Hermann Josef Gertz

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 Alzheimers 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), Alzheimers 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 α4β2*–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.

An object-based approach for detecting small brain lesions: application to Virchow-Robin spaces

This paper is concerned with the detection of multiple small brain lesions from magnetic resonance imaging (MRI) data. A model based on the marked point process framework is designed to detect Virchow-Robin spaces (VRSs). These tubular shaped spaces are due to retraction of the brain parenchyma from its supplying arteries. VRS are described by simple geometrical objects that are introduced as small tubular structures. Their radiometric properties are embedded in a data term. A prior model includes interactions describing the clustering property of VRS. A Reversible Jump Markov Chain Monte Carlo algorithm (RJMCMC) optimizes the proposed model, obtained by multiplying the prior and the data model. Example results are shown on T/sub 1/-weighted MRI datasets of elderly subjects.

Texture-based segmentation of diffuse lesions of the brain's white matter.

Diffuse lesions of the white matter of the human brain are common pathological findings in magnetic resonance images of elderly subjects. These lesions are typically caused by small vessel diseases (e.g., due to hypertension, diabetes), and related to cognitive decline. Because these lesions are inhomogeneous, unsharp, and faint, but show an intensity pattern that is different from the adjacent healthy tissue, a segmentation based on texture properties is proposed here. This method was successfully applied to a set of 116 image data sets of elderly subjects. Quantitative measures for the lesion load are derived that compare well with results from experts that visually rated lesions on a semiquantitative scale. Texture-based segmentation can be considered as a general method for lesion segmentation, and an outline for adapting this method to similar problems is presented.

The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey

We investigated the use of Alzheimers disease (AD) biomarkers in European Alzheimers Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG‐PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it “always/frequently”) followed by CSF markers (22%), FDG‐PET (16%), and amyloid‐PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as “moderate”. Seventy‐nine percent of responders felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

Morphometry of the amygdala in patients with questionable dementia and mild dementia

The volume of the amygdala is reduced in advanced Alzheimers disease (AD). However, there is controversy whether amygdala atrophy is present in mild AD and in the transitional phase between health and the onset of dementia. The aim of this prospective longitudinal study was to investigate whether amygdala atrophy is present in subjects with questionable dementia and mild dementia and whether amygdala volume is associated with the future rate of cognitive change, that is the annual change in the Mini Mental State Examination (MMSE). At baseline, volumes of the amygdala were measured in 97 participants aged 70-87 years (40 controls, 33 patients with questionable dementia, 24 patients with mild AD) using magnetic resonance imaging. Eighty-six participants were clinically re-examined after 2.3 years on average. At baseline, significant differences in mean amygdala volume were found between controls and participants with mild AD. There was no significant correlation between the longitudinal annual change in MMSE and the baseline amygdala volume in any of the three groups.

Association between reduced Alpha4Beta2 nicotinic acetylcholine receptor availability and nonmotor symptoms in early drug naive Parkinson disease

Purpose: Nonmotor (cognitive and mood) symptoms are common in patients with early stage, drug naive Parkinson disease (PD) (Poewe, 2008). The α4β2 nicotinic acetylcholine receptors (α4β2-nAChR) are expressed in cholinergic and non-cholinergic neurons throughout the human brain and play a role for addiction, cognition and mood by modulating neurotransmitter release (Dani and Bertrand, 2007). Previously, it has been demonstrated that there is an association between lower cortical and subcortical α4β2-nAChR binding and the degree of mental dysfunction in patients with moderate, medicated PD without dementia or depression (Meyer et al., 2009). To investigate the α4β2-nAChR availability and its relationship to cognitive and depressive symptoms in early PD, patients with early stage, drug naive PD were studied using α4β2-nAChR specific 2-[18F]F-A-85380 (2FA) PET and neuroscreening tests (MMSE, DemTect, BDI).

Compartment-model based quantification of beta-amyloid binding with Florbetaben PET in Alzheimer's disease and control subjects☆

Objectives: Florbetaben is a promising PET tracer for imaging of β-amyloid deposits in human brains. This F-labeled stilbene derivative is rapidly metabolized in vivo, producing low molecular weight, polar metabolite(s), which appear to enter the brain. We aimed to model the presence of the polar metabolite(s) in the brain in the quantification of β-amyloid binding from Florbetaben human PET data of Alzheimers disease (AD) and healthy control (HC) subjects.

Kinetic modeling of florbetaben binding to beta-amyloid in human brains using one and two input functions ☆

Methods: After i.v. administration of ∼300 MBq Florbetaben, 10 subjects with Alzheimers disease (AD) and 10 age-matched healthy volunteers (HV) underwent 3D-PET. Concentrations of parent compound and metabolites were determined in plasma and used as input functions. VOI-based tissue–activity curves (TACs) from 25 brain regions were analyzed using two tissue compartments with one input function (OIF) or three tissue compartments with two input functions (TIF) over a time range of 90 (OIF) and 200 (TIF) minutes. Also the multilinear reference tissue method MRTM3 was applied. The kinetics of the metabolite(s) was described by one tissue compartment (“simplified” K1 fixed). Distribution volume ratio (DVR), binding potential with reference to the total tracer plasma concentration (BPP) and standardized uptake value ratio (SUVR) were used to characterize specific binding (reference: cerebellar cortex). Effect size in group comparison was determined by Cohens d.