In adult humans, the aging process is marked by gradual declines in most bodily functions. Such decline is thought to begin sometime in early middle age. Declines in cognition and other functions have been well studied primarily in those over the age of 65. Cerebrovascular factors, amyloid deposition, and tau deposition have all been linked to declines in the brain’s ability to function in this older aged group. Less is known about the impact of these factors in a relatively younger group of aged adults. The series of studies in my dissertation were designed to fill this gap in our knowledge.
I was fortunate in my doctoral work to have been given access to data that was being collected by the Framingham Heart Study. This is a single-site, longitudinal community-based cohort study that was initiated in 1948 with a recruitment of 5209 participants. Since the inception of the study, three generations of participants have been enrolled. The Offspring cohort, recruited between 1971 and 1975, is comprised of a total of 5,124 participants. The generation 3 cohort recruited between 2002 and 2005 consists of 4,095 participants. They have been evaluated approximately every 4 years since, for a variety of factors including cardiovascular, socio-demographic, and cognition. For the purposes of this investigation, I was able to work with data from the Offspring and the generation 3 cohort participants who attended the 9th examination cycle (2011-2014), and the third examination cycle (2016-2019) respectively. Participants underwent an MRI scan, C-Pittsburgh Compound-B (PiB)-PET scan and F-Flortaucipir PET scan between 2016 and 2019. They were free of stroke, dementia and other neurological condition at the time of assessment. All the participants included in my work were cognitively normal.
To assess brain function, we examined functional connectivity with a focus on the default mode network (DMN). The goal of our first study was to determine whether vascular factors, expressed as the Framingham Stroke Risk Profile (FSRP), impact brain connectivity within and between various functional brain networks i.e. the default mode, frontoparietal, dorsal attention, ventral attention, somatomotor, limbic, and visual networks. Both T1 and resting state fMRI scans were acquired and processed using Freesurfer version 6.0 and FSL. Functional brain networks were constructed using the Yeo 7 network atlas. The FSRP score is a composite based on cardiovascular risk factors which were developed to quantify stroke risk. The FSRP is comprised of measures of systolic blood pressure, antihypertensive therapy, diabetes, cigarette smoking status, history of cardiovascular disease, and atrial fibrillation. In addition to FSRP, we examined the isolated effects of age, sex, total cholesterol to hdl cholesterol ratio, hypertention, and body mass index (BMI).
In our first study of 388 participants, we examined whether isolated vascular factors expressed separately or as a composite score using FSRP age, sex, total cholesterol to hdl cholesterol ratio, hypertention, body mass index (BMI), and/or ApoE status are associated with functional brain network connectivity with a primary focus on the DMN and a secondary focus on frontoparietal, dorsal attention, and ventral attention networks. We found that FSRP and ApoE status were not associated with functional connectivity within or between any of the functional brain networks. However, individual factors such as age, sex, total cholesterol to hdl cholesterol ratio, hypertention, and BMI had an effect on functional connectivity.
In our second study, we examined the relationship between global amyloid deposition and functional connectivity. This study included 305 out of the 388 individuals who participated in study one above and underwent PET imaging with the PiB compound. The primary analysis was focused on functional connectivity within the DMN as components of this network have been described as having a susceptiblety to amyloid plaque deposition. Secondary analyses were focused on functional connectivity within the remaining functional networks such as frontoparietal, dorsal attention, ventral attention, somatomotor, limbic, and visual networks. Interestingly, global amyloid deposition and ApoE status were not related to functional connectivity within any of the networks. Rather, connectivity within the DMN, frontoparietal and limbic networks were related to age and sex. Connectivity within the visual network was only related to age. No relationships were found for functional connectivity within the dorsal attention, ventral attention or somatosensory networks.
In our third study, we investigated the relationship between regional tau (hippocampus, parahippocampal gyrus, entorhinal cortex, precuneus, inferior temporal gyrus and rhinal cortex) and functional connectivity. This study included 247 out of the 388 individuals who participated in study one above and underwent PET imaging with the F-Flortaucipir (FTP) compound. The primary analyses here were focused on functional connectivity within the DMN and limbic networks. As with amyloid deposition, we did not find any relationship between regional tau or APOE status and functional connectivity in any of the functional networks. Age and sex were related to functional connectivity within the DMN, frontoparietal and limbic networks. Age alone was related to functional connectivity within the visual network. No relationships were found with functional connectivity within the dorsal attention, ventral attention or somatosensory networks.
The findings from our studies differ from what has been reported in an older populations (>65 years) where amyloid and tau accumulation along with vascular factors have a significant effect on functional network connectivity especially in the DMN in healthy older adults.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/44029 |
| Date | 15 March 2022 |
| Creators | Rahimpour, Yashar |
| Contributors | Killiany, Ronald |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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