Quantification approaches for magnetic resonance imaging following intravenous gadolinium injection: A window into brain-wide glymphatic function.

The glymphatic system is a brain-wide network of perivascular pathways along which cerebrospinal fluid and interstitial fluid rapidly exchange, facilitating solute and waste clearance from the brain parenchyma. The characterization of this exchange process in humans has relied primarily upon serial magnetic resonance imaging following intrathecal gadolinium-based contrast agent injection. However, less invasive approaches are needed. Here, we administered a gadolinium-based contrast agent intravenously in eight healthy participants and acquired magnetic resonance imaging scans prior to and 30, 90, 180, and 360 min post contrast injection. Using a region-of-interest approach, we observed that peripheral tissues and blood vessels exhibited high enhancement at 30 min after contrast administration, likely reflecting vascular and peripheral interstitial distribution of the gadolinium-based contrast agent. Ventricular, grey matter and white matter enhancement peaked at 90 min, declining thereafter. Using k-means clustering, we identify distinct distribution volumes reflecting the leptomeningeal perivascular network, superficial grey matter and deep grey/white matter that exhibit a sequential enhancement pattern consistent with parenchymal contrast enhancement via the subarachnoid cerebrospinal fluid compartment. We also outline the importance of correcting for (otherwise automatic) autoscaling of signal intensities, which could potentially lead to misinterpretation of gadolinium-based contrast agent distribution kinetics. In summary, we visualize and quantify delayed tissue enhancement following intravenous administration of gadolinium-based contrast agent in healthy human participants.

Bifurcated Topological Optimization for IVIM.

In this work, we shed light on the issue of estimating Intravoxel Incoherent Motion (IVIM) for diffusion and perfusion estimation by characterizing the objective function using simplicial homology tools. We provide a robust solution via topological optimization of this model so that the estimates are more reliable and accurate. Estimating the tissue microstructure from diffusion MRI is in itself an ill-posed and a non-linear inverse problem. Using variable projection functional (VarPro) to fit the standard bi-exponential IVIM model we perform the optimization using simplicial homology based global optimization to better understand the topology of objective function surface. We theoretically show how the proposed methodology can recover the model parameters more accurately and consistently by casting it in a reduced subspace given by VarPro. Additionally we demonstrate that the IVIM model parameters cannot be accurately reconstructed using conventional numerical optimization methods due to the presence of infinite solutions in subspaces. The proposed method helps uncover multiple global minima by analyzing the local geometry of the model enabling the generation of reliable estimates of model parameters.

White Matter Lesions in Mild Cognitive Impairment and Idiopathic Parkinson's Disease: Multimodal Advanced MRI and Cognitive Associations.

Cerebrovascular disease is a common comorbidity in older adults, typically assessed in terms of white matter hyperintensities (WMHs) on MRI. While it is well known that WMHs exacerbate cognitive symptoms, the exact relation of WMHs with cognitive performance and other degenerative diseases is unknown. Furthermore, based on location, WMHs are often classified into periventricular and deep WMHs and are believed to have different pathological origins. Whether the two types of WMHs influence cognition differently is unclear. Using regression models, we assessed the independent association of these two types of WMHs with cognitive performance in two separate studies focused on distinct degenerative diseases, early Alzheimer's (mild cognitive impairment), and Parkinson's disease. We further tested if the two types of WMHs were differentially associated with reduced cortical cerebral blood flow (CBF) as measured by arterial spin labeling and increased mean diffusivity (MD, a marker of tissue injury) as measured by diffusion imaging. Our approach revealed that both deep and periventricular WMHs were associated with poor performance on tests of global cognition (Montreal cognitive Assessment, MoCA), task processing (Trail making test), and category fluency in the study of mild cognitive impairment. They were associated with poor performance in global cognition (MoCA) and category fluency in the Parkinson's disease study. Of note, more associations were detected between cognitive performance and deep WMHs than between cognitive performance and periventricular WMHs. Mechanistically, both deep and periventricular WMHs were associated with increased MD. Both deep and periventricular WMHs were also associated with reduced CBF in the gray matter.

Concurrent Deep Brain Stimulation Reduces the Direct Cortical Stimulation Necessary for Motor Output.

