Longitudinal post-shunt outcomes in idiopathic normal pressure hydrocephalus with and without comorbid Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is highly comorbid with idiopathic normal pressure hydrocephalus (iNPH) and may diminish the benefits of shunting; however, findings in this area are mixed. We examined postoperative outcomes, with emphases on cognition and utilization of novel scoring procedures to enhance sensitivity. METHODS: Using participant data from an iNPH outcome study at Butler Hospital, a mixed effect model examined main and interaction effects of time since surgery (baseline, 3 months, 12 months, and 24-60 months) and AD comorbidity (20 iNPH and 11 iNPH+AD) on activities of daily living (ADLs) and iNPH symptoms. Regression modeling explored whether baseline variables predicted improvements 3 months postoperatively. RESULTS: There were no group differences in gait, incontinence, and global cognition over time, and neither group showed changes in ADLs. Cognitive differences were observed postoperatively; iNPH patients showed stable improvements in working memory (p = 0.012) and response inhibition (p = 0.010), while iNPH + AD patients failed to maintain initial gains. Regarding predicting postoperative outcomes, baseline AD biomarkers did not predict shunt response at 3 months; however, older age at surgery predicted poorer cognitive outcomes (p = 0.04), and presurgical Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (p = 0.035) and Mini-Mental Status Examination (MMSE) scores (p = 0.009) predicted improvements incontinence. CONCLUSION: iNPH + AD may be linked with greater declines in aspects of executive functioning postoperatively relative to iNPH alone. While baseline AD pathology may not prognosticate shunt response, younger age appears linked with postsurgical cognitive improvement, and utilizing both brief and comprehensive cognitive measures may help predict improved incontinence. These results illustrate the potential benefits of surgery and inform postoperative expectations for those with iNPH + AD.

Differential assessment of frontally-mediated behaviors between self- and informant-report in patients with obsessive-compulsive disorder following gamma ventral capsulotomy.

Obsessive-Compulsive Disorder (OCD) is a debilitating disorder causing marked distress and functional impairment. While advances in behavioral and pharmacotherapies have been effective for a majority of patients with OCD, 10-30% remain treatment refractory and severely impaired. For a subset of treatment-resistant individuals with the most severe and disabling (intractable) illness, gamma ventral capsulotomy (GVC) appears effective in reducing OCD symptoms and functional impairment. However, the effects of the ventral internal capsule lesion via GVC surgery on executive function in everyday life have been minimally investigated. Examining behavioral outcomes of GVC also provides a rare opportunity to probe the functional importance of the ventral prefrontal-subcortical connections of the internal capsule white matter tract in a relatively homogenous sample of patients with comparable white matter lesions. The present study investigated changes in frontally-mediated behaviors, measured by the Frontal Systems Behavior Scale (FrSBe), following GVC in 45 individuals with severe and otherwise intractable OCD, as rated by patients themselves and family members. Linear mixed effects models revealed a significant improvement in patient self-ratings on the FrSBe after surgery, while family ratings did not significantly change. Interestingly, improvement on the FrSBe for both self and family raters was significantly correlated with improvement in OCD symptomatology post-surgery, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). At the group level, we found no evidence of decline in frontally-mediated behaviors assessed by the FrSBe as a result of focal white matter disconnection via GVC. However, we cannot rule out the possibility that placebo effects or compromised patient self-awareness or insight contributed to the significant improvement in self ratings. Our measures may also have limited sensitivity to more selective impairments that could result from a small lesion to the ventral internal capsule. The present study demonstrates the need for detailed investigation of cognitive and behavioral changes as important factors when considering GVC as a viable treatment option for patients with refractory OCD.

Double blind randomized controlled trial of deep brain stimulation for obsessive-compulsive disorder: Clinical trial design.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

Adding cognition to AT(N) models improves prediction of cognitive and functional decline.

INTRODUCTION: This study sought to determine whether adding cognition to a model with Alzheimer's disease biomarkers based on the amyloid, tau, and neurodegeneration/neuronal injury-AT(N)-biomarker framework predicts rates of cognitive and functional decline in older adults without dementia. METHODS: The study included 465 participants who completed amyloid positron emission tomography, cerebrospinal fluid phosphorylated tau, structural magnetic resonance imaging, and serial neuropsychological testing. Using the AT(N) framework and a newly validated cognitive metric as the independent variables, we used linear mixed effects models to examine a 4-year rate of change in cognitive and functional measures. RESULTS: The inclusion of baseline cognitive status improved model fit in predicting rate of decline in outcomes above and beyond biomarker variables. Specifically, those with worse cognitive functioning at baseline had faster rates of memory and functional decline over a 4-year period, even when accounting for AT(N). DISCUSSION: Including a newly validated measure of baseline cognition may improve clinical prognosis in non-demented older adults beyond the use of AT(N) biomarkers alone.

