Lymphatic System Health in Alzheimer's Disease

This study hopes to investigate differences in lymphatic health of patients with Alzheimer's disease by analyzing diffusion-weight images in conscious and sleep states. Dexmedetomidine is a short-acting agent that facilitates a sedated state characterized by slow waves and inhibition of norepinephrine. Conceptually, dexmedetomidine may be preferred to other agents, because it is a short-acting norepinephrine blocker, which could mimic slow wave sleep architecture, opening interstitial spaces, and facilitating plaque removal. Dexmedetomidine may also be preferred given its safety profile among the elderly and acutely ill compared to other anesthetic agents. Sleep will be induced with dexmedetomidine, and interstitial fluid convection will be assessed by measuring free-water diffusion imaging. Freewater diffusion imaging separates out the contributions of extracellular free water and water in the vicinity of cellular tissue; it is used to evaluate abnormalities in extracellular space, such as neuroinflammation, which may contribute to long-term cellular degeneration. This method of analysis could be useful in assessing the lymph systems ability to remove extracellular debris.

The present study is designed as a prospective data analysis of lymphatic system health in Alzheimer's patients and controls. For Phase I trail, 50 patients of any gender with an age range of 18 to 90 who have undergone the outlined procedure will be recruited for inclusion. Patients will be examined by the principle investigator. All patients will complete neurocognitive testing (QDRS and RBANS) to assess cognitive impairment. A CDR score of 1 or above will be considered dementia. Lumbar punctures will be used to determine Alzheimer's disease status. Patients will be offered the option of participating in the study and provided informed consent for neuroimaging. The subjects will have three fMRI scans: structural T1 and two NOODI DTI scans. The scans take around 45 minutes at no charge to the patients. The dexmedetomidine will be given to the patient after the first DTI scan. The dexmedetomidine dosage will be congruent with patient height, weight, and medical history. This medication will be administered sublingually using an LMA Intranasal Mucosal Atomization Device, which allows the medication to be administered in the form of a spray. Patients will be instructed to keep the medication in their mouth for about 2 minutes, or until fully absorbed. Pulse oximetry and blood pressure will be monitored throughout the duration of treatment. After the subject is asleep, the second DTI scan will be done.

Lumbar punctures will be used to determine Alzheimer's disease status. The subjects will have three fMRI scans: structural T1 and two NOODI DTI scans. The scans take around 45 minutes at no charge to the patients. The dexmedetomidine will be given to the patient after the first DTI scan; this dosage will be congruent with patient height, weight, and medical history. After the subject is asleep, the second DTI scan will be done.

All patients will complete neurocognitive testing inclusive of the Quick Dementia Rating Scale (QDRS) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)) to assess cognitive impairment. A Clinical Dementia Rating (CDR) score of 1 or above will be considered dementia. Lumbar punctures will be used to determine Alzheimer's disease status.The subjects will have three fMRI scans: structural T1 and two NOODI DTI scans. The dexmedetomidine will be given to the patient after the first DTI scan with a dosage that will be congruent with patient height, weight, and medical history.

This medication will be administered sublingually using an LMA Intranasal Mucosal Atomization Device, which allows the medication to be administered in the form of a spray. Patients will be instructed to keep the medication in their mouth for about 2 minutes, or until fully absorbed. Pulse oximetry and blood pressure will be monitored throughout the duration of treatment. After the subject is asleep, the second DTI scan will be done.

T1-data was collected as a sagittal MPRAGE sequence. T1 images are corrected for field biasing and then skull stripped and linearly registered to standard MNI space. Each patients' T1 image is segmented into 100 cortical and 15 subcortical areas using the Harvard-Oxford Cortical and Subcortical structural atlas. Mean volume is computed for each of these regions for each patient, which can be used for quantitative comparison.

T1-data was collected as a sagittal MPRAGE sequence. T1 images are corrected for field biasing and then skull stripped and linearly registered to standard MNI space. Each patients' T1 image is segmented into 100 cortical and 15 subcortical areas using the Harvard-Oxford Cortical and Subcortical structural atlas. Mean volume is computed for each of these regions for each patient, which can be used for quantitative comparison.

Diffusion tensor imaging is acquired through diffusion weighted imaging (DWI)-a magnetic resonance techniques that evaluate water diffusion in terms of diffusion constants and diffusion anisotropy. From the acquired DWI, diffusion tensor imaging (DTI) allows us to model the degree of anisotropy and the structural orientation in a quantitative fashion. These DTI fractional anisotropy values will be compared pre and post-treatment.

Diffusion tensor imaging is acquired through diffusion weighted imaging (DWI)-a magnetic resonance techniques that evaluate water diffusion in terms of diffusion constants and diffusion anisotropy. From the acquired DWI, diffusion tensor imaging (DTI) allows us to model the degree of anisotropy and the structural orientation in a quantitative fashion. These DTI fractional anisotropy values will be compared pre and post-treatment.

RBANS assesses immediate memory, visuospatial skill, language, attention, and delayed memory. Patient performance on each subscale immediate memory, language, attention, visuospatial, and delayed memory are scored relative to validated norms for same-aged peers. A change of 8+ points in the Total Scale score, 11+ points in the Immediate Memory score, 9+ points in the Language score, 4+ points on the Attention score, 14+ points is considered significant for the Visuospatial score, and 10+ points for the Delayed Memory score are considered significant.

The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study officials to participants' caregivers used to obtain observations from a consistent source. The QDRS form consists of 10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 (mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 (mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).

Inclusion Criteria: In order for a subject to be considered for this study, the subject must be willing to comply with the study protocol. They must be between 18 and 90 years old. They must complete neurocognitive testing to assess cognitive impairment (QDRS and RBANS). Exclusion Criteria: Advanced stages of any terminal illness or any active cancer that requires chemotherapy Hepatic impairment Significant cytopenia Cardiovascular, cerebrovascular, and peripheral vascular arterial thrombosis Women who are pregnant, may become pregnant, or are breastfeeding Any counter indications to dexmedetomidine Subjects unable to give informed consent or in vulnerable categories, such as prisoners

Data from this study will not be made publicly available due to ethical and privacy concerns. Anonymized data will be available upon reasonable request from any qualified investigator.

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