BACKGROUND: Converging literatures suggest that deep brain stimulation (DBS) in Parkinson's disease affects multiple circuit mechanisms. One proposed mechanism is the normalization of primary motor cortex (M1) pathophysiology via effects on the hyperdirect pathway. OBJECTIVES: We hypothesized that DBS would reduce the current intensity necessary to modulate motor-evoked potentials from focally applied direct cortical stimulation (DCS). METHODS: Intraoperative subthalamic DBS, DCS, and preoperative diffusion tensor imaging data were acquired in 8 patients with Parkinson's disease. RESULTS: In 7 of 8 patients, DBS significantly reduced the M1 DCS current intensity required to elicit motor-evoked potentials. This neuromodulation was specific to select DBS bipolar configurations. In addition, the volume of activated tissue models of these configurations were significantly associated with overlap of the hyperdirect pathway. CONCLUSIONS: DBS reduces the current necessary to elicit a motor-evoked potential using DCS. This supports a circuit mechanism of DBS effectiveness, potentially involving the hyperdirect pathway that speculatively may underlie reductions in hypokinetic abnormalities in Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society.

Arterial spin labeling detects perfusion patterns related to motor symptoms in Parkinson's disease.

INTRODUCTION: Imaging neurovascular disturbances in Parkinson's disease (PD) is an excellent measure of disease severity. Indeed, a disease-specific regional pattern of abnormal metabolism has been identified using positron emission tomography. Only a handful of studies, however, have applied perfusion MRI to detect this disease pattern. Our goal was to replicate the evaluation of a PD-related perfusion pattern using scaled subprofile modeling/principal component analysis (SSM-PCA). METHODS: We applied arterial spin labeling (ASL) MRI for this purpose. Uniquely, we assessed this pattern separately in PD individuals ON and OFF dopamine medications. We further compared the existence of these patterns and their strength in each individual with their Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor (MDS-UPDRS) scores, cholinergic tone as indexed by short-term afferent inhibition (SAI), and other neuropsychiatric tests. RESULTS: We observed a PD-related perfusion pattern that was similar to previous studies. The patterns were observed in both ON and OFF states but only the pattern in the OFF condition could significantly (AUC=0.72) differentiate between PD and healthy subjects. In the ON condition, PD subjects were similar to controls from a CBF standpoint (AUC=0.45). The OFF pattern prominently included the posterior cingulate, precentral region, precuneus, and the subcallosal cortex. Individual principal components from the ON and OFF states were strongly associated with MDS-UPDRS scores, SAI amplitude and latency. CONCLUSION: Using ASL, our study identified patterns of abnormal perfusion in PD and were associated with disease symptoms.

Resting-State Cerebello-Cortical Dysfunction in Parkinson's Disease.

Purpose: Recently, the cerebellum's role in Parkinson's disease (PD) has been highlighted. Therefore, this study sought to test the hypothesis that functional connectivity (FC) between cerebellar and cortical nodes of the resting-state networks differentiates PD patients from controls by scanning participants at rest using functional magnetic resonance imaging (fMRI) and investigating connectivity of the cerebellar nodes of the resting-state networks. Materials and Methods: Sixty-two PD participants off medication for at least 12 h and 33 normal controls (NCs) were scanned at rest using blood oxygenation level-dependent fMRI scans. Motor and cognitive functions were assessed with the Movement Disorder Society's Revision of the Unified Parkinson's Disease Rating Scale III and Montreal Cognitive Assessment, respectively. Connectivity was investigated with cerebellar seeds defined by Buckner's 7-network atlas. Results: PD participants had significant differences in FC when compared to NC participants. Most notably, PD patients had higher FC between cerebellar nodes of the somatomotor network (SMN) and the corresponding cortical nodes. Cognitive functioning was differentially associated with connectivity of the cerebellar SMN and dorsal attention network. Further, cerebellar connectivity of frontoparietal and default mode networks correlated with the severity of motor function. Conclusion: Our study demonstrates altered cerebello-cortical FC in PD, as well as an association of this FC with PD-related motor and cognitive disruptions, thus providing additional evidence for the cerebellum's role in PD.