The Behavioral Dyscontrol Scale in the differential diagnosis of behavioral variant of frontotemporal dementia and Alzheimer disease.

OBJECTIVE: The Behavioral Dyscontrol Scale (BDS) is a brief measure of frontal systems that is adopted from Luria's syndrome analysis approach. The aim of this study was to evaluate the diagnostic utility of the BDS as an objective measure of self-regulation in behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). METHODS: Two patient groups matched in education and dementia severity (n = 21 bvFTD and 21 AD) recruited from a memory clinic and a matched normal control (NC) group (n = 21) were administered a battery of neuropsychological tests including the BDS. RESULTS: ROC analyses revealed that performance on the BDS discriminated between the bvFTD group and the AD and NC groups, as well as between AD and NC groups. Hierarchical multiple linear regression analysis showed that the majority of the variance in BDS performance was explained by executive tests. CONCLUSIONS: the BDS has good psychometric prosperities; is easy to administer and score; is well tolerated by geriatric patients; and is useful diagnostically for discriminating bvFTD from AD, yielding good to excellent sensitivity and specificity values.

Machine Learning Classification Identifies Cerebellar Contributions to Early and Moderate Cognitive Decline in Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common forms of dementia, marked by progressively degrading cognitive function. Although cerebellar changes occur throughout AD progression, its involvement and predictive contribution in its earliest stages, as well as gray or white matter components involved, remains unclear. We used MRI machine learning-based classification to assess the contribution of two tissue components [volume fraction myelin (VFM), and gray matter (GM) volume] within the whole brain, the neocortex, the whole cerebellum as well as its anterior and posterior parts and their predictive contribution to the first two stages of AD and typically aging controls. While classification accuracy increased with AD stages, VFM was the best predictor for all early stages of dementia when compared with typically aging controls. However, we document overall higher cerebellar prediction accuracy when compared to the whole brain with distinct structural signatures of higher anterior cerebellar contribution to mild cognitive impairment (MCI) and higher posterior cerebellar contribution to mild/moderate stages of AD for each tissue property. Based on these different cerebellar profiles and their unique contribution to early disease stages, we propose a refined model of cerebellar contribution to early AD development.

Neuropsychological features of delusions in hospitalized older adults with neurocognitive disorders.

Individuals with neurocognitive disorders (NCD) frequently experience psychotic symptoms, such as delusions. Delusions can contribute to other behavior problems, create dangers for patients and caregivers, and contribute to inpatient hospitalization of individuals with NCD. The current study aimed to identify cognitive symptoms associated with the presence of delusions and to differentiate delusion types based on cognitive profiles among hospitalized older adults with NCD. A review of electronic medical records of hospitalized older adults from an inpatient geriatric psychiatry setting yielded 185 patients with a diagnosis of mild or major NCD who had a neuropsychological evaluation during their admission and whose documentation described a clear delusion. We identified a comparison group of 185 patients without delusions well matched for age, education, and sex, and similar in global cognitive status. Exclusion criteria included delirium and history of a psychotic disorder. We first compared the groups' performances on a dementia battery. Then, cognitive performances of subgroups with specific delusion types (harm, theft, jealousy, and misidentification) were each compared to the remainder of the delusion-positive group. Exploratory analyses revealed that the delusion-positive group had a greater rate of discontinuation on Trails B and performed worse than the delusion-negative group on Trails A, Behavioral Dyscontrol Scale, Semantic Fluency, and Hopkins Verbal Learning Test-Revised (HVLT-R) initial registration. Theft delusions were associated with worse performance on HVLT-R recognition, misidentification delusions were associated with worse performance on Trails B, and harm delusions were associated with worse performance on a verbal generativity test. The presence of delusions in hospitalized older adults with NCD was associated with worse performance on several cognitive tasks with many being suggestive of associated with frontal-subcortical network integrity. Delusions of theft may be a consequence of reduced integrity of medial temporal lobe memory system.

Frontal Behavior Syndromes in Idiopathic Normal Pressure Hydrocephalus as a Function of Alzheimer's Disease Biomarker Status.

