Faculty Bibliography

Background: Numerous studies have linked depressive symptoms, or syndromal depression, to increased risk for Alzheimer's disease (AD) irrespective of its onset age. The neurobiological basis for this association, however, remains poorly understood. Studies which have examined biomarkers of AD in peripheral and central tissues in depression, including CSF Abeta42 (Abeta42) and brain amyloid using PET ligands, have provided conflicting results. These discrepant results may have been due to methodological differences across studies, including heterogeneity in study populations (e.g., inclusion of individuals with mild cognitive impairment) and the use of approaches for detecting depression (e.g., patients' self-ratings) that lack diagnostic specificity. In addition, only a few studies have employed structured interviews based on DSM diagnostic criteria or standardized pre-analytical and laboratory procedures for quantifying Abeta. Finally, all of the existing studies have been limited to cross sectional comparisons based on a single Abeta determination; thus, it is not known if these abnormalities persist over time and if depressive symptoms influence Abeta levels. The current study was conducted to address the aforementioned limitations. Methods: Our baseline sample consisted of 47 subjects aged 60 years and older; 28 with LMDD and 19 controls. Of the 47 older subjects, 31 were e4 non-carriers and 16 were e4 carriers. All subjects were cognitively-intact and had a) no evidence of dementia, b) a Mini-Mental State Exam score of at least 28, and c) no gross MRI abnormalities other than white matter hyperintensities. CSF collection was repeated after 3 years for 36 of these individuals: 19 with LLMD and 17 controls. We evaluated the effects of diagnosis and time on Abeta42 levels with 2 x 2 repeated measures ANOVA. Results: Longitudinal comparisons of controls and LLMD revealed that the LLMD group was significantly less depressed at follow up than at baseline, as determined by the HAM-D, whereas controls remained unchanged. There was a significant interaction between diagnosis and time on CSF Abeta42 levels. Importantly, the reductions in depressive symptoms observed over time were significantly correlated with increases in CSF Abeta42 levels, both in the entire cohort (r =-.451, p =.006) and within the LLMD group (r =-.547, p =.015), but not in the control group (p =.809). The same relationship was not significant with Abeta40 (Pomara et al., 2016). Performance on cognitive indices remained unchanged and was not significantly correlated with changes in AD Biomarkers. Conclusions: Cognitively-intact, elderly individuals with LLMD, who were more depressed at baseline, but less depressed at the 3 year follow-up, showed both a reduction in baseline CSF Abeta42 (Pomara et al., 2012) and elevation in Abeta42 at 3 year follow-up. In addition, changes in CSF Abeta42 were correlated with changes in depressive symptoms. Future studies should determine if these state-dependent changes in Abeta42 mediate the increased risk of AD contributed by LLMD. If this is the case, the need for more aggressive treatment of LLMD cannot be underestimated