Extracting Reproducible Time-Resolved Resting State Networks Using Dynamic Mode Decomposition.

Resting state networks (RSNs) extracted from functional magnetic resonance imaging (fMRI) scans are believed to reflect the intrinsic organization and network structure of brain regions. Most traditional methods for computing RSNs typically assume these functional networks are static throughout the duration of a scan lasting 5-15 min. However, they are known to vary on timescales ranging from seconds to years; in addition, the dynamic properties of RSNs are affected in a wide variety of neurological disorders. Recently, there has been a proliferation of methods for characterizing RSN dynamics, yet it remains a challenge to extract reproducible time-resolved networks. In this paper, we develop a novel method based on dynamic mode decomposition (DMD) to extract networks from short windows of noisy, high-dimensional fMRI data, allowing RSNs from single scans to be resolved robustly at a temporal resolution of seconds. After validating the method on a synthetic dataset, we analyze data from 120 individuals from the Human Connectome Project and show that unsupervised clustering of DMD modes discovers RSNs at both the group (gDMD) and the single subject (sDMD) levels. The gDMD modes closely resemble canonical RSNs. Compared to established methods, sDMD modes capture individualized RSN structure that both better resembles the population RSN and better captures subject-level variation. We further leverage this time-resolved sDMD analysis to infer occupancy and transitions among RSNs with high reproducibility. This automated DMD-based method is a powerful tool to characterize spatial and temporal structures of RSNs in individual subjects.

MRI techniques to measure arterial and venous cerebral blood volume.

The measurement of cerebral blood volume (CBV) has been the topic of numerous neuroimaging studies. To date, however, most in vivo imaging approaches can only measure CBV summed over all types of blood vessels, including arterial, capillary and venous vessels in the microvasculature (i.e. total CBV or CBVtot). As different types of blood vessels have intrinsically different anatomy, function and physiology, the ability to quantify CBV in different segments of the microvascular tree may furnish information that is not obtainable from CBVtot, and may provide a more sensitive and specific measure for the underlying physiology. This review attempts to summarize major efforts in the development of MRI techniques to measure arterial (CBVa) and venous CBV (CBVv) separately. Advantages and disadvantages of each type of method are discussed. Applications of some of the methods in the investigation of flow-volume coupling in healthy brains, and in the detection of pathophysiological abnormalities in brain diseases such as arterial steno-occlusive disease, brain tumors, schizophrenia, Huntington's disease, Alzheimer's disease, and hypertension are demonstrated. We believe that the continual development of MRI approaches for the measurement of compartment-specific CBV will likely provide essential imaging tools for the advancement and refinement of our knowledge on the exquisite details of the microvasculature in healthy and diseased brains.

Amnestic mild cognitive impairment individuals with dissimilar pathologic origins show common regional vulnerability in the default mode network.

INTRODUCTION: Alzheimer's and Parkinson's disease (AD and PD) are distinct disorders but share similar biomarker profiles. The regions of the default mode network are implicated in these diseases and are associated with amnestic symptoms. The role of apolipoprotein-ε4 (APOE-ε4), which is associated with cognitive function, is unclear in PD. METHODS: In this work, we evaluated cortical thickness of default mode network regions that are likely affected in both early AD and PD individuals, that is, with amnestic mild cognitive impairment. We identified the prevalence of APOE-ε4 and evaluated its association with cortical atrophy. RESULTS: We observed significant parahippocampal atrophy and hippocampal atrophy rates in amnestic mild cognitive impairment subjects, regardless of disease origins (AD or PD). Similarly, mild cognitive impairment ε4 carriers showed significant precuneal atrophy compared with noncarriers. DISCUSSION: This work supports that converging changes to default mode network regions, especially the temporal lobe and precuneus, are shared in AD and PD.

Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults.

