Medical College of Wisconsin Neurodegenerative & Memory Disorders Research

NTRP & Neuroimaging

NTRP’s strong collaborations with MCW Radiology (Drs. Yang Wang, Andrew Nencka, and Mohit Agarwal) are vital to recent and future research successes. We have developed a clinical database of over 250 patients, primarily with MCI, that combines cognitive data from clinical comprehensive neuropsychological evaluations with multimodal neuroimaging biomarkers including brain magnetic resonance imaging (MRI) with quantitative volumetric analysis, arterial spin labeling (ASL), and diffusion tensor imaging (see example in Figure 1).

Figure 1. FLAIR-MRI in a patient with cognitive complaints showing progression of microangiopathic white matter disease (top images) over a 6-year period. DTI map (lower left image) shows microangiopathic white matter disease to much greater extent than visible on standard FLAIR-MRI. Volumetric segmentation (lower left image) shows abnormal volume loss in the parietal and frontal lobes with sparing of other structures (graphs). The case illustrates the coexistence of white matter disease and brain substructure volume loss.

Dr. Wang’s specialization in advanced neuroimaging research including clinical and experimental functional MRI, arterial spin labeling, and diffusion tensor imaging and extensive history of obtaining NIH-funding for his work have fostered research growth in the NTRP. Dr. Wang’s published work has shown that fMRI is a viable biomarker for AD, and his novel neuroimaging techniques will yield neuroimaging discoveries for AD and related dementias. Dr. Wang and colleagues (Wang et al., 2013) previously published on default mode network (DMN) connectivity in older adults with subjective cognitive complaints (SCC) compared to patients with amnestic MCI (aMCI) and found decreased DMN connectivity in both groups but significantly decreased connectivity in the right hippocampus in the aMCI group compared to the SCC group. Their results support DMN dysconnectivity as a sensitive fMRI biomarker to prodromal AD. Figure 2 shows the DMN (top) and regional connectively differences between cognitively normal and MCI groups (bottom). Dr. Wang is actively involved in processing and analyzing data for the Alzheimer Disease Connectome Project and is committed to furthering the success of NTRP with his cutting-edge neuroimaging techniques.

Figure 2. (Top) Brain activity corresponding to the default mode network. (Bottom) Sites showing regional differences in default mode network connectivity between healthy controls (HC) and MCI patients.

NTRP & the Human Microbiome (research in progress)

Drs. Umfleet, Wang, and Franczak are collaborating with Dr. John Kirby (MCW Department of Microbiology & Immunology) to interdigitate the human microbiome with cutting-edge multimodal neuroimaging (MRI, functional MRI, and PET) and fluid (CSF and blood) biomarkers of AD and both related and unrelated dementias. Research investigating the role of the gut-brain axis in neurological disease is rapidly evolving and has much potential for finding solutions in dementia. Our current overall research goal is to determine the specific bacterial strains and their metabolic properties that drive the transition from normal brain aging to dementia. One grant proposal has been submitted, and an NIH proposal is in progress. If successful, our efforts will improve precision diagnosis and lead to future clinical trials.

Cognitive Neuroscience Collaboration

There is an aging continuum from being symptom free, to self-reported cognitive decline, to objective cognitive impairment, and to objective cognitive impairment with functional difficulties. It is possible that current neuropsychological evaluations are not sensitive enough to pick up on cognitive decline in the very early stages of neurodegenerative diseases. A budding research collaboration between clinician scientists in neurology (Drs. Umfleet, Franczak, and Pillay) and Dr. Adam Greenberg (a cognitive neuroscientist and biomedical engineer) represents another research arm of NTRP. These researchers seek to improve the examination (behavioral and neurological) of older persons who have cognitive complaints but perform normally on traditional clinical neuropsychological examination. Such efforts could lead to early identification of neurodegenerative diseases and subsequent resulting collaborations will work toward intervention to prevent transition from pre-MCI to MCI.

Behavioral measures developed through the above collaboration can contribute to the field of neuropsychological assessment. Dr. Umfleet is the site PI for the National Neuropsychology Network (NNN). This National Institute of Mental Health (NIMH) funded project will increase efficiency and validity of neuropsychological assessment using modern technology and psychometric methods. The NNN includes four clinical research sites (University of California- Los Angeles, Emory, University of Florida, and MCW). The mature NNN will serve as a conduit for data aggregation that enables shared analysis and collaborative research, provides data to enable robust diagnostic inferences about neuropsychological test patterns, ultimately enabling more efficient and precise adaptive assessments that are sensitive to clinical contexts and individual/cultural differences and promote the validation of novel assessment strategies. The NNN will revolutionize the field of neuropsychology, including the evaluation of persons with neurodegenerative diseases.