To understand how microglial cell function may change with aging, various protocols have been developed to isolate microglia from the young and aged central nervous system (CNS). Here we report modification of an existing protocol that is marked by less debris contamination and improved yields and demonstrates that microglial functions are varied and dependent on age. Specifically, we found that microglia from aged mice constitutively secrete greater amounts of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) relative to microglia from younger mice and are less responsive to stimulation. Also, microglia from aged mice have reduced glutathione levels and internalize less amyloid beta peptide (Aβ) while microglia from mice of all ages do not retain the amyloid beta peptide for a significant length of time. These studies offer further support for the idea that microglial cell function changes with aging. They suggest that microglial Aβ phagocytosis results in Aβ redistribution rather than biophysical degradation in vivo and thereby provide mechanistic insight to the lack of amyloid burden elimination by parenchymal microglia in aged adults and those suffering from Alzheimer’s disease.

We have long promulgated the idea that microglial cells serve an entirely beneficial role in the central nervous system (CNS), not only as immunological sentinels to fend off potentially dangerous infections, but also as constitutively neuroprotective glia that help sustain neuronal function in the normal and especially in the injured CNS when microglia become activated. In recent years, we have reported on the presence of degenerating microglial cells, which are prominent in the brains of aged humans and humans with neurodegenerative diseases, and this has led us to propose a hypothesis stating that loss of microglia and microglial neuroprotective functions could, at least in part, account for aging-related neurodegeneration. In the current review, we sum up the many aspects that characterize microglial activation and compare them to those that characterize microglial senescence and degeneration. We also consider the possible role of oxidative stress as a cause of microglial degeneration. We finish up by discussing the role microglial cells play in terms of amyloid clearance and degradation with the underlying idea that removal of amyloid constitutes a microglial neuroprotective function, which may become compromised during aging.

Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Aβ peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy.

Multidisciplinary neurotechnology holds the promise of understanding and non-invasively treating neurodegenerative diseases. In this preclinical trial on Parkinson's disease (PD), we combined neuroscience together with the nascent field of medical virtual reality and generated several important observations. First, we established the Oculus Rift virtual reality system as a potent measurement device for parkinsonian involuntary hand tremors (IHT). Interestingly, we determined changes in rotation were the most sensitive marker of PD IHT. Secondly, we determined parkinsonian tremors can be abolished in VR with algorithms that remove tremors from patients' digital hands. We also found that PD patients were interested in and were readily able to use VR hardware and software. Together these data suggest PD patients can enter VR and be asymptotic of PD IHT. Importantly, VR is an open-medium where patients can perform actions, activities, and functions that positively impact their real lives - for instance, one can sign tax return documents in VR and have them printed on real paper or directly e-sign via internet to government tax agencies. Lastly, we generated a technical framework wherein movements in the real world can be measured side-by-side with those in virtual reality. With this framework, we observed anecdotal evidence of parkinsonian tremors being reduced in real life when our algorithms abolished digital hand tremors in VR.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, affecting approximately 6-7 million patients worldwide. Involuntary hand tremor (IHT), one of the cardinal motor symptoms of PD, is extremely debilitating to patients reducing their quality of life. In this study, we combined neuroscience together with the nascent field of medical virtual reality (VR). Our goals were to 1) generate technology to enable PD patients to leapfrog the real life difficulties of living with IHT by entering VR metaverse worlds in which they are tremor-free and can function at new heights, 2) to determine whether lack of tremors in VR modifies central biofeedback mechanisms to non-invasively reduce tremors in real life. We thus generated algorithms that adjusted the moving average centroid of digital hands to stabilize tremors in VR. We implemented these algorithms in the Oculus Rift VR system and enrolled nine subjects with PD in a trial that yielded several important observations. First, we established the Oculus Rift as a potent measurement device for IHT. Secondly, we determined parkinsonian tremors can be abolished in VR with algorithms that removed up to 99% of tremors from PD subjects' digital hands (76% average reduction). These data suggest PD subjects can enter VR and be asymptomatic of PD IHT. To test whether our algorithms have measurable practical utility, we created a VR painting application, FingerPaint, and tested it against TiltBrush the leading VR painting application. We empirically demonstrate that complex freeform art created in FingerPaint had up to 51% reduction in tremor-associated parkinsonian drawing irregularities (24% average reduction). Lastly, we generated a technical framework wherein movements in the real-world can be measured side-by-side with those in VR. With this framework, we observed real life parkinsonian tremors were significantly reduced by up to 87% in real life when our algorithms abolished digital hand tremors in VR (35% average reduction). This reduction was observed in 78% of subjects and was progressive as subjects had increasingly reduced real life tremors the longer they were in VR.

Artificial intelligence (AI) holds great promise to precisely classify human ancestry and the genetic causes of complex diseases. I have constructed an unsupervised machine learning paradigm that examines the whole genome as a hyper-dense, nonlinear, multidimensional feature space. The AI system culminates in 26 neural network neurons each sensitive to a specific heritage that can identify an individual’s component genetic heritages with a top-5 error of <0.5%. Importantly, I observed some populations previously thought to belong to single stratum are composed of multiple strata – for instance Japan is defined as a uniform population using previous methods. I found that the Japanese individuals segregate to two very distinct populations. This work represents an essential step towards understanding the genetic background of patients to enable precision medicine causal disease gene identification.