OBJECTIVES: Cognitive impairment and apathy are well-documented features of idiopathic normal pressure hydrocephalus (iNPH). However, research examining other neuropsychiatric manifestations of iNPH is scant, and it is unknown whether the neuropsychiatric presentation differs for iNPH patients with comorbid Alzheimer's disease (AD) versus iNPH without AD. This study aims to advance our understanding of neuropsychiatric syndromes associated with iNPH. METHODS: Fifty patients from Butler Hospital's Normal Pressure Hydrocephalus Clinic met inclusion criteria. Caregiver ratings on the Frontal Systems Behavior Scale (FrSBe) were examined to appraise changes in apathy, executive dysfunction, and disinhibition. Patients also completed cognitive tests of global cognition, psychomotor speed, and executive functioning. AD biomarker status was determined by either amyloid-beta (Aß) positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) total tau to Aß-42 ratio. RESULTS: Results revealed clinically significant elevations on the FrSBe's apathy and executive dysfunction scales and modest correlations among these scales and cognitive measures. Of the 44 patients with available neuroimaging or CSF draw data, 14 presented with comorbid AD. Relative to the iNPH-only group, the iNPH + AD group showed a larger increase from pre-illness to current informant ratings on the executive dysfunction scale, but not the apathy or disinhibition scales. CONCLUSIONS: These results replicate and extend prior research by identifying apathy and executive dysfunction as prominent neuropsychiatric symptoms of iNPH and suggest comorbid AD exacerbates dysexecutive behaviors. Future research is warranted to examine the effects of comorbid AD pathology in response to shunt surgery for iNPH, neuropsychiatric symptom changes, and resultant caregiver burden.

The Role of Sexual Disinhibition to Predict Caregiver Burden and Desire to Institutionalize Among Family Dementia Caregivers.

Neuropsychiatric symptoms in dementia are associated with greater caregiver burden and desire to institutionalize, though previous work largely examines the cumulative effects of many behavioral symptoms. Sexual disinhibition could be particularly stressful due to stigma attached to these behaviors. Links between care recipient sexual disinhibition, caregiver burden, and caregiver desire to institutionalize were examined by analyzing cross-sectional data from 730 family caregivers recruited online. Caregiver burden, caregiver desire to institutionalize, and neuropsychiatric symptoms, including sexual disinhibition, were assessed via caregiver report. Burden (P < .001) and desire to institutionalize (P = .008) were greater among caregivers who endorsed sexual disinhibition. Sexual disinhibition uniquely predicted desire to institutionalize after accounting for presence (P = .02) and severity (P = .03) of other neuropsychiatric symptoms. A similar pattern was seen for burden (presence P < .04; severity P = .06), and follow-up analyses revealed caregiver burden mediated the relationship between care recipient sexual disinhibition and caregiver desire to institutionalize (presence bias-corrected 95% confidence intervals [BCa 95% CI] [0.003, 0.08], severity BCa 95% CI [0.007, 0.06]). Sexual disinhibition appears to be a particularly difficult neuropsychiatric symptom for the family caregiver, contributing to desire to institutionalize via caregiver burden.

Discrepancy-Based Evidence for Loss of Thinking Abilities (DELTA): Development and Validation of a Novel Approach to Identifying Cognitive Changes.

OBJECTIVE: To develop and validate the Discrepancy-based Evidence for Loss of Thinking Abilities (DELTA) score. The DELTA score characterizes the strength of evidence for cognitive decline on a continuous spectrum using well-established psychometric principles for improving detection of cognitive changes. METHODS: DELTA score development used neuropsychological test scores from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (two tests each from Memory, Executive Function, and Language domains). We derived regression-based normative reference scores using age, gender, years of education, and word-reading ability from robust cognitively normal ADNI participants. Discrepancies between predicted and observed scores were used for calculating the DELTA score (range 0-15). We validated DELTA scores primarily against longitudinal Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Functional Activities Questionnaire (FAQ) scores (baseline assessment through Year 3) using linear mixed models and secondarily against cross-sectional Alzheimer's biomarkers. RESULTS: There were 1359 ADNI participants with calculable baseline DELTA scores (age 73.7 ± 7.1 years, 55.4% female, 100% white/Caucasian). Higher baseline DELTA scores (stronger evidence of cognitive decline) predicted higher baseline CDR-SOB (ΔR2 = .318) and faster rates of CDR-SOB increase over time (ΔR2 = .209). Longitudinal changes in DELTA scores tracked closely and in the same direction as CDR-SOB scores (fixed and random effects of mean + mean-centered DELTA, ΔR2 > .7). Results were similar for FAQ scores. High DELTA scores predicted higher PET-Aß SUVr (ρ = 324), higher CSF-pTau/CSF-Aß ratio (ρ = .460), and demonstrated PPV > .9 for positive Alzheimer's disease biomarker classification. CONCLUSIONS: Data support initial development and validation of the DELTA score through its associations with longitudinal functional changes and Alzheimer's biomarkers. We provide several considerations for future research and include an automated scoring program for clinical use.

