Cerebrospinal Fluid Flow in Patients with Huntington's Disease.

OBJECTIVE: Investigations of cerebrospinal fluid (CSF) flow aberrations in Huntington's disease (HD) are of growing interest, as impaired CSF flow may contribute to mutant Huntington retention and observed heterogeneous responsiveness to intrathecally administered therapies. METHOD: We assessed net cerebral aqueduct CSF flow and velocity in 29 HD participants (17 premanifest and 12 manifest) and 51 age- and sex matched non-HD control participants using 3-Tesla magnetic resonance imaging methods. Regression models were applied to test hypotheses regarding: (i) net CSF flow and cohort, (ii) net CSF flow and disease severity (CAP-score), and (iii) CSF volume after correcting for age and sex. RESULTS: Group-wise analyses support a decrease in net CSF flow in HD (mean 0.14 ± 0.27 mL/min) relative to control (mean 0.32 ± 0.20 mL/min) participants (p = 0.02), with lowest flow in the manifest HD cohort (mean 0.04 ± 0.25 mL/min). This finding was explained by hyperdynamic CSF movement, manifesting as higher caudal systolic CSF flow velocity and higher diastolic cranial CSF flow velocity across the cardiac cycle, in HD (caudal flow: 0.17 ± 0.07 mL/s, cranial flow: 0.14 ± 0.08 mL/s) compared to control (caudal flow: 0.13 ± 0.06 mL/s, cranial flow: 0.11 ± 0.04 mL/s) participants. A positive correlation between cranial diastolic flow and disease severity was observed (p = 0.02). INTERPRETATIONS: Findings support aqueductal CSF flow dynamics changing with disease severity in HD. These accelerated changes are consistent with changes observed over the typical adult lifespan, and may have relevance to mutant Huntington retention and intrathecally administered therapeutics responsiveness. ANN NEUROL 2023;94:885-894.

Deep learning segmentation of the choroid plexus from structural magnetic resonance imaging (MRI): validation and normative ranges across the adult lifespan.

BACKGROUND: The choroid plexus functions as the blood-cerebrospinal fluid (CSF) barrier, plays an important role in CSF production and circulation, and has gained increased attention in light of the recent elucidation of CSF circulation dysfunction in neurodegenerative conditions. However, methods for routinely quantifying choroid plexus volume are suboptimal and require technical improvements and validation. Here, we propose three deep learning models that can segment the choroid plexus from commonly-acquired anatomical MRI data and report performance metrics and changes across the adult lifespan. METHODS: Fully convolutional neural networks were trained from 3D T1-weighted, 3D T2-weighted, and 2D T2-weighted FLAIR MRI using gold-standard manual segmentations in control and neurodegenerative participants across the lifespan (n = 50; age = 21-85 years). Dice coefficients, 95% Hausdorff distances, and area-under-curve (AUCs) were calculated for each model and compared to segmentations from FreeSurfer using two-tailed Wilcoxon tests (significance criteria: p < 0.05 after false discovery rate multiple comparisons correction). Metrics were regressed against lateral ventricular volume using generalized linear models to assess model performance for varying levels of atrophy. Finally, models were applied to an expanded cohort of adult controls (n = 98; age = 21-89 years) to provide an exemplar of choroid plexus volumetry values across the lifespan. RESULTS: Deep learning results yielded Dice coefficient = 0.72, Hausdorff distance = 1.97 mm, AUC = 0.87 for T1-weighted MRI, Dice coefficient = 0.72, Hausdorff distance = 2.22 mm, AUC = 0.87 for T2-weighted MRI, and Dice coefficient = 0.74, Hausdorff distance = 1.69 mm, AUC = 0.87 for T2-weighted FLAIR MRI; values did not differ significantly between MRI sequences and were statistically improved compared to current commercially-available algorithms (p < 0.001). The intraclass coefficients were 0.95, 0.95, and 0.96 between T1-weighted and T2-weighted FLAIR, T1-weighted and T2-weighted, and T2-weighted and T2-weighted FLAIR models, respectively. Mean lateral ventricle choroid plexus volume across all participants was 3.20 ± 1.4 cm3; a significant, positive relationship (R2 = 0.54-0.60) was observed between participant age and choroid plexus volume for all MRI sequences (p < 0.001). CONCLUSIONS: Findings support comparable performance in choroid plexus delineation between standard, clinically available, non-contrasted anatomical MRI sequences. The software embedding the evaluated models is freely available online and should provide a useful tool for the growing number of studies that desire to quantitatively evaluate choroid plexus structure and function ( https://github.com/hettk/chp_seg ).

