Pillai, Jay J.

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.

Abstract Background Recently, a posterior pathway for fluid drainage from the retina to the meningeal lymphatics in the optic nerve (ON) sheath was identified in rodents using intravitreal imaging tracers directly injected into the ocular-globe. Fluid and solute clearance along this pathway may be associated with many diseases. However, intravitreal tracers are rarely used in clinical imaging. As intravenous Gadolinium-based-contrast-agent (GBCA) can enter the globe via the blood-ocular-barriers, it may provide an alternative approach to image this pathway. Purpose To establish a clinically feasible intravenous GBCA-based MRI approach for tracking fluid and solute transport along the posterior lymphatic pathway in the ocular glymphatic system. Materials&Methods This prospective study was conducted from March 2021 to September 2022 in healthy participants. Dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI was performed before, immediately and 4 hours after intravenous-GBCA administration to track GBCA distribution in aqueous humor (AH) and cerebrospinal fluid (CSF) in regions-of-interest (ROIs) in the globe (anterior-cavity, vitreous-body), in the intraorbital and extraorbital ON, and in the intracranial CSF space proximal to the ON (chiasmatic-cistern, interpeduncular-cistern). Kruskal–Wallis tests with post-hoc Dunn’s tests were used for group comparisons. Results Sixteen healthy participants (mean age±SD: 51±21 years, 5 men) were recruited. Intravenous-GBCA enhancement was observed in all ROIs immediately after injection. At 4-hour-post-GBCA, the vitreous body showed a trend of smaller enhancement area (55±11% versus 49±11%, P =.14) and lower GBCA-concentration (0.044±0.014 versus 0.028±0.010 mmol/L, P =.07) compared to immediate-post-GBCA. The intraorbital ON showed more widespread enhancement (39±5% versus 59±6%, P =.01) and significantly higher GBCA-concentration (0.023±0.009 versus 0.059±0.015 mmol/L, P <.001) at 4-hour-post-GBCA. Conclusion Dynamic fluid and solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy participants was measured by tracking intravenous-GBCAs entering the globe via the blood-ocular-barriers using cDSC-MRI. Summary Statement Dynamic fluid and solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy participants was measured by tracking intravenous-Gadolinium-based-contrast-agents entering ocular-globe via blood-ocular-barriers using dynamic-susceptibility-contrast-in-the-CSF (cDSC)-MRI. Key Results In this prospective study of sixteen participants, Gadolinium-based-contrast-agent (GBCA)-induced signal changes were detected in the aqueous-humor and cerebrospinal fluid immediately following intravenous administration using dynamic-susceptibility-contrast-in-the-CSF (cDSC)-MRI. At 4-hour-post-GBCA, the vitreous-body showed a trend of smaller enhancement area (55±11% versus 49±11%, P =.14) and lower GBCA-concentration (0.044±0.014 versus 0.028±0.010 mmol/L, P =.07) compared to immediate-post-GBCA. The intraorbital-optic-nerve showed more widespread enhancement (39±5% versus 59±6%, P =.01) and higher GBCA-concentration (0.023±0.009 versus 0.059±0.015 mmol/L, P <.001) at 4-hour-post-GBCA.

Dynamic fluid and solute transportation across the arachnoid barrier in the meninges of healthy participants was measured by tracking intravenous gadolinium-based contrast agent entering cerebrospinal fluid from dural blood vessels using dynamic dual-spin-echo perfusion MRI.

Abstract Background Plasma neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) are blood‐based biomarkers of axonal injury and astrocytic activation, respectively, that are elevated in those with Alzheimer's disease (AD) and mild cognitive impairment (MCI) relative to cognitively unimpaired (CU) individuals. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method capable of evaluating tissue microstructure at the axonal and dendritic level. We evaluated associations between temporal cortex orientation dispersion index (ODI), neurite density index (NDI) and isotropic volume fraction (ISOVF) and plasma NfL and GFAP concentrations. Method We included Mayo Clinic Study of Aging (MCSA) participants (ages 60‐95 years) with diagnoses or CU ( n = 356) or MCI ( n = 60), and Alzheimer's Dementia Research Center (ADRC) participants with dementia ( n = 51). NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. NfL and GFAP were measured using the Simoa® Neurology 4‐Plex E Advantage kit. We fit separate linear regression models within each MCALT_ADIR122 cortical ROI with regional NODDI as the primary predictor and log‐transformed plasma concentration as the outcome. Models were adjusted for age, sex, BMI, cortical thickness (or hippocampal & amygdalar volume) and total intracranial volume. Result The Table displays demographic data. Figures 1 and 2 show the relationship of NDI and ISOVF measures to plasma NfL concentrations across participants in individual ROIs (similar findings were noted with GFAP). A significant inverse relationship between NfL concentrations and NDI was observed in hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus as well as all temporal neocortical regions except the superior temporal gyrus ( p <0.001) (Figure 1), whereas higher NfL concentrations were associated with higher ISOVF in all regions ( p <0.001) (Figure 2). Fewer significant associations were also seen with ODI. After adjusting for age, cortical thickness/volume and other confounds, significant associations with NDI remain, particularly in hippocampal and amygdalar regions. Conclusion NODDI‐derived measures (NDI and ISOVF) within the temporal lobe cortical regions demonstrate significant associations with plasma biomarkers of axonal and astrocytic dysfunction that are elevated during cognitive decline. This association provides preliminary validation of the utility of NODDI in assessing cortical microstructural changes associated with cognitive decline.

