1. Fultz NE, Bonmassar G, Setsompop K, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019;366(6465):628-631. doi:10.1126/science.aax5440

2. Editorial Grubb S, Lauritzen M. Deep sleep drives brain fluid oscillations. Science (80- ). 2019;366(6465):572-573. doi:10.1126/science.aaz5191

Fultz et al simultaneously measured BOLD fMRI dynamics, EEG, and CSF flow during human sleep. To achieve high–temporal-resolution imaging, they acquired fMRI data at fast rates TR< 400 ms. While fMRI is often used to detect local oxygenation changes, fast acquisition paradigms also enable detection of fluid inflow: Fresh fluid arriving at the edge of the imaging volume has high signal intensity because it has not yet experienced RF pulses. By placing the boundary edge of the imaging volume at the fourth ventricle, CSF flow into the brain was detected as increased signal in the lower slices, allowing them to measure dynamics of CSF flow simultaneously with BOLD fMRI. They combined this imaging with simultaneous EEG (n = 13 participants).

Slow-wave sleep (SWS) represents high-intensity sleep and predominates in the first part of the night. Rapid eye movement (REM) sleep accompanies dreaming and is not influenced by prior sleep or waking and shows a rhythmicity with the body clock: Sleep starts with a light form of SWS, progresses to deeper SWS and then shallow SWS, and concludes with REM sleep before beginning a new cycle. During SWS, the cerebral blood flow is reduced by 25%, which lowers cerebral blood volume (CBV) by ~10%. Fultz et al. show that this reduction in CBV in the human brain allows inflow of cerebrospinal fluid (CSF) to the third and fourth ventricles—which may facilitate communication between fluid compartments and clearance of waste products.

CSF flow mediates mixing of brain fluids, facilitates signaling through volume transmission of neuromodulators, and increases the disposal of potentially harmful substances. There is substantial variation in brain volume, but an estimate of 1260 ml is reasonable for an average adult human brain, and the global reduction in cerebral blood flow during SWS gives rise to an overall reduction in CBV of 1.26 ml, which corresponds to ~1% of the CSF present at any one time. Thus, the CSF volume available for fluid oscillations is small, but the data presented by Fultz et al. suggest that the fluctuations occur in structures that are crucial for CSF exchange between the central cavities and the convexity. The CSF oscillations in human sleep described by Fultz et al. may contribute to the disposal of waste products, such as toxic brain proteins that cause neurodegeneration.

Fultz et al – 4 figures

3. Mackay DF, Russell ER, Stewart K, MacLean JA, Pell JP, Stewart W. Neurodegenerative Disease Mortality among Former Professional Soccer Players. N Engl J Med. 2019;381(19):1801-1808. doi:10.1056/NEJMoa1908483

The authors conducted a retrospective cohort study to compare mortality from neurodegenerative disease among 7676 former professional soccer players (identified from databases of Scottish players) with that among 23,028 controls from the general population who were matched to the players on the basis of sex, age, and degree of social deprivation. Causes of death were determined from death certificates. Data on medications dispensed for the treatment of dementia in the two cohorts were also compared. Over a median of 18 years, 1180 former soccer players (15.4%) and 3807 controls (16.5%) died. All-cause mortality was lower among former players than among controls up to the age of 70 years and was higher thereafter. Mortality with neurodegenerative disease listed as the primary cause was 1.7% among former soccer players and 0.5% among controls.  Among former players, mortality with neurodegenerative disease listed as the primary or a contributory cause on the death certificate varied according to disease subtype and was highest among those with Alzheimer’s disease and lowest among those with Parkinson’s disease. Dementia-related medications were prescribed more frequently to former players than to controls.

In this retrospective epidemiologic analysis, mortality from neurodegenerative disease was higher and mortality from other common diseases lower among former Scottish professional soccer players than among matched controls. Dementia-related medications were prescribed more frequently to former players than to controls.

4. Graham NS, Sharp DJ. Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. J Neurol Neurosurg Psychiatry. 2019;90(11):1221-1233. doi:10.1136/jnnp-2017-317557

Very complete review article:

Highlights:

Traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease including Alzheimer’s disease, Parkinson’s disease and chronic traumatic encephalopathy.

All-cause dementia risk is increased by around 1.5 times, and it has been estimated that around 5% of all dementia cases worldwide may be attributable to TBI.

The systematic use of neuroimaging and fluid biomarker measures of neurodegeneration will allow the definition of endophenotypes of post-traumatic dementias.

Progressive neurodegeneration is common after TBI and can be identified using MRI and positron emission tomography (PET) imaging, as well as fluid biomarkers such as neurofilament light.

There is increasing acceptance among regulators that biomarkers such as brain atrophy rates are valid trial endpoints in presymptomatic Alzheimer’s disease.

There is a therapeutic opportunity to intervene after TBI before significant neurodegeneration takes place, and there are good reasons to think that treatments should be initially judged against biomarkers such as brain atrophy rather than clinical endpoints.

Trial populations in this presymptomatic group could be enriched on the basis of biomarkers of axonal injury and neurodegeneration, including diffusion tensor imaging, blood neurofilament levels or amyloid positive PET scans.