Intravenous arachnoid granulation hypertrophy in patients with Parkinson disease.

Intravenous arachnoid granulations (AGs) are protrusions of the arachnoid membrane into the venous lumen and function as contributors to the cerebrospinal fluid (CSF) flow circuit. Patients with Parkinson disease (PD) often present with accumulation of alpha synuclein. Previous works have provided evidence for neurofluid circulation dysfunction in neurodegenerative diseases associated with changes in CSF egress, which may have implications regarding AG morphology. The present study aims to investigate group differences in AG volumetrics between healthy and PD participants, as well as relationships between AG characteristics and clinical assessments. Generalized linear models revealed significant increases in AG volumetrics and number in PD compared to healthy controls. Partial Spearman-rank correlation analyses demonstrated significant relationships between AG metrics and motor and cognitive assessments. Finally, AG volumetrics were positively correlated with objective actigraphy measures of sleep dysfunction, but not self-report sleep symptoms.

Reduced cerebrospinal fluid motion in patients with Parkinson's disease revealed by magnetic resonance imaging with low b-value diffusion weighted imaging.

BACKGROUND: Parkinson's disease is characterized by dopamine-responsive symptoms as well as aggregation of α-synuclein protofibrils. New diagnostic methods assess α-synuclein aggregation characteristics from cerebrospinal fluid (CSF) and recent pathophysiologic mechanisms suggest that CSF circulation disruptions may precipitate α-synuclein retention. Here, diffusion-weighted MRI with low-to-intermediate diffusion-weightings was applied to test the hypothesis that CSF motion is reduced in Parkinson's disease relative to healthy participants. METHODS: Multi-shell diffusion weighted MRI (spatial resolution = 1.8 × 1.8 × 4.0 mm) with low-to-intermediate diffusion weightings (b-values = 0, 50, 100, 200, 300, 700, and 1000 s/mm2) was applied over the approximate kinetic range of suprasellar cistern fluid motion at 3 Tesla in Parkinson's disease (n = 27; age = 66 ± 6.7 years) and non-Parkinson's control (n = 32; age = 68 ± 8.9 years) participants. Wilcoxon rank-sum tests were applied to test the primary hypothesis that the noise floor-corrected decay rate of CSF signal as a function of b-value, which reflects increasing fluid motion, is reduced within the suprasellar cistern of persons with versus without Parkinson's disease and inversely relates to choroid plexus activity assessed from perfusion-weighted MRI (significance-criteria: p < 0.05). RESULTS: Consistent with the primary hypothesis, CSF decay rates were higher in healthy (D = 0.00673 ± 0.00213 mm2/s) relative to Parkinson's disease (D = 0.00517 ± 0.00110 mm2/s) participants. This finding was preserved after controlling for age and sex and was observed in the posterior region of the suprasellar cistern (p < 0.001). An inverse correlation between choroid plexus perfusion and decay rate in the voxels within the suprasellar cistern (Spearman's-r=-0.312; p = 0.019) was observed. CONCLUSIONS: Multi-shell diffusion MRI was applied to identify reduced CSF motion at the level of the suprasellar cistern in adults with versus without Parkinson's disease; the strengths and limitations of this methodology are discussed in the context of the growing literature on CSF flow.

Deep learning segmentation of peri-sinus structures from structural magnetic resonance imaging: validation and normative ranges across the adult lifespan.

