Gregory H. Pelton

Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease.

Objective: To evaluate the utility of MRI hippocampal and entorhinal cortex atrophy in predicting conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). Methods: Baseline brain MRI was performed in 139 patients with MCI, broadly defined, and 63 healthy controls followed for an average of 5 years (range 1 to 9 years). Results: Hippocampal and entorhinal cortex volumes were each largest in controls, intermediate in MCI nonconverters, and smallest in MCI converters to AD (37 of 139 patients converted to AD). In separate Cox proportional hazards models, covarying for intracranial volume, smaller hippocampal volume (risk ratio [RR] 3.62, 95% CI 1.93 to 6.80, p < 0.0001), and entorhinal cortex volume (RR 2.43, 95% CI 1.56 to 3.79, p < 0.0001) each predicted time to conversion to AD. Similar results were obtained for hippocampal and entorhinal cortex volume in patients with MCI with Mini-Mental State Examination (MMSE) scores ≥ 27 out of 30 (21% converted to AD) and in the subset of patients with amnestic MCI (35% converted to AD). In the total patient sample, when both hippocampal and entorhinal volume were entered into an age-stratified Cox model with sex, MMSE, education, and intracranial volume, smaller hippocampal volume (RR 2.21, 95% CI 1.14 to 4.29, p < 0.02) and entorhinal cortex volume (RR 2.48, 95% CI 1.54 to 3.97, p < 0.0002) predicted time to conversion to AD. Similar results were obtained in a Cox model that also included Selective Reminding Test (SRT) delayed recall and Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol as predictors. Based on logistic regression models in the 3-year follow-up sample, for a fixed specificity of 80%, the sensitivities for MCI conversion to AD were as follows: age 43.3%, MMSE 43.3%, age + MMSE 63.7%, age + MMSE + SRT delayed recall + WAIS-R Digit Symbol 80.6% (79.6% correctly classified), hippocampus + entorhinal cortex 66.7%, age + MMSE + hippocampus + entorhinal cortex 76.7% (85% correctly classified), age + MMSE + SRT delayed recall + WAIS-R Digit Symbol + hippocampus + entorhinal cortex 83.3% (86.8% correctly classified). Conclusions: Smaller hippocampal and entorhinal cortex volumes each contribute to the prediction of conversion to Alzheimer disease. Age and cognitive variables also contribute to prediction, and the added value of hippocampal and entorhinal cortex volumes is small. Nonetheless, combining these MRI volumes with age and cognitive measures leads to high levels of predictive accuracy that may have potential clinical application.

Functional deficits in patients with mild cognitive impairment Prediction of AD

ObjectiveTo evaluate the predictive utility of self-reported and informant-reported functional deficits in patients with mild cognitive impairment (MCI) for the follow-up diagnosis of probable AD. MethodsThe Pfeffer Functional Activities Questionnaire (FAQ) and Lawton Instrumental Activities of Daily Living (IADL) Scale were administered at baseline. Patients were followed at 6-month intervals, and matched normal control subjects (NC) were followed annually. ResultsSelf-reported deficits were higher for patients with MCI than for NC. At baseline, self- and informant-reported functional deficits were significantly greater for patients who converted to AD on follow-up evaluation than for patients who did not convert, even after controlling for age, education, and modified Mini-Mental State Examination scores. While converters showed significantly more informant- than self-reported deficits at baseline, nonconverters showed the reverse pattern. Survival analyses further revealed that informant-reported deficits (but not self-reported deficits) and a discrepancy score indicating greater informant- than self-reported functional deficits significantly predicted the development of AD. The discrepancy index showed high specificity and sensitivity for progression to AD within 2 years. ConclusionsThese findings indicate that in patients with MCI, the patient’s lack of awareness of functional deficits identified by informants strongly predicts a future diagnosis of AD. If replicated, these findings suggest that clinicians evaluating MCI patients should obtain both self-reports and informant reports of functional deficits to help in prediction of long-term outcome.

Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer's disease.

