overcome many of the logistic constraints associated with current functional assessment protocols.