BACKGROUND: Peri-sinus structures such as arachnoid granulations (AG) and the parasagittal dural (PSD) space have gained much recent attention as sites of cerebral spinal fluid (CSF) egress and neuroimmune surveillance. Neurofluid circulation dysfunction may manifest as morphological changes in these structures, however, automated quantification of these structures is not possible and rather characterization often requires exogenous contrast agents and manual delineation. METHODS: We propose a deep learning architecture to automatically delineate the peri-sinus space (e.g., PSD and intravenous AG structures) using two cascaded 3D fully convolutional neural networks applied to submillimeter 3D T2-weighted non-contrasted MRI images, which can be routinely acquired on all major MRI scanner vendors. The method was evaluated through comparison with gold-standard manual tracing from a neuroradiologist (n = 80; age range = 11-83 years) and subsequently applied in healthy participants (n = 1,872; age range = 5-100 years), using data from the Human Connectome Project, to provide exemplar metrics across the lifespan. Dice-Sørensen and a generalized linear model was used to assess PSD and AG changes across the human lifespan using quadratic restricted splines, incorporating age and sex as covariates. RESULTS: Findings demonstrate that the PSD and AG volumes can be segmented using T2-weighted MRI with a Dice-Sørensen coefficient and accuracy of 80.7 and 74.6, respectively. Across the lifespan, we observed that total PSD volume increases with age with a linear interaction of gender and age equal to 0.9 cm3 per year (p < 0.001). Similar trends were observed in the frontal and parietal, but not occipital, PSD. An increase in AG volume was observed in the third to sixth decades of life, with a linear effect of age equal to 0.64 mm3 per year (p < 0.001) for total AG volume and 0.54 mm3 (p < 0.001) for maximum AG volume. CONCLUSIONS: A tool that can be applied to quantify PSD and AG volumes from commonly acquired T2-weighted MRI scans is reported and exemplar volumetric ranges of these structures are provided, which should provide an exemplar for studies of neurofluid circulation dysfunction. Software and training data are made freely available online ( https://github.com/hettk/spesis ).

Deep learning segmentation of the choroid plexus from structural magnetic resonance imaging (MRI): validation and normative ranges across the adult lifespan.

Background: The choroid plexus functions as the blood-cerebrospinal fluid barrier, plays an important role in neurofluid production and circulation, and has gained increased attention in light of the recent elucidation of neurofluid circulation dysfunction in neurodegenerative conditions. However, methods for routinely quantifying choroid plexus volume are suboptimal and require technical improvements and validation. Here, we propose three deep learning models that can segment the choroid plexus from commonly-acquired anatomical MRI data and report performance metrics and changes across the adult lifespan. Methods: Fully convolutional neural networks were trained from 3-D T1-weighted, 3-D T2-weighted, and 2-D T2-weighted FLAIR MRI and gold-standard manual segmentations in healthy and neurodegenerative participants across the lifespan (n=50; age=21-85 years). Dice coefficients, 95% Hausdorff distances, and area-under-curve (AUCs) were calculated for each model and compared to segmentations from FreeSurfer using two-tailed Wilcoxon tests (significance criteria: p<0.05 after false discovery rate multiple comparisons correction). Metrics were regressed against lateral ventricular volume using generalized linear models to assess model performance for varying levels of atrophy. Finally, models were applied to an expanded cohort of healthy adults (n=98; age=21-89 years) to provide an exemplar of choroid plexus volumetry values across the lifespan. Results: Deep learning results yielded Dice coefficient=0.72, Hausdorff distance=1.97 mm, AUC=0.87 for T1-weighted MRI, Dice coefficient=0.72, Hausdorff distance=2.22 mm, AUC=0.87 for T2-weighted MRI, and Dice coefficient=0.74, Hausdorff distance=1.69 mm, AUC=0.87 for T2-weighted FLAIR MRI; values did not differ significantly between2 MRI sequences and were statistically improved compared to current commercially-available algorithms (p<0.001). The intraclass coefficients were 0.95, 0.95, and 0.96 between T1-weighted and T2-FLAIR, T1-weighted and T2-weighted, and T2-weighted and T2-FLAIR models, respectively. Mean lateral ventricle choroid plexus volume across all participants was 3.20±1.4 cm3; a significant, positive relationship (R2=0.54; slope=0.047) was observed between participant age and choroid plexus volume for all MRI sequences (p<0.001). Conclusions: Findings support comparable performance in choroid plexus delineation between standard, clinically available, non-contrasted anatomical MRI sequences. The software embedding the evaluated models is freely available online and should provide a useful tool for the growing number of studies that desire to quantitatively evaluate choroid plexus structure and function (https://github.com/hettk/chp_seg).

Choroid plexus perfusion and bulk cerebrospinal fluid flow across the adult lifespan.

