Faculty Bibliography

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: 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

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

In the USA, between w250,000 e 400,000 individuals have Down syn-drome, and nearly all of them will develop Alzheimer's disease pathology starting in their 30s. By age 70, 50-70% will have dementia. There are numerous pathogenic and mechanistic links between the two disorders. Individuals with DS comprise a potential ideal population for AD clinical trials. The presence of AD pathology in DS has led to greater collaborative research toward the parallel goals of providing effective treatment for individuals with DS and AD, as well as, expediting AD drug development. Similarities and differences between DS and AD will be reviewed. Examples of immunomodulatory and other therapeutic strategies that may benefit both DS and AD will be presented. Over-dosage of the amyloid precursor protein (APP) is believed to be responsible for the high incidence of early-onset AD-like amyloidosis observed in DS patients. APP is cleaved by the sequential proteolytic activity of the B-secretase and the g-secretase complex which is responsible for the formation of amyloid b (Ab). Since activation of the g-secretase complex is the required final step for the formation of Ab, there has been a tremendous effort to develop drugs that block this complex activity as a disease-modifying therapeutic approach for lowering Ab levels. The g-secretase activating protein (GSAP) is a newly recognized protein derived from a larger precursor molecule via a caspase-3-dependent proteolytic cleavage, which by directly interacting with key components of the g-secretase complex acts as a rate-limiting step in Ab formation. Evidence suggests that GSAP is increased in post-mortem brain tissues of AD patients, and its inhibition leads to reduction of AD pathology in transgenic mouse models. Our recent evidence shows that in health control DS brains there is a significant elevation of GSAP protein and mRNA. Targeting of g-secretase as an AD therapy is problematic as it has multiple substrates including Notch. GSAP interacts with g-secretase to enhance Ab production, without affecting Notch. Pharmacological targeting of GSAP is a potentially important therapeutic approach for both DS and AD pathology

Because of an extra copy of the Abeta precursor protein gene on chromosome 21, Down syndrome (DS) individuals develop high levels of Abeta peptides and Alzheimer disease-like brain amyloidosis early in life. Here we show that the gamma-secretase activating protein (GSAP), a key enzyme in amyloidogenesis, is increased in DS brains and specifically regulated at the transcriptional level by GATA1 transcription factor. The discovery of this novel pathway has translational implications for DS, because pharmacological inhibition of GSAP is an attractive and viable Abeta-lowering therapeutic strategy for this disorder. ANN NEUROL 2016;79:138-143.