Objectives: MicroPET imaging has been increasingly performed on mouse models for a variety of human CNS disorders. Despite high demand, digital mouse brain atlases based on PET are still lacking. Further, most microPET systems do not provide means of mapping mouse brain with atlas. For quantitative data analysis and accurate anatomical localization, the development and evaluation of an automated atlas-based data analysis on microPET mouse brain studies is presented. Methods: MicroPET imaging studies were performed after injection of F-18 labeled Amyvid (a tracer for imaging amyloid (Aa) plaques) in isoflurane-anesthetized adult mice using Inveon PET/CT (Siemens). The list mode dynamic PET data were collected for 30-60 min and rebinned using a Fourier rebinning algorithm. A CT scan was also performed for attenuation correction and anatomical co-registration. A 3D digital magnetic resonance microscopy (MRM)-based volume of interest (VOI) atlas generated from live C57BL/6J adult mouse brain was used for brain mapping (Ma et al., 2008). Landmarks, including left and right centroids of midears and eyes (4 landmarks), were generated on atlas template and individual mouse CT images. Co-registration of atlas, CT and PET was performed using Firevoxel (FVX) (https://urldefense.proofpoint.com/v2/url?u=https- 3A__wp.nyu.edu_Firevoxel&d=DgIBAg&c=j5oPpO0eBH1iio48DtsedbOBGmuw5jHLjgvtN2r4ehE&r=KRXe NoRy5_8lkSwAJG5vjS1yT0aFSItfe494dmkdSVs&m=B4bFtJccWjUzJ- dbK1qURkxJmihDqjf87yIgZlYKTMk&s=soyp2V3_QGPs--q8qXcfkDHjv7kMngxeekpEknOQoi8&e= ) and time-activity curves (TAC) for 20 specific 3D brain regions were generated. For comparison, an expert in mouse neuroanatomy manually drew corresponding VOIs on PET-CT co-registered images derived from IRW (Inveon data analysis software without atlas). The TACs thus generated via both methods were compared. For further evaluation, the tracer uptake and kinetics in both tau and Aa transgenic mouse models were also compared. Results: Using FVX, single step co-registration of atlas, CT and PET was accomplished in seconds (by one-button pressing) and the TACs for specific ROIs of mouse brain were automatically generated after co-registration. In contrast, it took an average of 15 min to manually draw a single VOI (total 5 hours/mouse for 20 VOIs) directly on CT images using Inveon IRW without an atlas, a process that required an expert in mouse neuroanatomy. Overall, the TACs for the corresponding VOIs derived from IRW and FVX were similar in counts and shapes. Most importantly, this VOI atlas-based method can provide unbiased measures of radioactivity concentration from PET studies. The results from studies of tau vs. Aa transgenic mouse models after injection of Amyvid showed an apparent difference in the tracer uptake and kinetics (Fig. 1). Conclusions: We have demonstrated the feasibility to map mouse brain with an automated atlas-based co-registration for data analysis of microPET brain studies using FVX. This novel time-saving data analysis methodology, unachievable with current microPET imaging systems, will facilitate accurate assessment and spatial localization of brain signals in mouse model studies for a variety of human CNS disorders

Alzheimer disease (AD) represents one of the greatest medical challenges of this century; the condition is becoming increasingly prevalent worldwide and no effective treatments have been developed for this terminal disease. Because the disease manifests at a late stage after a long period of clinically silent neurodegeneration, knowledge of the modifiable risk factors and the implementation of biomarkers is crucial in the primary prevention of the disease and presymptomatic detection of AD, respectively. This article discusses the growing epidemic of AD and antecedent risk factors in the disease process. Disease biomarkers are discussed, and the implications that this may have for the treatment of this currently incurable disease.

Depression has been linked to Alzheimer's disease as either an increased risk factor for its development or as a prodromal symptom. The neurobiological basis for such an association, however, remains poorly understood. Numerous studies have examined whether changes in amyloid beta (Abeta) metabolism, which are implicated in the pathogenesis of Alzheimer's disease, are also found in depression. In this paper, we investigated the relationship between depressive symptoms and cerebrospinal fluid (CSF) Abeta indices in otherwise healthy, cognitively normal elderly with late-life major depression (LLMD) and controls using a longitudinal approach, which is a novel contribution toward the literature. Significantly lower levels of CSF Abeta42 were observed in the LLMD group at baseline and were associated with more severe depressive symptoms. During longitudinal follow-up, the depressed group remained cognitively unchanged, but was significantly less depressed than at baseline. A greater improvement in depressive symptoms was associated with increases in CSF Abeta42 levels in both groups. Increases in CSF Abeta42 and Abeta40 were also associated with increased CSF total-tau levels. Our results suggest that LLMD may be associated with state-dependent effects of CSF Abeta42 levels. Future studies should determine whether the association reflects state-dependent changes in neuronal activity and/or brain amyloid burden in depression.