The choroid plexus (ChP) comprises a collection of modified ependymal cells that play an important role in the production of brain cerebrospinal fluid (CSF), and ChP perfusion aberrations have been implicated in a range of cerebrovascular and neurodegenerative disorders. To provide an exemplar for the growing interest in ChP activity, we evaluated ChP perfusion and bulk CSF flow cross-sectionally across the healthy adult lifespan. Participants (n = 77; age range = 21-86 years) were scanned at 3T using T1-weighted, T2-weighted-FLAIR, perfusion-weighted pCASL, and phase contrast MRI to calculate ChP anatomy, perfusion, and aqueductal CSF flow, respectively. Regression models were applied to evaluate aging effects on ChP volume and ChP perfusion in the lateral ventricles, as well as CSF flow. ChP volume (mean ± std = 2.81 ± 1.1 cm3) increased (p < 0.001), ChP perfusion (36.3 ± 8.6 mL/100 g/min) decreased (p = 0.0078), and ChP total blood flow (1.13 ± 0.34 mL/min) increased (p < 0.001) with age. Cranial-to-caudal net CSF flow (0.245 ± 0.20 mL/min) decreased, absolute CSF flow (4.86 ± 2.96 mL/min) increased, and CSF regurgitant fraction (0.87 ± 0.126) increased with age (all: p < 0.001). ChP perfusion was directly related to net cranial-to-caudal CSF flow through the aqueduct (p = 0.033). The implications of these findings are discussed in the context of the growing literature on CSF circulatory dysfunction in neurodegeneration and cerebrovascular disease.

Parasagittal dural space hypertrophy and amyloid-ß deposition in Alzheimer's disease.

One of the pathological hallmarks of Alzheimer's and related diseases is the increased accumulation of protein amyloid-ß in the brain parenchyma. As such, recent studies have focused on characterizing protein and related clearance pathways involving perivascular flow of neurofluids, but human studies of these pathways are limited owing to limited methods for evaluating neurofluid circulation non-invasively in vivo. Here, we utilize non-invasive MRI methods to explore surrogate measures of CSF production, bulk flow and egress in the context of independent PET measures of amyloid-ß accumulation in older adults. Participants (N = 23) were scanned at 3.0 T with 3D T2-weighted turbo spin echo, 2D perfusion-weighted pseudo-continuous arterial spin labelling and phase-contrast angiography to quantify parasagittal dural space volume, choroid plexus perfusion and net CSF flow through the aqueduct of Sylvius, respectively. All participants also underwent dynamic PET imaging with amyloid-ß tracer 11C-Pittsburgh Compound B to quantify global cerebral amyloid-ß accumulation. Spearman's correlation analyses revealed a significant relationship between global amyloid-ß accumulation and parasagittal dural space volume (rho = 0.529, P = 0.010), specifically in the frontal (rho = 0.527, P = 0.010) and parietal (rho = 0.616, P = 0.002) subsegments. No relationships were observed between amyloid-ß and choroid plexus perfusion nor net CSF flow. Findings suggest that parasagittal dural space hypertrophy, and its possible role in CSF-mediated clearance, may be closely related to global amyloid-ß accumulation. These findings are discussed in the context of our growing understanding of the physiological mechanisms of amyloid-ß aggregation and clearance via neurofluids.

Reduced suprasellar cistern cerebrospinal fluid motion in patients with Parkinson's disease revealed by magnetic resonance imaging with dynamic cycling of diffusion weightings.

BACKGROUND: Parkinson's disease is characterized by dopamine-responsive symptoms as well as aggregation and accumulation of a-synuclein protofibrils. New diagnostic methods assess a-synuclein aggregation characteristics from cerebrospinal fluid and recent pathophysiologic mechanisms suggest that cerebrospinal fluid circulation disruptions may precipitate a-synuclein retention. Here, we test the hypothesis that cerebrospinal fluid motion at the level of the suprasellar cistern is reduced in Parkinson's disease relative to healthy participants and this reduction relates to choroid plexus perfusion. METHODS: Diffusion weighted imaging (spatial resolution=1.8×1.8×4 mm) magnetic resonance imaging with cycling of diffusion weightings (b-values=0, 50, 100, 200, 300, 700, and 1000 s/mm2) over the approximate kinetic range of suprasellar cistern neurofluid motion was applied at 3-Tesla in Parkinson's disease (n=27; age=66±6.7 years) and healthy (n=32; age=68±8.9 years) participants. Wilcoxon rank-sum tests were applied to test the primary hypothesis that the decay rate of cerebrospinal fluid signal as a function of b-value, which reflects increasing fluid motion, is reduced in persons with versus without Parkinson's disease and inversely relates to choroid plexus activity assessed from perfusion-weighted magnetic resonance imaging (Spearman rank-order correlation; significance-criteria: p<0.05). RESULTS: Consistent with the primary hypothesis, decay rates were higher in healthy (D=0.00328±0.00123mm2/s) relative to Parkinson's disease (D=0.00256±0.0094mm2/s) participants (p=0.016). This finding was preserved after controlling for age and sex. An inverse correlation between choroid plexus perfusion and decay rate (p=0.011) was observed in Parkinson's disease participants. CONCLUSIONS: Cerebrospinal fluid motion at the level of the suprasellar cistern is often reduced in adults with versus without Parkinson's disease and this reduction correlates on average with choroid plexus perfusion.

