Faculty Bibliography

To test the hypothesis that developmental anomalies of the corpus callosum (CC), contribute to the pathogenesis of autism, we characterized the type, topography, and severity of CC pathology corresponding to reduced CC areas that are detected by magnetic resonance imaging in the brains of 11 individuals with autism and 11 controls. In the brains of 3 autistic subjects, partial CC agenesis resulted in complete or partial lack of interhemispheric axonal connections in CC segments III-V. In these cases, a combination of focal agenesis and uniform axonal deficit caused reduction of CC areas by 37%, of axon numbers by 62%, and of the numerical density of axons by 39%. In the CC of 8 autistic subjects without agenesis, there was an 18% deficit of the midsagittal CC area, 48.4% deficit of axon numbers, and 37% reduction of the numerical density of axons. The significantly thinner CC, reduced CC area, and uniform axonal deficit in all autistic subjects were classified as CC hypoplasia. Thus, the byproduct of partial CC agenesis and hypoplasia is reduction of axonal connections between cortical areas known to be involved in behavioral alterations observed in people with autism.

Experimental models of Alzheimer's disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of novel therapeutic approaches. The most commonly used experimental animal models are transgenic mice that overexpress human genes associated with familial AD (FAD) that result in the formation of amyloid plaques. However, AD is defined by the presence and interplay of both amyloid plaques and neurofibrillary tangle pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. A greater understanding of the strengths and weakness of each of the various models and the use of more than one model to evaluate potential therapies would help enhance the success of therapy translation from preclinical studies to patients. In this review, we summarize the pathological features and limitations of the major experimental models of AD, including transgenic mice, transgenic rats, various physiological models of sporadic AD and in vitro human cell culture models.

Alzheimer's disease (AD) is characterized by the presence of parenchymal amyloid-beta (Abeta) plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles. Currently there are no effective treatments for AD. Immunotherapeutic approaches under development are hampered by complications related to ineffectual clearance of CAA. Genome-wide association studies have demonstrated the importance of microglia in AD pathogenesis. Microglia are the primary innate immune cells of the brain. Depending on their activation state and environment, microglia can be beneficial or detrimental. In our prior work, we showed that stimulation of innate immunity with Toll-like receptor 9 agonist, class B CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs), can reduce amyloid and tau pathologies without causing toxicity in Tg2576 and 3xTg-AD mouse models. However, these transgenic mice have relatively little CAA. In the current study, we evaluated the therapeutic profile of CpG ODN in a triple transgenic mouse model, Tg-SwDI, with abundant vascular amyloid, in association with low levels of parenchymal amyloid deposits. Peripheral administration of CpG ODN, both before and after the development of CAA, negated short-term memory deficits, as assessed by object-recognition tests, and was effective at improving spatial and working memory evaluated using a radial arm maze. These findings were associated with significant reductions of CAA pathology lacking adverse effects. Together, our extensive evidence suggests that this innovative immunomodulation may be a safe approach to ameliorate all hallmarks of AD pathology, supporting the potential clinical applicability of CpG ODN. SIGNIFICANCE STATEMENT: Recent genetic studies have underscored the emerging role of microglia in Alzheimer's disease (AD) pathogenesis. Microglia lose their amyloid-beta-clearing capabilities with age and as AD progresses. Therefore, the ability to modulate microglia profiles offers a promising therapeutic avenue for reducing AD pathology. Current immunotherapeutic approaches have been limited by poor clearance of a core AD lesion, cerebral amyloid angiopathy (CAA). The present study used Tg-SwDI mice, which have extensive CAA. We found that stimulation of the innate immune system and microglia/macrophage activation via Toll-like receptor 9 using CpG (cytosine-phosphate-guanine) oligodeoxynucleotides (ODNs) leads to cognitive improvements and CAA reduction, without associated toxicity. Our data indicate that this novel concept of immunomodulation represents a safer method to reduce all aspects of AD pathology and provide essential information for potential clinical use of CpG ODN.

Recently, a few case reports of thymoma-associated panencephalitis (TAPE) have brought to light a disease entity that has not been fully characterized. Literature review of TAPE reveals an array of associated neuronal antibodies, with varied responses to thymomectomy with or without immunotherapy. This report describes a case of TAPE and proposes that the GABA_A receptor antibody is a potential target antigen driving the immune process in this disease entity. Treatment-wise, early thymomectomy consistently improves the overall course of disease. Further study of such cases will be critical in clarifying the mechanisms of disease, improving early diagnosis, and developing targeted approaches to treatment.

INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia. The search for new treatments is made more urgent given its increasing prevalence resulting from the aging of the global population. Over the past two decades, stem cell technologies have become an increasingly attractive option to both study and potentially treat neurodegenerative diseases. Several investigators reported a beneficial effect of different types of stem or progenitor cells on the pathology and cognitive function in AD models. Mouse models are among the most important research tools for AD treatment discovery. We aimed to explore the possible therapeutic potential of human umbilical cord mesenchymal stem cell xenografts in a transgenic (Tg) mouse model of AD. METHODS: APP/PS1 Tg AD model mice received human umbilical cord stem cells, directly injected into the carotid artery. To test the efficacy of the umbilical cord stem cells in this AD model, behavioral tasks (sensorimotor and cognitive tests) and immunohistochemical quantitation of the pathology was performed. RESULTS: Treatment of the APP/PS1 AD model mice, with human umbilical cord stem cells, produced a reduction of the amyloid beta burden in the cortex and the hippocampus which correlated with a reduction of the cognitive loss. CONCLUSION: Human umbilical cord mesenchymal stem cells appear to reduce AD pathology in a transgenic mouse model as documented by a reduction of the amyloid plaque burden compared to controls. This amelioration of pathology correlates with improvements on cognitive and sensorimotor tasks.

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.