Background: It is now accepted that mitochondrial dysfunction is a key early event in the progression of neuronal and vascular degeneration in Alzheimer's disease (AD) and that therapies aimed at preventing mitochondrial failure may represent promising new strategies in the pursue of a cure for this devastating disease. Carbonic anhydrases (CAs) are a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons (or vice versa), maintaining acid-base balance in blood and other tissues. CA isoforms are present in the mitochondria. CA inhibitors (CAIs), such as metazolamide (MTZ) and acetazolamide (ATZ) are clinically used for glaucoma, epilepsy (rarely), and high altitude sickness. Methods: We analyzed the effects of two main CAIs used in clinical settings (MTZ and ATZ) on the mechanism of mitochondrial damage and neurovascular degeneration induced by amyloid beta (Abeta), using cerebral vascular and neural cells as well as the TgSwDI (Swedish- Dutch-Iowa) transgenic mouse model of cerebral amyloidosis. Results: Both CAIs consistently prevented specific pathways of mitochondrial dysfunction induced by Abeta in cerebral microvascular endothelial, neuronal and glial cells, without affecting ATP production, pH, and Calcium flux. Increase of hydrogen peroxide, loss of mitochondrial membrane potential, release of Cytochrome C, caspase activation, and apoptotic cell death were inhibited by CAIs. ATZ was effective at concentrations lower than MTZ. Both drugs, given with diet, were able to ameliorate behavioral paradigms in relatively young TgSwDI mice. Conclusions: CAIs might represent a potentially successful strategy to prevent early mitochondrial dysfunction and neurovascular loss in AD. Further studies in animal models and clinical settings are needed to confirm our hypothesis

Background: We have previously demonstrated that anti-beta-sheet conformational monoclonal antibodies (mAbs) recognize pathological oligomeric forms of Abeta and Tau in tissue samples of human Alzheimer's Disease (AD) brains and in AD mouse models (Goni et al 2015, Alzheimer & Dementia pp 845-6). We have now tested one of our mAbs in aged 3xTg AD animals with extensive preexisting Abeta and Tau related pathology with weekly injections of the TABP1 mAb. Methods: Two groups of 16 months old 3xTg AD animals were inoculated i.p. biweekly for three weeks and weekly thereafter for 5 weeks with either 100 mug of TABP1 in 100 muL of sterile saline or with 100 muL of vehicle alone. Radial Arm Maze behavioral analysis was performed after the treatment, followed by sacrifice and harvesting of the brains for immuno-histochemical and biochemical analyses. Results: No adverse reactions were demonstrated during the treatment. The TABP1 infused animals showed significant cognitive rescue compared to the controls. No significant differences were noted with the immunohistochemical quantitation of amyloid plaques or tau pathology; although there was a trend for reduced deposition in the infused animals. However, there was a significant decrease of the soluble and oligomeric Abeta (mainly Abeta1-42) and pathological Tau in the infused animals versus the controls. Conclusions: Anti-conformational monoclonal antibodies infused i.p. can ameliorate behavioral deficits in AD model mice. The mechanism is likely related to reductions of the levels of soluble oligomeric forms of Abeta and Tau; these species have been most closely linked to the cognitive deficits in AD patients. The results are encouraging for the further testing of humanized versions of these mAbs in clinical trials

Background: The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SP) and neurofibrillary tangles (NFTs). Passive immunization with anti-Abeta antibodies is a promising therapeutic approach for AD with several on-going clinical trials; however, toxicity with amyloid related imaging abnormalities (ARIA) is problematic in many of these trails. This toxicity is in part related to the effector function of the antibodies used. Recently, an affibody molecule that lacks effector function, but binds to monomeric Abeta peptides, with aggregation inhibition capacity, was generated and tested in AD model transgenic fruit flies, demonstrating abolition of Abeta related neurotoxic effects and restoration of their life span. Here we assessed the efficacy of passive immunization with the affibody in a mouse model of AD. Methods: APP/ PS1 transgenic AD model mice were injected intraperitoneally twice a week with the Abeta-binding ZSYM73-ABD Affibody molecule from the age of 6 months (at a point where the mice already have amyloid deposition). Control mice received a non-Abeta binding affibody. Their behavior was assessed at 9 months of age and brain tissue subsequently was harvested for analysis of treatment efficacy. Results: The treated (Abeta-binding ZSYM73-ABD) mice didn't show a significant difference from controls on locomotor testing. ZSYM73- ABD treated-mice performed the same as wild-type mice. The amyloid burden of in treated animals was reduced by 49 % in the cortex and 50% in the hippocampus. There was no significant difference in astrogliosis or microhemorrhages between treated and control mice. Conclusions: These results indicate that passive immunization with an Affibody molecule can significantly decrease the amyloid burden and improve cognitive function in a transgenic mouse model of AD