Parasagittal dural space and cerebrospinal fluid (CSF) flow across the lifespan in healthy adults.

BACKGROUND: Recent studies have suggested alternative cerebrospinal fluid (CSF) clearance pathways for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of these pathways is the anatomic region surrounding the superior sagittal sinus, which has been shown to have relevance to trans-arachnoid molecular passage. This so-called parasagittal dural (PSD) space may play a physiologically significant role as a distal intracranial component of the human glymphatic circuit, yet fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport. METHODS: We re-parameterized MRI methods to assess CSF circulation in humans using high resolution imaging of the PSD space and phase contrast measures of flow through the cerebral aqueduct to test the hypotheses that volumetric measures of PSD space (1) are directly related to CSF flow (mL/s) through the cerebral aqueduct, and (2) increase with age. Multi-modal 3-Tesla MRI was applied in healthy participants (n = 62; age range = 20-83 years) across the adult lifespan whereby phase contrast assessments of CSF flow through the aqueduct were paired with non-contrasted T1-weighted and T2-weighted MRI for PSD volumetry. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flow (significance criteria: two-sided p < 0.05). RESULTS: A significant PSD volume enlargement in relation to normal aging (p < 0.001, Spearman's-[Formula: see text] = 0.6), CSF volume (p < 0.001, Spearman's-[Formula: see text] = 0.6) and maximum CSF flow through the aqueduct of Sylvius (anterograde and retrograde, p < 0.001) were observed. The elevation in PSD volume was not significantly related to gray or white matter tissue volumes. Findings are consistent with PSD volume increasing with age and bulk CSF flow. CONCLUSIONS: Findings highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Additionally, findings demonstrate that PSD volume increases with age and relates to CSF volume and bi-directional flow. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

Joint analysis of structural connectivity and cortical surface features: correlates with mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a complex syndrome that affects up to 600 per 100,000 individuals, with a particular concentration among military personnel. About half of all mTBI patients experience a diverse array of chronic symptoms which persist long after the acute injury. Hence, there is an urgent need for better understanding of the white matter and gray matter pathologies associated with mTBI to map which specific brain systems are impacted and identify courses of intervention. Previous works have linked mTBI to disruptions in white matter pathways and cortical surface abnormalities. Herein, we examine these hypothesized links in an exploratory study of joint structural connectivity and cortical surface changes associated with mTBI and its chronic symptoms. Briefly, we consider a cohort of 12 mTBI and 26 control subjects. A set of 588 cortical surface metrics and 4,753 structural connectivity metrics were extracted from cortical surface regions and diffusion weighted magnetic resonance imaging in each subject. Principal component analysis (PCA) was used to reduce the dimensionality of each metric set. We then applied independent component analysis (ICA) both to each PCA space individually and together in a joint ICA approach. We identified a stable independent component across the connectivity-only and joint ICAs which presented significant group differences in subject loadings (p<0.05, corrected). Additionally, we found that two mTBI symptoms, slowed thinking and forgetfulness, were significantly correlated (p<0.05, corrected) with mTBI subject loadings in a surface-only ICA. These surface-only loadings captured an increase in bilateral cortical thickness.

Connections between intrinsically photosensitive retinal ganglion cells and TBI symptoms.

The majority of patients with traumatic brain injury (TBI) are classified as having a mild TBI. Despite being categorized as mild, these individuals report ongoing and complex symptoms, which negatively affect their ability to complete activities of daily living and overall quality of life. Some of the major symptoms include anxiety, depression, sleep problems, headaches, light sensitivity, and difficulty reading. The root cause for these symptoms is under investigation by many in the field. Of interest, several of these symptoms such as headaches, ocular pain, light sensitivity, and sleep disturbances may overlap and share underlying circuitry influenced by the intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells are light sensing, but non-image forming, and they influence corneal function, pupillary constriction, and circadian rhythm. In this review, we discuss these symptoms and propose a role of the ipRGCs as at least one underlying and unifying cause for such symptoms.