Identification of Sexual Disinhibition in Dementia by Family Caregivers.

PURPOSE: Sexual disinhibition in dementia is understudied and discrepant frequency rates are reported. Measures designed to capture general disinhibition may under-identify sexual disinhibition, and lack of assessment uniformity may contribute to inconsistent endorsement. The current study aimed to determine: (1) whether an item from a commonly used measure tapping into general disinhibition would detect sexual disinhibition, (2) whether differently worded items specifically addressing sexual disinhibition would elicit inconsistent endorsement, and (3) whether different caregiver types would yield discrepant endorsement. METHODS: Data for this cross-sectional, observational study were collected online using items from the Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory, and novel items developed to assess sexual disinhibition. PATIENTS: In total, 779 family dementia caregivers were recruited from social media caregiver groups. RESULTS: In total, 26.2% of caregivers who explicitly endorsed sexual disinhibition did not endorse general disinhibition. Frequency of endorsement for sexual disinhibition differed depending upon item wording and nature of the caregiver relationship, including higher endorsement by spouses overall. DISCUSSION: Inquiring generally about disinhibition may under-identify presence of sexual disinhibition. Lack of standardization may contribute to inconsistent frequency rates and characterization of this problem. More work is needed to better understand and identify sexual disinhibition in dementia.

Gamma Ventral Capsulotomy in Intractable Obsessive-Compulsive Disorder.

BACKGROUND: Despite the development of effective pharmacologic and cognitive behavioral treatments for obsessive-compulsive disorder (OCD), some patients continue to be treatment-refractory and severely impaired. Fiber tracts connecting orbitofrontal and dorsal anterior cingulate cortex with subcortical nuclei have been the target of neurosurgical lesions as well as deep brain stimulation in these patients. We report on the safety and efficacy of ventral gamma capsulotomy for patients with intractable OCD. METHODS: Fifty-five patients with severely disabling, treatment-refractory OCD received bilateral lesions in the ventral portion of the anterior limb of the internal capsule over a 20-year period using the Leksell Gamma Knife. The patients were prospectively followed over 3 years with psychiatric, neurologic, and neuropsychological assessments of safety and efficacy, as well as structural neuroimaging. RESULTS: Thirty-one of 55 patients (56%) had an improvement in the primary efficacy measure, the Yale-Brown Obsessive Compulsive Scale, of ≥35% over the 3-year follow-up period. Patients had significant improvements in depression, anxiety, quality of life, and global functioning. Patients tolerated the procedure well without significant acute adverse events. Five patients (9%) developed transient edema that required short courses of dexamethasone. Three patients (5%) developed cysts at long-term follow-up, 1 of whom developed radionecrosis resulting in an ongoing minimally conscious state. CONCLUSIONS: Gamma Knife ventral capsulotomy is an effective radiosurgical procedure for many treatment-refractory OCD patients. A minority of patients developed cysts at long-term follow-up, 1 of whom had permanent neurological sequelae.

Cognitive outcome after ventral capsule/ventral striatum stimulation for treatment-resistant major depression.

BACKGROUND: We report the neuropsychological outcome of 25 patients with treatment-resistant major depressive disorder (TRD) who participated in an Institutional Review Board (IRB)-approved randomised double-blind trial comparing active to sham deep brain stimulation (DBS) in the anterior limb of the ventral capsule/ventral striatum (VC/VS). METHODS: Participants were randomised to active (n=12) versus sham (n=13) DBS for 16 weeks. Data were analysed at the individual and group levels. Group differences were analysed using repeated measures ANOVAs. Relationships between depression severity and cognition were examined using partial correlations. The false discovery rate method controlled for multiple analyses. RESULTS: No significant interactions comparing active versus sham stimulation over time were evident. Change in depression was unrelated to change in neuropsychological measures. Twenty patients declined by ≥1 SD on at least one measure (41.3% of declines occurred in active group participants; 63.0% in older participants regardless of stimulation status). Twenty-two patients exhibited improvements >1 SD on neuropsychological measures (47.7% in the active group; 63.1% in younger participants). CONCLUSIONS: These data suggest that VC/VS DBS in patients with TRD does not significantly affect neuropsychological function. Age at surgery, regardless of stimulation status, may be related to cognitive outcome at the individual patient level. TRIAL REGISTRATION NUMBER: NCT00837486; Results.