Abstract Background Plasma neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) are blood‐based biomarkers of axonal injury and astrocytic activation, respectively, that are elevated in those with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) relative to cognitively unimpaired (CU) individuals. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method capable of evaluating tissue microstructure at the axonal and dendritic level. We evaluated associations between temporal cortex orientation dispersion index (ODI), neurite density index (NDI) and isotropic volume fraction (ISOVF) and plasma NfL and GFAP concentrations. Method We included Mayo Clinic Study of Aging (MCSA) participants (ages 60‐95 years) with diagnoses or CU ( n = 356) or MCI ( n = 60), and Alzheimer’s Dementia Research Center (ADRC) participants with dementia ( n = 51). NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. NfL and GFAP were measured using the Simoa® Neurology 4‐Plex E Advantage kit. We fit separate linear regression models within each MCALT_ADIR122 cortical ROI with regional NODDI as the primary predictor and log‐transformed plasma concentration as the outcome. Models were adjusted for age, sex, BMI, cortical thickness (or hippocampal & amygdalar volume) and total intracranial volume. Result The Table displays demographic data. Figures 1 & 2 show the relationship of NDI and ISOVF measures to plasma NfL concentrations across participants in individual ROIs (similar findings were noted with GFAP). A significant inverse relationship between NfL concentrations and NDI was observed in hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus as well as all temporal neocortical regions except the superior temporal gyrus ( p <0.001) (Figure 1), whereas higher NfL concentrations were associated with higher ISOVF in all regions ( p <0.001) (Figure 2). Fewer significant associations were also seen with ODI. After adjusting for age, cortical thickness/volume and other confounds, significant associations with NDI remain, particularly in hippocampal and amygdalar regions. Conclusion NODDI‐derived measures (NDI and ISOVF) within the temporal lobe cortical regions demonstrate significant associations with plasma biomarkers of axonal and astrocytic dysfunction that are elevated during cognitive decline. This association provides preliminary validation of the utility of NODDI in assessing cortical microstructural changes associated with cognitive decline.

Abstract INTRODUCTION Temporal cortical microstructural changes precede cortical atrophy during memory decline. We used neurite orientation dispersion and density imaging (NODDI) to assess such early microstructural change. METHODS Cognitively unimpaired (CU, n = 725) and mildly cognitively impaired (MCI, n = 111) participants from the Mayo Clinic Study of Aging underwent 3T magnetic resonance imaging (MRI), including NODDI and neuropsychological evaluation for calculation of memory z scores. Linear mixed effects modelling assessed the relationship between temporal cortical Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and both baseline and mean annual change in memory z scores. RESULTS NDI was significantly associated with both baseline memory z scores and mean annual change of memory z scores, in the hippocampi and amygdalae. Similar significant associations with ODI were seen in hippocampi, parahippocampal, and fusiform gyri. DISCUSSION Temporal cortical NDI and ODI are early imaging biomarkers of cortical microstructural integrity that may predict memory decline in CU and MCI individuals. Highlights We imaged 836 participants in the Mayo Clinic Study of Aging, who were either cognitively unimpaired (CU) or suffered from mild cognitive impairment (MCI). Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion magnetic resonance imaging (MRI) technique We found significant associations between new NODDI imaging biomarkers of microstructural integrity and memory function in CU and MCI individuals These relationships were both cross‐sectional in nature and associated with future memory decline Future application of NODDI imaging biomarkers in the setting of anti‐amyloid monoclonal antibody therapy may provide greater insight into memory decline than current cortical atrophy measures.

AbstractBackgroundCortical structural changes in the temporal lobes including global and hippocampal volume loss and decrease in cortical thickness are well‐associated findings linked to cognitive decline in MCI and dementia patients. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method enabling assessment of tissue microstructural integrity at the axonal and dendritic level. We wished to determine whether changes in temporal cortex orientation dispersion index (ODI) & neurite density index (NDI) correlate with decreases in memory function.MethodThe MCALT_ADIR122 cortical atlas was used for ROI designation. NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. Participants (ages 60‐95 years) were cognitively unimpaired (CU) or had mild cognitive impairment (MCI). CU & MCI subjects were enrolled in the Mayo Clinic Study of Aging (MCSA) and underwent neuropsychological testing including 3 memory tests from which a composite memory z score was calculated. A generalized additive regression model was used to estimate z scores as a smooth function of ODI, NDI and cortical thickness or volume with adjustment for age, gender, education, MCSA cycle number, WMH and intracranial volume.ResultThe Table displays demographic data. Figures 1 and 2 show the relationship of NDI and ODI measures to memory z scores across participants in individual ROIs both before and after adjustment for cortical thickness (“structural MRI”) as well as for confounds listed above. Both higher cortical thickness and higher NDI values in the hippocampus and entorhinal cortex were associated with significantly higher memory z‐scores (p<0.001) (Figure 1). Higher ODI values in addition to greater cortical thickness in temporal lobe regions, including within the hippocampus, parahippocampal gyrus, entorhinal cortex and inferior temporal gyrus, were associated with higher memory z‐scores (Figure 2). These significant associations (p <=0.01) were maintained after adjusting for cortical thickness in all these regions except entorhinal cortex for ODI.ConclusionNODDI‐derived measures of microstructural integrity (NDI & ODI) within the temporal cortex may provide information about memory decline, beyond what cortical thickness analysis provides, and may be potentially useful for monitoring therapeutic effects of AD immunotherapy in the future.