BACKGROUND: Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults. METHODS: Vanderbilt Memory & Aging Project participants free of clinical dementia, stroke, and heart failure were studied, including older adults with normal cognition (n=155; age, 72±7 years; 59% male) or mild cognitive impairment (n=115; age, 73±7 years; 57% male). Aortic pulse wave velocity (PWV; meters per second) was quantified from cardiac magnetic resonance. Resting CBF (milliliters per 100 g per minute) and CVR (CBF response to hypercapnic normoxia stimulus) were quantified from pseudocontinuous arterial spin labeling magnetic resonance imaging. Linear regression models related aortic PWV to regional CBF, adjusting for age, race/ethnicity, education, Framingham Stroke Risk Profile (diabetes mellitus, smoking, left ventricular hypertrophy, prevalent cardiovascular disease, atrial fibrillation), hypertension, body mass index, apolipoprotein E4 ( APOE ε4) status, and regional tissue volume. Models were repeated testing PWV× APOE ε4 interactions. Sensitivity analyses excluded participants with prevalent cardiovascular disease and atrial fibrillation. RESULTS: Among participants with normal cognition, higher aortic PWV related to lower frontal lobe CBF (ß=-0.43; P=0.04) and higher CVR in the whole brain (ß=0.11; P=0.02), frontal lobes (ß=0.12; P<0.05), temporal lobes (ß=0.11; P=0.02), and occipital lobes (ß=0.14; P=0.01). Among APOE ε4 carriers with normal cognition, findings were more pronounced with higher PWV relating to lower whole-brain CBF (ß=-1.16; P=0.047), lower temporal lobe CBF (ß=-1.81; P=0.004), and higher temporal lobe CVR (ß=0.26; P=0.08), although the last result did not meet the a priori significance threshold. Results were similar in sensitivity models. Among participants with mild cognitive impairment, higher aortic PWV related to lower CBF in the occipital lobe (ß=-0.70; P=0.02), but this finding was attenuated when participants with prevalent cardiovascular disease and atrial fibrillation were excluded. Among APOE ε4 carriers with mild cognitive impairment, findings were more pronounced with higher PWV relating to lower temporal lobe CBF (ß=-1.20; P=0.02). CONCLUSIONS: Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity.

Quantitative cerebrovascular pathology in a community-based cohort of older adults.

Cerebrovascular disease, especially small vessel pathology, is the leading comorbidity in degenerative disorders. We applied arterial spin labeling and cerebrovascular reserve (CVR) imaging to quantify small vessel disease and study its effect on cognitive symptoms in nondemented older adults from a community-based cohort. We evaluated baseline cerebral blood flow (CBF) using arterial spin labeling and percent signal change as a marker of CVR using blood-oxygen level-dependent imaging following a breath-hold stimulus. Measurements were performed in and near white matter hyperintensities, which are currently the standard to assess severity of vascular pathology. We show that similar to other studies (1) CBF and CVR are markedly reduced in the hyperintensities as well as in the tissue surrounding them, indicating susceptibility to infarction; (2) low CBF and CVR are significantly correlated with poor cognitive performance; and (3) in addition, compared to a 58.4% reduction in CBF, larger exhaustion (79.3%) of CVR was observed in the hyperintensities with a faster, nonlinear rate of decline. We conclude that CVR may be a more sensitive biomarker of small vessel disease than CBF.

Lower cardiac index levels relate to lower cerebral blood flow in older adults.

OBJECTIVE: To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults. METHODS: Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), APOE ε4 status, cognitive diagnosis, and regional tissue volume. RESULTS: Lower cardiac index corresponded to lower resting CBF in the left (ß = 2.4, p = 0.001) and right (ß = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe ß = 2.3, p = 0.003; right temporal lobe ß = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes. CONCLUSIONS: Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.

Comparison of Cortical and Subcortical Measurements in Normal Older Adults across Databases and Software Packages.