Two Novel Psychomotor Tasks in Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (INPH) is a neurological disorder presenting with gait, cognitive, and bladder symptoms in the context of ventricular enlargement. Although gait is the primary indicator for treatment candidacy and outcome, additional monitoring tools are needed. Line Tracing Test (LTT) and Serial Dotting Test (SDT), two psychomotor tasks, have been introduced as potential outcome measures but have not been widely studied. This preliminary study examined whether LTT and SDT are sensitive to motor dysfunction in INPH and determined if accuracy and time are important aspects of performance. METHODS: Eighty-four INPH subjects and 36 healthy older adults were administered LTT and SDT. Novel error scoring procedures were developed to make scoring practical and efficient; interclass correlation showed good reliability of scoring procedures for both tasks (0.997; p<.001). RESULTS: The INPH group demonstrated slower performance on SDT (p<.001) and made a greater number of errors on both tasks (p<.001). Combined Time/Error scores revealed poorer performance in the INPH group for original-LTT (p<.001), modified-LTT (p ≤ .001) and SDT (p<.001). CONCLUSIONS: These findings indicate LTT and SDT may prove useful for monitoring psychomotor skills in INPH. While completion time reflects impaired processing speed, reduced accuracy may suggest planning and self-monitoring difficulties, aspects of executive functioning known to be compromised in INPH. This is the first study to underscore the importance of performance accuracy in INPH and introduce practical/reliable error scoring for these tasks. Future work will establish reliability and validity of these measures and determine their utility as outcome tools.

Lowering the Floor on Trail Making Test Part B: Psychometric Evidence for a New Scoring Metric.

The Trail Making Test Part B (TMT-B) is widely used in clinical and research settings as a measure of executive function. Standard administration allows a maximal time score (i.e., floor score) of 300 s. This practice potentially masks performance variability among cognitively impaired individuals who cannot complete the task. For example, performances that are nearly complete receive the same 300-s score as a performance of only a few moves. Such performance differences may have utility in research and clinical settings. To address this, we propose a new TMT-B efficiency metric designed to capture clinically relevant performance variability below the standard administration floor. Our metric takes into account time, correct moves, and errors of commission and omission. We demonstrate that the metric has concurrent validity, permits statistical analysis of performances that fall below the test floor, and captures clinically relevant performance variability missed by alternative methods.

Depression and Apathy Among People Living with HIV: Implications for Treatment of HIV Associated Neurocognitive Disorders.

Depression and apathy are common among people living with HIV (PLWH). However, in PLWH, it is unclear whether depression and apathy are distinct conditions, which contribute to different patterns of disruption to cognitive processing and brain systems. Understanding these conditions may enable the development of prognostic indicators for HIV associated neurocognitive disorders (HAND). The present study examined substance use behavior and cognitive deficits, associated with depression and apathy, in 120 PLWH, using hierarchical regression analyses. Higher levels of depression were associated with a history of alcohol dependence and greater deficits in processing speed, motor and global cognitive functioning. Higher levels of apathy were associated with a history of cocaine dependence. It is recommended that PLWH get screened appropriately for apathy and depression, in order to receive the appropriate treatment, considering the comorbidities associated with each condition. Future research should examine the neurological correlates of apathy and depression in PLWH.

Neuropsychological outcome after deep brain stimulation in the ventral capsule/ventral striatum for highly refractory obsessive-compulsive disorder or major depression.

BACKGROUND: Deep brain stimulation (DBS) has shown promise as a treatment for severe, highly treatment-refractory obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). We describe the neuropsychological outcome in 21 patients (10 OCD and 11 MDD) who received DBS in the anterior limb of the internal capsule/ventral striatum (VC/VS). METHODS: All patients completed a preoperative and postoperative neuropsychological battery. Average duration of DBS stimulation was 8.91 months (SD = 4.63) at the time of follow-up testing. Data were analyzed using practice-effect-corrected change scores. RESULTS: No significant cognitive declines were seen. There were significant improvements in prose passage recall after chronic DBS. The cognitive improvements were not related to change in severity of OCD, depression or global impairment. CONCLUSIONS: This preliminary study suggests that VC/VS DBS does not result in cognitive declines. The observations that verbal memory improved are consistent with current theories on the role of the VS in the memory, but require replication in larger studies.