BACKGROUND The utility of combining early markers to predict conversion from mild cognitive impairment (MCI) to Alzheimers Disease (AD) remains uncertain. METHODS Included in the study were 148 outpatients with MCI, broadly defined, followed at 6-month intervals. Hypothesized baseline predictors for follow-up conversion to AD (entire sample: 39/148 converters) were cognitive test performance, informant report of functional impairment, apolipoprotein E genotype, olfactory identification deficit, and magnetic resonance imaging (MRI) hippocampal and entorhinal cortex volumes. RESULTS In the 3-year follow-up patient sample (33/126 converters), five of eight hypothesized predictors were selected by backward and stepwise logistic regression: Pfeffer Functional Activities Questionnaire (FAQ; informant report of functioning), University of Pennsylvania Smell Identification Test (UPSIT; olfactory identification), Selective Reminding Test (SRT) immediate recall (verbal memory), MRI hippocampal volume, and MRI entorhinal cortex volume. For 10% false positives (90% specificity), this five-predictor combination showed 85.2% sensitivity, combining age and Mini-Mental State Examination (MMSE) showed 39.4% sensitivity; combining age, MMSE, and the three clinical predictors (SRT immediate recall, FAQ, and UPSIT) showed 81.3% sensitivity. Area under ROC curve was greater for the five-predictor combination (.948) than age plus MMSE (.821; p = .0009) and remained high in subsamples with MMSE > or = 27/30 and amnestic MCI. CONCLUSIONS The five-predictor combination strongly predicted conversion to AD and was markedly superior to combining age and MMSE. Combining the clinically administered measures also led to strong predictive accuracy. If independently replicated, the findings have potential utility for early detection of AD.

Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial

IMPORTANCE Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. OBJECTIVE The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. DESIGN, SETTING, AND PARTICIPANTS The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. INTERVENTIONS Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. MAIN OUTCOMES AND MEASURES Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. RESULTS Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. CONCLUSIONS AND RELEVANCE Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00898807.

A 10-item smell identification scale related to risk for Alzheimer's disease

University of Pennsylvania Smell Identification Test data from control subjects (n = 63), patients with mild cognitive impairment (n = 147), and patients with Alzheimers disease (n = 100) were analyzed to derive an optimal subset of items related to risk for Alzheimers disease (ie, healthy through mild cognitive impairment to early and moderate disease stages). The derived 10‐item scale performed comparably with the University of Pennsylvania Smell Identification Test in classifying subjects, and it strongly predicted conversion to Alzheimers disease on follow‐up evaluation in patients with mild cognitive impairment. Independent replication is needed to validate these findings. Ann Neurol 2005;58:155–160

Relapse Risk after Discontinuation of Risperidone in Alzheimer’s Disease

BACKGROUND Among patients with Alzheimers disease who have had a response to antipsychotic medication for psychosis or agitation-aggression, the risk of a recurrence of symptoms after discontinuation of the medication has not been established. METHODS Patients with Alzheimers disease and psychosis or agitation-aggression received open-label treatment with risperidone for 16 weeks. Those who had a response to risperidone therapy were then randomly assigned, in a double-blind fashion, to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3). The primary outcome was the time to relapse of psychosis or agitation. RESULTS A total of 180 patients received open-label risperidone (mean dose, 0.97 mg daily). The severity of psychosis and agitation were reduced, although there was a mild increase in extrapyramidal signs; 112 patients met the criteria for response to treatment, of whom 110 underwent randomization. In the first 16 weeks after randomization, the rate of relapse was higher in the group that received placebo than in the groups that received risperidone (60% [24 of 40 patients in group 3] vs. 33% [23 of 70 in groups 1 and 2]; P=0.004; hazard ratio with placebo, 1.94; 95% confidence interval [CI], 1.09 to 3.45; P=0.02). During the next 16 weeks, the rate of relapse was higher in the group that was switched from risperidone to placebo than in the group that continued to receive risperidone (48% [13 of 27 patients in group 2] vs. 15% [2 of 13 in group 1]; P=0.02; hazard ratio, 4.88; 95% CI, 1.08 to 21.98; P=0.02). The rates of adverse events and death after randomization did not differ significantly among the groups, although comparisons were based on small numbers of patients, especially during the final 16 weeks. CONCLUSIONS In patients with Alzheimers disease who had psychosis or agitation that had responded to risperidone therapy for 4 to 8 months, discontinuation of risperidone was associated with an increased risk of relapse. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00417482.).

Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance.

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimers disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.

Pittsburgh Compound B (11C-PIB) and Fluorodeoxyglucose (18 F-FDG) PET in Patients With Alzheimer Disease, Mild Cognitive Impairment, and Healthy Controls

Amyloid load in the brain using Pittsburgh compound B (11C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose (18F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). 11C-PIB binding potential (BPND) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For 18F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI—CTR differences. For the AD—CTR comparison, precuneus BPND area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. 11C-PIB PET BPND clearly distinguished diagnostic groups and combined with 18F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

Late onset dysthymic disorder and major depression differ from early onset dysthymic disorder and major depression in elderly outpatients

BACKGROUND Age of onset may affect clinical features and prognosis in elderly patients with major depression (MDD), but there is a lack of such data in elderly patients with dysthymic disorder (DD) and systematic comparisons of late onset MDD and DD have not been conducted. METHODS In a Late Life Depression Clinic, patients > or = 60 years old who met DSM-III-R or DSM-IV criteria for MDD or DD were studied. The 24-item Hamilton Rating Scale for Depression (HRSD) and SCID-P were completed, family history was obtained, and medical illnesses were assessed. RESULTS In the total sample (n=370; 211 MDD and 159 DD), compared to early onset patients, late onset (onset > or =60 years) patients had a higher rate of cardiovascular disease (chi(2)=4.12, df=1, P<0.05), lower rate of anxiety disorder (chi(2)=4.19, df=1, P<0.05), and a lower rate of family history of affective disorder (chi(2)=9.37, df=1, P<0.002). Late onset DD patients were more likely to have cardiovascular disease than early onset DD patients (chi(2)=5.63, df=1, P<0.02), but the rate of cardiovascular disease did not differ between late and early onset MDD patients (chi(2)=0.35, df=1, P<0.6). Late onset MDD patients were less likely to have a family history of affective disorder than early onset MDD patients (chi(2)=10.71, df=1, P<0.001). Prevalence of anxiety disorders did not differ between the early and late onset MDD patients (chi(2)=0.07, df=1, P<0.79), but was more common in the early onset DD compared to the late onset DD patients (17.98% versus 4.29%, chi(2)=6.98, df=1, P<0.01). Late onset DD did not differ from late onset MDD in the rates of cardiovascular disease, anxiety disorders, and family history of affective disorder. Excluding patients with double depression (n=32) did not alter the cardiovascular or family history findings, but the difference in anxiety disorders between early and late onset DD patients was no longer significant. LIMITATIONS Academic clinic sample results may not generalize to community populations. CONCLUSIONS In the elderly, late-onset DD is typically different from early onset DD. Cerebrovascular disease appears to play a role in the etiology of late onset DD. The similarities between late onset DD and late onset MDD suggest a single condition along a continuum.

The neurobiology of tryptophan depletion in depression: effects of intravenous tryptophan infusion.

BACKGROUND Previous work has suggested that acute depletion of the serotonin (5-HT) precursor tryptophan (TRP) causes transient compensatory changes in the 5-HT system that might be exploited for their antidepressant effects. In this study, neuroendocrine and mood responses to intravenous (i.v.) infusion of TRP were examined in order to evaluate central 5-HT function in depressed patients undergoing acute TRP depletion. METHODS Thirty-eight drug-free patients with DSM-III-R major depression participated. Each patient underwent two randomized, double-blind TRP depletion tests, one sham and one active. At the estimated time of maximum TRP depletion, each patient received an i.v. infusion of TRP 100 mg/kg. Blood was obtained for serum cortisol, prolactin, and growth hormone. Mood was assessed using standardized rating scales. RESULTS The cortisol response to i.v. TRP was significantly greater during TRP depletion than during sham depletion. Depressive symptoms showed a tendency to decrease after i.v. TRP following active, but not sham, TRP depletion. CONCLUSIONS These findings are consistent with the present hypothesis and previous evidence that acute TRP depletion in drug-free depressed patients induces compensatory upregulation of postsynaptic 5-HT receptors. These changes are insufficient to serve as a means of effecting clinical improvement, but suggest that the antidepressant properties of rapid, marked manipulations of 5-HT function warrant further study.