This work explores the feasibility of combining anatomical MRI data across two public repositories namely, the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Progressive Parkinson's Markers Initiative (PPMI). We compared cortical thickness and subcortical volumes in cognitively normal older adults between datasets with distinct imaging parameters to assess if they would provide equivalent information. Three distinct datasets were identified. Major differences in data were scanner manufacturer and the use of magnetization inversion to enhance tissue contrast. Equivalent datasets, i.e., those providing similar volumetric measurements in cognitively normal controls, were identified in ADNI and PPMI. These were datasets obtained on the Siemens scanner with TI = 900 ms. Our secondary goal was to assess the agreement between subcortical volumes that are obtained with different software packages. Three subcortical measurement applications (FSL, FreeSurfer, and a recent multi-atlas approach) were compared. Our results show significant agreement in the measurements of caudate, putamen, pallidum, and hippocampus across the packages and poor agreement between measurements of accumbens and amygdala. This is likely due to their smaller size and lack of gray matter-white matter tissue contrast for accurate segmentation. This work provides a segue to combine imaging data from ADNI and PPMI to increase statistical power as well as to interrogate common mechanisms in disparate pathologies such as Alzheimer's and Parkinson's diseases. It lays the foundation for comparison of anatomical data acquired with disparate imaging parameters and analyzed with disparate software tools. Furthermore, our work partly explains the variability in the results of studies using different software packages.

Cortical asymmetry in Parkinson's disease: early susceptibility of the left hemisphere.

BACKGROUND AND PURPOSE: Clinically, Parkinson's disease (PD) presents with asymmetric motor symptoms. The left nigrostriatal system appears more susceptible to early degeneration than the right, and a left-lateralized pattern of early neuropathological changes is also described in several neurodegenerative conditions, including Alzheimer's disease, frontotemporal dementia, and Huntington's disease. In this study, we evaluated hemispheric differences in estimated rates of atrophy in a large, well-characterized cohort of PD patients. METHODS: Our cohort included 205 PD patients who underwent clinical assessments and T1-weighted brain MRI's. Patients were classified into Early (n = 109) and Late stage (n = 96) based on disease duration, defined as greater than or less than 10 years of motor symptoms. Cortical thickness was determined using FreeSurfer, and a bootstrapped linear regression model was used to estimate differences in rates of atrophy between Early and Late patients. RESULTS: Our results show that patients classified as Early stage exhibit a greater estimated rate of cortical atrophy in left frontal regions, especially the left insula and olfactory sulcus. This pattern was replicated in left-handed patients, and was not influenced by the degree of motor symptom asymmetry (i.e., left-sided predominant motor symptoms). Patients classified as Late stage exhibited greater atrophy in the bilateral occipital, and right hemisphere-predominant cortical areas. CONCLUSIONS: We show that cortical degeneration in PD differs between cerebral hemispheres, and findings suggest a pattern of early left, and late right hemisphere with posterior cortical atrophy. Further investigation is warranted to elucidate the underlying mechanisms of this asymmetry and pathologic implications.

Hippocampal arterial cerebral blood volume in early psychosis.

Recent studies of patients in the early stage of psychosis have revealed increased cerebral blood volume (CBV) in specific subfields of the anterior hippocampus. These studies required injection of a contrast agent to measure steady state CBV. Here we used a novel, non-invasive method, inflow-based-vascular-space-occupancy with dynamic subtraction (iVASO-DS), to measure the arterial component of CBV (aCBV) in a single slice of the hippocampus. Based on evidence from contrast-enhanced CBV studies, we hypothesized increased aCBV in the anterior hippocampus in early psychosis. We used 3T MRI to generate iVASO-derived aCBV maps in 17 medicated patients (average duration of illness = 7.6 months) and 25 matched controls. We did not find hemispheric or regional group differences in hippocampal aCBV. The limited spatial resolution of the iVASO-DS method did not allow us to test for aCBV differences in specific subfields of the hippocampus. Future studies should investigate venous and arterial CBV changes in the hippocampus of early psychosis patients.

Linear and Curvilinear Trajectories of Cortical Loss with Advancing Age and Disease Duration in Parkinson's Disease.