Confirmatory factor analysis of the Frontal Systems Behavior Scale (FrSBe).

The Frontal Systems Behavior Scale (FrSBe) is a 46-item questionnaire that measures behaviors associated with frontal subcortical deficits (apathy, disinhibition, and executive dysfunction) in adult neurologic populations. Based on findings from a previous exploratory factor analysis on the scale, the current study used confirmatory factor analysis to explore and potentially improve on the measurement model fit of current FrSBe scores. Model fit indices and reliabilities (measured using internal consistency reliability) were compared in the original and in several alternative models. The original scale demonstrated a generally good fitting model, although the best fitting model (referred to as the reduced model) removed eight items from the original measure and modestly improved model fit over the original FrSBe. Strong reliability was found in both versions. Results from the current study provide a critical first step in a potential FrSBe scale revision.

The APOE ε4 allele is associated with increased frontally mediated neurobehavioral symptoms in amnestic MCI.

The apolipoprotein E ε4 allele is a risk factor for late-onset Alzheimer disease (AD), and the frontal lobes may be among the regions that manifest effects of ε4 even early in the disease. We predicted that among patients with amnestic mild cognitive impairment (aMCI) and AD, ε4 would be associated with increased neurobehavioral symptoms when assessed using a measure sensitive to frontal lobe integrity. We obtained cognitive data and caregiver ratings on the Frontal Systems Behavior Scale (FrSBe) for aMCI patients (N=29 ε4 carriers; N=29 noncarriers) and AD patients (N=47 carriers; N=42 noncarriers). In both diagnostic groups, ε4 carriers had lower scores on tests of memory but did not differ on cognitive screening measures or tests of executive functioning. There were no differences in retrospective caregiver ratings of preillness status on the FrSBe by ε4 status in either diagnostic group. However, in the aMCI group, ε4 carriers had elevated current FrSBe Executive Dysfunction scores in comparison with noncarriers. In the AD group, there were no differences in current FrSBe scores by genotype group. Results indicate that ε4-related behavior change occurs in the aMCI stage but may not be apparent by the AD stage.

A randomized, double-blind, placebo-controlled trial of modafinil for the treatment of apathy in individuals with mild-to-moderate Alzheimer's disease.

OBJECTIVE: This study examined the effects of modafinil on apathetic symptomatology, performance of activities of daily living (ADLs), and caregiver burden in individuals with Alzheimer's disease (AD). METHOD: 23 participants with a diagnosis of mild-to-moderate probable AD according to National Institute of Neurologic and Communicative Disorder and Stroke-Alzheimer's Disease and Related Disorders criteria were randomized into the experimental (modafinil 200 mg daily) or control (placebo) groups. All participants were also receiving stable doses of a cholinesterase inhibitor medication. Participants completed assessments at baseline and after 8 weeks of treatment. Outcome measures included family report measures of apathy, ADL performance, and caregiver burden, as well as direct assessment of ADL performance. The study was conducted at a private psychiatric hospital in Rhode Island from September 2005 until September 2007. RESULTS: Both the experimental and control groups showed reductions in apathy on the Frontal Systems Behavior Scale between baseline and final assessments (F1,20 = 18.017, P < .001, η2 = 0.474), and there was no significant additional reduction in apathy with modafinil (F1,20 = 0.008, P = .932, η2 = 0.000). Groups did not show significant changes in caregiver report of ADL performance over time (F1,19 = 0.268, P = .611). The correlation between change in apathy and change in caregiver burden was not significant (r = 0.355, P = .053), but there was a trend toward improved levels of apathy being related to decreased levels of caregiver burden. CONCLUSIONS: The addition of modafinil to the standard of care treatment (cholinesterase inhibitor medication) did not result in significant additional reductions in apathy or improvements in ADL functioning. The reduction in reported apathy observed in both groups between baseline and final assessments was likely due to placebo effect. However, reductions in perceived apathetic symptomatology were correlated with reductions in reported caregiver distress and burden. Larger studies with more statistical power are needed to confirm the absence of significant effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01172145.