An Open-Label, Pilot Study of Daratumumab SC in Mild to Moderate Alzheimer's Disease.

We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer's disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures.

The Relational and Item-Specific Encoding Task in Mild Cognitive Impairment and Alzheimer Disease.

BACKGROUND: The Relational and Item-Specific Encoding task (RISE) measures episodic memory subcomponents, including item-specific and relational encoding of to-be-remembered stimuli. These memory components are neurobiologically relevant because they may engage distinct subregions of the medial temporal lobe, perirhinal and entorhinal cortices, parahippocampus, and hippocampus. METHODS: A total of 125 participants, including 84 healthy controls (HC), 22 mild cognitive impairment-diagnosed and 19 Alzheimer disease (AD)-diagnosed participants, were administered the RISE and neuropsychological measures. Stepwise linear regressions assessed prediction of functional ability from RISE d' measures. ANOVAs and logistic regressions determined the ability of the RISE to discriminate between the diagnostic groups. In addition, the psychometric properties of the RISE were examined. RESULTS: RISE measures predicted diagnosis with pseudo R2 values in the range of 0.25-0.30. Receiver operating characteristic curves demonstrated adequate sensitivity and specificity with areas under the curve in the range of 0.78-0.98. Memory following relational encoding was a significant predictor of everyday functional competence. The RISE had acceptable psychometric properties, with the exception of floor effects in the AD group. CONCLUSION: The RISE measures significantly predicted diagnosis and predicted everyday functional competence. The RISE offers unique advantages in the assessment of HC and individuals with preclinical AD.

APOE genotype modulates proton magnetic resonance spectroscopy metabolites in the aging brain.

BACKGROUND: Proton magnetic resonance spectroscopy ((1)H-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimer's disease. Additionally, we examined these measures in relation to cognition. METHODS: We studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of (1)H-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained. RESULTS: General linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myo-inositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE × age interaction and APOE status each had a significant effect on (1)H-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE × age variable modulation of cognition was mediated by (1)H-MRS metabolites. CONCLUSIONS: In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers.

An Open-Label Exploratory Study with Memantine: Correlation between Proton Magnetic Resonance Spectroscopy and Cognition in Patients with Mild to Moderate Alzheimer's Disease.

AIM: To characterize progression of Alzheimer's disease (AD) using proton magnetic resonance spectroscopy ((1)H MRS). METHODS: Eleven subjects with mild to moderate AD underwent neurocognitive testing and single-voxel (1)H MRS from the precuneus and posterior cingulate region at baseline, after 24 weeks of monotherapy with a cholinesterase inhibitor, and after another 24 weeks of combination therapy with open-label memantine and a cholinesterase inhibitor. Baseline metabolites [N-acetylaspartate (NAA), myo-inositol (mI), choline (Cho), and creatine (Cr)] and their ratios in AD subjects were compared with those of an age-matched control group of 28 cognitively normal subjects. RESULTS: AD subjects had significantly higher mI/Cr and lower NAA, NAA/Cr, NAA/Cho, and NAA/mI. Baseline Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores significantly correlated with NAA/Cr, mI/Cr, and NAA/mI. There was an increase in mI and a decrease in NAA/mI, but no significant change in other metabolites or ratios, or neurocognitive measures, when memantine was added to a cholinesterase inhibitor. CONCLUSION: Metabolite ratios significantly differed between AD and control subjects. Baseline metabolite ratios correlated with function (ADCS-ADL). There was an increase in mI and a decrease in NAA/mI, but no changes in other metabolites, ratios, or cognitive measures, when memantine was added to a cholinesterase inhibitor.

Performance-based measures of everyday function in mild cognitive impairment.

OBJECTIVE: The view that everyday function is preserved in mild cognitive impairment may be problematic. The objectives of this study were to determine the magnitude of impairment in everyday function in patients with mild cognitive impairment and Alzheimer's disease using a novel sensitive performance-based measure (the UCSD Performance-Based Skills Assessment; UPSA), contrast it with use of an informant-based measure (the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory; ADCS-ADL), and model the relationship between cognitive measures and the performance-based measure. METHOD: Fifty cognitively normal elders, 26 patients who met criteria for amnestic mild cognitive impairment, and 22 patients who suffered from mild to moderate Alzheimer's disease were assessed on the UPSA, the ADCS-ADL, and a battery of neurocognitive tests. RESULTS: Patients with mild cognitive impairment had significant impairments on the UPSA but not on the ADCS-ADL. The magnitude of the effect size between the cognitively healthy and the mild cognitive impairment group for the UPSA was large (d=0.86). A strong and significant relationship was observed between cognitive performances in speed (R(2)=0.37), episodic memory (R(2)=0.10), and semantic processing (R(2)=0.03) and UPSA score using multiple regression models. The psychometric properties of the UPSA were acceptable, as were its sensitivity and specificity in contrasts between cognitively normal elders and patients with mild cognitive impairment and between the latter group and patients with Alzheimer's disease. CONCLUSIONS: These findings indicate that performance-based measures of function may be a sensitive tool in studies of Alzheimer's disease and mild cognitive impairment and suggest the need for a reconceptualization of the relationship between cognition and function in mild cognitive impairment so that they can be usefully aligned.

Neurocognitive profile in adolescents with early-onset schizophrenia: clinical correlates.

BACKGROUND: Neurocognitive impairments have been documented in adolescents with early-onset schizophrenia (EOS; onset by age 18) and are important treatment targets. Information concerning the severity, pattern, and clinical correlates of these deficits in EOS remains limited. METHODS: Tests assessing motor skills, attention, memory, visuospatial abilities and executive functioning were administered to 54 clinically stabilized adolescents with EOS and 52 age- and sex-matched healthy controls. Childhood-onset patients (onset by age 13) were compared to those with an adolescent onset of illness. Patients' neurocognitive profiles were compared to those of controls. Relationships between neurocognitive deficits and demographic and clinical characteristics were explored. RESULTS: Neurocognitive profiles did not differ between childhood- and adolescent-onset participants. Patients showed a generalized neurocognitive deficit of 2.0 SDs compared to controls, with relative deficit in executive functioning and relative sparing of language and visuospatial abilities. Degree of generalized neurocognitive impairment was associated with premorbid adjustment and negative symptom severity (Adjusted R(2) = .39). CONCLUSIONS: Results document both a significant generalized deficit and a relative deficit of executive functioning in adolescents with EOS. The overall pattern is similar to that observed in severely ill first-episode adult patients. The impairments across multiple neurocognitive domains suggest widespread brain dysfunction in EOS.