AbstractBackgroundCerebral small vessel disease (SVD) related vascular contributions represent a major factor contributing to cognitive decline and dementia (VCID) in older adults. However, there has not been a validated biomarker for the diagnosis and treatment monitoring of this condition. Recently, the US National Institute on Neurological Disorders and Stroke (NINDS) funded the MarkVCID Consortium to identify and validate clinical‐trial‐ready biomarkers for VCID. Cerebrovascular reactivity (CVR) MRI is one of the selected biomarkers that underwent multi‐site testing in the Consortium. The present study aimed to report the relationship between CVR and cognitive function at independent sites, based on a pre‐specified hypothesis.MethodCVR, the ability of cerebral small vessels to dilate upon stimulus, is thought to directly reflect physiological function of the brain microvasculature. Based on previous single‐site findings, the pre‐defined hypothesis was that CVR will be associated with the global cognitive function measured by Montreal Cognitive Assessment (MoCA) after adjusting for age, sex, and education, and this association will be observed in data collected and analyzed at each individual site.A total of 264 older participants from three sites were included (Table 1). Each site performed an identical CVR MRI procedure using 5% CO2 inhalation, and a standardized clinical and cognitive evaluation. Multi‐linear regression analysis was conducted on a site‐by‐site basis to examine the pre‐defined hypothesis.ResultGray‐matter CVR showed a positive association with MoCA score after adjustment for age, sex, and education, in which participants with higher CVR had higher MoCA scores. This relationship was reproduced at each site (Figure 1, p<0.05 for each), confirming our pre‐specified hypothesis.In the secondary analysis of all data together, higher gray‐matter CVR was found to be significantly associated with better executive function measure of item response theory (IRT) score (β=2.87, p=0.003).ConclusionThe present study evaluated the relationship between CVR and cognition in a multi‐center setting. CVR was found to be positively associated with global cognitive function measured by the MoCA, which was shown to be reproducible across different sites with diverse cohorts. These findings support the utility of CVR as a biomarker in future clinical trials of SVD and VCID.

AbstractBackgroundCortical structural changes in the temporal lobes including global and hippocampal volume loss and decrease in cortical thickness are well‐associated findings linked to cognitive decline in MCI and dementia patients. Neurite orientation dispersion and density imaging (NODDI) is a multishell diffusion MRI method enabling assessment of tissue microstructural integrity at the axonal and dendritic level. We wished to determine whether changes in temporal cortex orientation dispersion index (ODI) & neurite density index (NDI) correlate with decreases in memory function.MethodThe MCALT_ADIR122 cortical atlas was used for ROI designation. NODDI imaging was obtained on a 3T Siemens Prisma scanner with 2 mm isotropic resolution. Participants (ages 60‐95 years) were cognitively unimpaired (CU) or had mild cognitive impairment (MCI). CU & MCI subjects were enrolled in the Mayo Clinic Study of Aging (MCSA) and underwent neuropsychological testing including 3 memory tests from which a composite memory z score was calculated. A generalized additive regression model was used to estimate z scores as a smooth function of ODI, NDI and cortical thickness or volume with adjustment for age, gender, education, MCSA cycle number, WMH and intracranial volume.ResultThe Table displays demographic data. Figures 1 and 2 show the relationship of NDI and ODI measures to memory z scores across participants in individual ROIs both before and after adjustment for cortical thickness (“structural MRI”) as well as for confounds listed above. Both higher cortical thickness and higher NDI values in the hippocampus and entorhinal cortex were associated with significantly higher memory z‐scores (p<0.001) (Figure 1). Higher ODI values in addition to greater cortical thickness in temporal lobe regions, including within the hippocampus, parahippocampal gyrus, entorhinal cortex and inferior temporal gyrus, were associated with higher memory z‐scores (Figure 2). These significant associations (p <=0.01) were maintained after adjusting for cortical thickness in all these regions except entorhinal cortex for ODI.ConclusionNODDI‐derived measures of microstructural integrity (NDI & ODI) within the temporal cortex may provide information about memory decline, beyond what cortical thickness analysis provides, and may be potentially useful for monitoring therapeutic effects of AD immunotherapy in the future.