Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases.

The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals

The lymphatic clearance pathways of the brain are different compared to the other organs of the body and have been the subject of heated debates. Drainage of brain extracellular fluids, particularly interstitial fluid (ISF) and cerebrospinal fluid (CSF), is not only important for volume regulation, but also for removal of waste products such as amyloid beta (Aβ). CSF plays a special role in clinical medicine, as it is available for analysis of biomarkers for Alzheimer's disease. Despite the lack of a complete anatomical and physiological picture of the communications between the subarachnoid space (SAS) and the brain parenchyma, it is often assumed that Aβ is cleared from the cerebral ISF into the CSF. Recent work suggests that clearance of the brain mainly occurs during sleep, with a specific role for peri- and para-vascular spaces as drainage pathways from the brain parenchyma. However, the direction of flow, the anatomical structures involved and the driving forces remain elusive, with partially conflicting data in literature. The presence of Aβ in the glia limitans in Alzheimer's disease suggests a direct communication of ISF with CSF. Nonetheless, there is also the well-described pathology of cerebral amyloid angiopathy associated with the failure of perivascular drainage of Aβ. Herein, we review the role of the vasculature and the impact of vascular pathology on the peri- and para-vascular clearance pathways of the brain. The different views on the possible routes for ISF drainage of the brain are discussed in the context of pathological significance.

/pdf/lymphatic-clearance-of-the-brain-perivascular-paravascular-5gbbrcfi5x.pdf

Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases.

High-resolution phase-contrast magnetic resonance imaging can now assess flow in proximal and distal cerebral arteries. The aim of this study was to describe how total cerebral blood flow (tCBF) is ...

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2014.241

Blood Flow Distribution in Cerebral Arteries

PURPOSE OF REVIEW: This article provides neurologists with a pragmatic approach to the diagnosis and treatment of idiopathic normal pressure hydrocephalus (iNPH), including an overview of: (1) key ...

/pdf/diagnosis-and-treatment-of-idiopathic-normal-pressure-1m624hmqb8.pdf

Diagnosis and Treatment of Idiopathic Normal Pressure Hydrocephalus.

Background:The primary role of brain imaging in idiopathic intracranial hypertension (IIH) is to exclude other pathologies causing intracranial hypertension. However, subtle radiologic findings suggestive of IIH have emerged with modern neuroimaging. This review provides a detailed description of th

Brain Imaging in Idiopathic Intracranial Hypertension.

Background
It has been well documented that along with tonsillar herniation, Chiari Malformation Type I (CMI) is associated with smaller posterior cranial fossa (PCF) and altered CSF flow and tissue motion in the cranio-cervical junction (CCJ).

/pdf/magnetic-resonance-imaging-measures-of-posterior-cranial-biout9fshi.pdf

Magnetic resonance imaging measures of posterior cranial fossa morphology and cerebrospinal fluid physiology in Chiari malformation type I.

Objective: To assess the effects of low-dose acetazolamide treatment on volumetric MRI markers and clinical outcome in idiopathic normal-pressure hydrocephalus (iNPH). Methods: We analyzed MRI and gait measures from 8 patients with iNPH with serial MRIs from an institutional review board–approved imaging protocol who had been treated off-label with low-dose acetazolamide (125–375 mg/day). MRI studies included fluid-attenuated inversion recovery and 3D T1-weighted high-resolution imaging. Automated analyses were employed to quantify each patient9s ventricular, global white matter hyperintensities (WMH), and periventricular WMH (PVH) volumes prior to and throughout treatment. Clinical outcome was based on gait changes assessed quantitatively using the Boon scale. Results: Five of 8 patients responded positively to treatment, with median gait improvement of 4 points on the Boon scale. A significant decrease in PVH volume (−6.1 ± 1.9 mL, p = 0.002) was seen in these patients following treatment. One patient9s gait was unchanged and 2 patients demonstrated worsened gait and were referred for shunt surgery. No reduction in PVH volume was detected in the latter 2 patients. Nonperiventricular WMH and lateral ventricle volumes remained largely unchanged in all patients. Conclusions: These preliminary findings provide new evidence that low-dose acetazolamide can reduce PVH and may improve gait in iNPH. PVH volume, reflecting transependymal CSF, is shown to be a potential MRI indicator of pharmacologic intervention effectiveness. Further studies of pharmacologic treatment of iNPH are needed and may be enhanced by incorporating quantitative MRI outcomes. Classification of evidence: This study provides Class IV evidence that low-dose acetazolamide reverses PVH volume and, in some cases, improves gait in iNPH.

Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH

Objective: To assess the effect of weightlessness and the respective roles of CSF and vascular fluid on changes in white matter hyperintensity (WMH) burden in astronauts. Methods: We analyzed prespaceflight and postspaceflight brain MRI scans from 17 astronauts, 10 who flew a long-duration mission on the International Space Station (ISS) and 7 who flew a short-duration mission on the Space Shuttle. Automated analysis methods were used to determine preflight to postflight changes in periventricular and deep WMH, CSF, and brain tissue volumes in fluid-attenuated inversion recovery and high-resolution 3-dimensional T1-weighted imaging. Differences between cohorts and associations between individual measures were assessed. The short-term reversibility of the identified preflight to postflight changes was tested in a subcohort of 5 long-duration astronauts who had a second postflight MRI scan 1 month after the first postflight scan. Results: Significant preflight to postflight changes were measured only in the long-duration cohort and included only the periventricular WMH and ventricular CSF volumes. Changes in deep WMH and brain tissue volumes were not significant in either cohort. The increase in periventricular WMH volume was significantly associated with an increase in ventricular CSF volume (ρ = 0.63, p = 0.008). A partial reversal of these increases was observed in the long-duration subcohort with a 1-month follow-up scan. Conclusions: Long-duration exposure to microgravity is associated with an increase in periventricular WMH in astronauts. This increase was linked to an increase in ventricular CSF volume documented in ISS astronauts. There was no associated change in or abnormal levels of WMH volumes in deep white matter as reported in U-2 high-altitude pilots.

Spaceflight-induced changes in white matter hyperintensity burden in astronauts

Objective The study was undertaken to determine whether normobaric hypoxia causes elevated brain volume and intracranial pressure in individuals with symptoms consistent with acute mountain sickness (AMS). Methods Thirteen males ageâ��=â��(26 (sd 6)) years were exposed to normobaric hypoxia (12% O2) and normoxia (21% O2). After 2 and 10 hours, AMS symptoms were assessed alongside ventricular and venous vessel volumes, cerebral blood flow, regional brain volumes, and intracranial pressure, using high-resolution magnetic resonance imaging. Results In normoxia, neither lateral ventricular volume (R2â��=â��0.07, pâ��=â��0.40) nor predominance of unilateral transverse venous sinus drainage (R2â��=â��0.07, pâ��=â��0.45) was related to AMS symptoms. Furthermore, despite an increase in cerebral blood flow after 2 hours of hypoxia (hypoxia vs normoxia: I�148ml/minâ��1, 95% confidence interval [CI]â��=â��58 to 238), by 10 hours, when AMS symptoms had developed, cerebral blood flow was normal (I�â��51ml/minâ��1, 95% CIâ��=â��â��141 to 39). Conversely, at 10 hours brain volume was increased (I�59ml, 95% CIâ��=â��8 to 110), predominantly due to an increase in gray matter volume (I�73ml, 95% CIâ��=â��25 to 120). Therefore, cerebral spinal fluid volume was decreased (I�â��40ml, 95% CIâ��=â��â��67 to â��14). The intracranial pressure response to hypoxia varied between individuals, and as hypothesized, the most AMS-symptomatic participants had the largest increases in intracranial pressure (AMS present, I�7mmHg, 95% CIâ��=â��â��2.5 to 17.3; AMS not present, I�â��1mmHg, 95% CIâ��=â��â��3.3 to 0.5). Consequently, there was a significant relationship between the change in intracranial pressure and AMS symptom severity (R2â��=â��0.71, pâ��=â��0.002). Interpretation The data provide the strongest evidence to date to support the hypothesis that the â��randomâ�� nature of AMS symptomology is explained by a variable intracranial pressure response to hypoxia. ANN NEUROL 2014

Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension

To compare venous drainage patterns and associated intracranial hydrodynamics between subjects who experienced mild traumatic brain injury (mTBI) and age- and gender-matched controls.
Thirty adult subjects (15 with mTBI and 15 age- and gender-matched controls) were investigated using a 3T MR scanner. Time since trauma was 0.5 to 29 years (mean 11.4 years). A 2D-time-of-flight MR-venography of the upper neck was performed to visualize the cervical venous vasculature. Cerebral venous drainage through primary and secondary channels, and intracranial compliance index and pressure were derived using cine-phase contrast imaging of the cerebral arterial inflow, venous outflow, and the craniospinal CSF flow. The intracranial compliance index is the defined as the ratio of maximal intracranial volume and pressure changes during the cardiac cycle. MR estimated ICP was then obtained through the inverse relationship between compliance and ICP.
Compared to the controls, subjects with mTBI demonstrated a significantly smaller percentage of venous outflow through internal jugular veins (60.9±21% vs. controls: 76.8±10%; p = 0.01) compensated by an increased drainage through secondary veins (12.3±10.9% vs. 5.5±3.3%; p<0.03). Mean intracranial compliance index was significantly lower in the mTBI cohort (5.8±1.4 vs. controls 8.4±1.9; p<0.0007). Consequently, MR estimate of intracranial pressure was significantly higher in the mTBI cohort (12.5±2.9 mmHg vs. 8.8±2.0 mmHg; p<0.0007).
mTBI is associated with increased venous drainage through secondary pathways. This reflects higher outflow impedance, which may explain the finding of reduced intracranial compliance. These results suggest that hemodynamic and hydrodynamic changes following mTBI persist even in the absence of clinical symptoms and abnormal findings in conventional MR imaging.

https://epub.ub.uni-muenchen.de/15251/1/pone.0055447.pdf

Sang H. Lee

Papers

Magnetic resonance imaging measures of posterior cranial fossa morphology and cerebrospinal fluid physiology in Chiari malformation type I.

Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH

Spaceflight-induced changes in white matter hyperintensity burden in astronauts

Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension

MRI Evidence for Altered Venous Drainage and Intracranial Compliance in Mild Traumatic Brain Injury