Advancing age and disease duration both contribute to cortical thinning in Parkinson's disease (PD), but the pathological interactions between them are poorly described. This study aims to distinguish patterns of cortical decline determined by advancing age and disease duration in PD. A convenience cohort of 177 consecutive PD patients, identified at the Vanderbilt University Movement Disorders Clinic as part of a clinical evaluation for Deep Brain Stimulation (age: M= 62.0, SD 9.3), completed a standardized clinical assessment, along with structural brain Magnetic Resonance Imaging scan. Age and gender matched controls (n=53) were obtained from the Alzheimer Disease Neuroimaging Initiative and Progressive Parkinson's Marker Initiative (age: M= 63.4, SD 12.2). Estimated changes in cortical thickness were modeled with advancing age, disease duration, and their interaction. The best-fitting model, linear or curvilinear (2(nd), or 3(rd) order natural spline), was defined using the minimum Akaike Information Criterion, and illustrated on a 3-dimensional brain. Three curvilinear patterns of cortical thinning were identified: early decline, late decline, and early-stable-late. In contrast to healthy controls, the best-fit model for age related changes in PD is curvilinear (early decline), particularly in frontal and precuneus regions. With advancing disease duration, a curvilinear model depicts accelerating decline in the occipital cortex. A significant interaction between advancing age and disease duration is evident in frontal, motor, and posterior parietal areas. Study results support the hypothesis that advancing age and disease duration differentially affect regional cortical thickness and display regional dependent linear and curvilinear patterns of thinning.

Cortical Implications of Advancing Age and Disease Duration in Parkinson's Disease Patients with Postural Instability and Gait Dysfunction.

BACKGROUND: Parkinson's Disease patients with predominant gait dysfunction appear to have reduced cortical thickness compared to other motor phenotypes. The extent to which advancing age or disease duration impact the pattern of these distinctions is unclear. OBJECTIVE: We examine if PD patients with predominant signs of postural instability and gait dysfunction are distinguished by distinct patterns of cerebral atrophy, and how these differences are influenced by age and disease duration. METHODS: The Unified Parkinson's Disease Rating Score (UPDRS) was administered to 196 PD patients (age = 61.4±8.9yrs) in the Off and On dopamine state. All completed a structural T1-weighted brain MRI. We defined 3 motor phenotypes: tremor dominant, akinetic-rigid, and postural instability with gait disorder. General linear modeling quantified cortical thickness in relation to disease duration, and motor improvement after dopaminergic therapy. Cortical thickness and subcortical volumes were compared between the three motor subtypes, after controlling for disease duration and age. RESULTS: We identified 177/196 patients who met criteria for a motor subtype. When corrected for disease duration, postural-instability patients had marked cortical thinning of the bilateral frontal-temporal and posterior cortical regions (cuneus/precuneus). After regressing for age, reduced frontal thickness was evident in patients with gait dysfunction. Widespread cortical thinning was associated with increasing disease duration and reduced motor improvement to dopaminergic therapy. CONCLUSIONS: Results emphasize that the profile of motor signs, especially prominent gait manifestations, relate to cortical thinning in distinct regions. Unique patterns of atrophy appear to be driven by advancing pathology related to age and disease duration.

On the Fallacy of Quantitative Segmentation for T1-Weighted MRI.

T1-weighted magnetic resonance imaging (MRI) generates contrasts with primary sensitivity to local T1 properties (with lesser T2 and PD contributions). The observed signal intensity is determined by these local properties and the sequence parameters of the acquisition. In common practice, a range of acceptable parameters is used to ensure "similar" contrast across scanners used for any particular study (e.g., the ADNI standard MPRAGE). However, different studies may use different ranges of parameters and report the derived data as simply "T1-weighted". Physics and imaging authors pay strong heed to the specifics of the imaging sequences, but image processing authors have historically been more lax. Herein, we consider three T1-weighted sequences acquired the same underlying protocol (MPRAGE) and vendor (Philips), but "normal study-to-study variation" in parameters. We show that the gray matter/white matter/cerebrospinal fluid contrast is subtly but systemically different between these images and yields systemically different measurements of brain volume. The problem derives from the visually apparent boundary shifts, which would also be seen by a human rater. We present and evaluate two solutions to produce consistent segmentation results across imaging protocols. First, we propose to acquire multiple sequences on a subset of the data and use the multi-modal imaging as atlases to segment target images any of the available sequences. Second (if additional imaging is not available), we propose to synthesize atlases of the target imaging sequence and use the synthesized atlases in place of atlas imaging data. Both approaches significantly improve consistency of target labeling.

Improving Cerebellar Segmentation with Statistical Fusion.

The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multi-atlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non-Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold-standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution.

The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview.

BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aß42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.