Incremental value of biomarker combinations to predict progression of mild cognitive impairment to Alzheimer's dementia.

BACKGROUND: The progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1-42 (Aß42), amyloid-beta1-40 (Aß40) levels, the ratio of Aß42/Aß40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia. METHODS: We used 115 complete datasets from MCI patients of the "Dementia Competence Network", a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%. RESULTS: Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aß40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80-0.83, and the four-parameter combination from AUC 0.81-0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone. CONCLUSION: A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials.

Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study.

This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.

Reduced alpha4beta2*-nicotinic acetylcholine receptor binding and its relationship to mild cognitive and depressive symptoms in Parkinson disease.

CONTEXT: Cognitive or depressive disorders are frequently noted in patients with Parkinson disease (PD) and may be related to altered signaling through alpha4beta2*-nicotinic acetylcholine receptors (alpha4beta2*-nAChRs). OBJECTIVE: To assess the availability of alpha4beta2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD. DESIGN: Crossover comparison between patients with PD and healthy volunteers (control group) using the alpha4beta2*-nAChR-specific radioligand 2-[(18)F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[(18)F]FA-85380) and positron emission tomography. SETTING: Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany. PARTICIPANTS: Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers. MAIN OUTCOME MEASURES: Level of 2-[(18)F]FA-85380 binding potential (2-FA BP), a measure of alpha4beta2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed. RESULTS: In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum. CONCLUSIONS: There is a broad reduction of alpha4beta2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.