6 figures, 1 table

5. Smith C, Malek N, Grosset K, Cullen B, Gentleman S, Grosset DG. Neuropathology of dementia in patients with Parkinson’s disease: a systematic review of autopsy studies. J Neurol Neurosurg Psychiatry. 2019:jnnp-2019-321111. doi:10.1136/jnnp-2019-321111

The authors evaluated 44 reports involving 2002 cases, 57.2% with dementia, met inclusion criteria. While limbic and neocortical α-synuclein pathology had the strongest association with dementia, between a fifth and a third of all PD cases in the largest studies had comorbid AD. In PD cases with dementia, tau pathology was moderate or severe in around a third, and amyloid-β pathology was moderate or severe in over half. Amyloid-β was associated with a more rapid cognitive decline and earlier mortality, and in the striatum, distinguished PD dementia from DLB. Positive correlations between multiple measures of α-synuclein, tau and amyloid-β were found. Cerebrovascular and TDP-43 pathologies did not generally contribute to dementia in PD. TDP-43 and amyloid angiopathy correlated with coexistent Alzheimer pathology.

They conclude that several disease processes (particularly Alzheimer related) are common in PD and are often severe enough to affect cognition, thereby adding to the effects of α-synuclein pathology. Tau pathology contributes to dementia in a subset of cases, and amyloid-β pathology confers a worse prognosis, characterized by an accelerated cognitive decline and earlier mortality. A synergistic interaction between α-synuclein, tau and amyloid-β means that they promote one another’s aggregation, leading to a more aggressive disease course. Accordingly, both tau and amyloid-β should be assessed in clinical trials of new disease-modifying therapies targeting α-synuclein, particularly when cognition is included as a study outcome.

2 figures, 2 tables

6. Chin AL, Fujimoto D, Kumar KA, et al. Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors. Neurosurgery. 2019;85(5):708-716. doi:10.1093/neuros/nyy442

While primary spinal cord tumors are rare and account for a minority (4%-8%) of all neoplasms of the central nervous system, meningiomas and nerve sheath tumors, including neurofibromas and schwannomas, account for 60% to 70% of all primary spinal tumors. Spinal meningiomas, neurofibromas, and schwannomas are benign tumors, typically in the intradural extramedullary compartment, that, while nonmalignant and typically slow-growing, can have a significant detrimental impact on patient quality of life by causing pain and neurological symptoms due to tumor mass effect.

Microsurgical resection is the established standard of care for the management of spinal meningiomas and benign nerve sheath tumors. However, spinal surgery is not without associated risks and certain patient characteristics may preclude surgical intervention, including advanced age, medical comorbidities, and familial phakomatoses. As such, the long-term efficacy and safety of noninvasive treatment options are important to characterize.

The authors performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy. They observed cumulative incidence of local failure of 2% at 3 years, 5% at 5 years, and 12% at 10 years. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10-yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient-years of follow-up, no SRS-related secondary malignancies were observed.

They conclude that comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection.

3 figures, 5 tables

7. Press RH, Zhang C, Chowdhary M, et al. Hemorrhagic and Cystic Brain Metastases Are Associated With an Increased Risk of Leptomeningeal Dissemination After Surgical Resection and Adjuvant Stereotactic Radiosurgery. Neurosurgery. 2019;85(5):632-641. doi:10.1093/neuros/nyy436

One hundred thirty-four consecutive patients with a single resected brain metastases treated with adjuvant stereotactic radiosurgery from 2008 to 2016 were identified. Intracranial outcomes including leptomeningeal dissemination were calculated using the cumulative incidence model with death as a competing risk. Median imaging follow-up was 14.2 mo. Hemorrhagic and cystic features were present in 46 (34%) and 32 (24%) patients, respectively. The overall 12- and 24-mo cumulative incidence of leptomeningeal dissemination with death as a competing risk was 11.0 and 22.4%, respectively. On multivariable analysis, hemorrhagic features,, cystic features, breast histology, and number of brain metastases >1 were independently associated with increased risk of leptomeningeal dissemination.

They conclude that hemorrhagic and cystic features were independently associated with increased risk for postoperative LMD. Patients with brain metastases containing these intralesion features may benefit from alternative treatment strategies to mitigate this risk.

3 figures, 4 tables

8. Tani S, Imamura H, Asai K, et al. Comparison of practical methods in clinical sites for estimating cerebral blood flow during balloon test occlusion. J Neurosurg. 2019;131(5):1430-1436. doi:10.3171/2018.5.JNS18858

Balloon test occlusion (BTO) is a technique used for predicting ischemic tolerance of cerebral hemispheres and for preventing incidental strokes in the treatment of aneurysms or neoplasms that require therapeutic occlusion of a carotid artery. Presently, in this era of flow diversion, performing a BTO procedure may be declining, but it remains an important preliminary examination. Two parameters, mean stump pressure (MSTP) and venous phase delay (VPD), have been most frequently adopted at clinical sites as practical indices for ischemic hypoperfusion of cerebral blood flow (CBF) in patients undergoing BTO.

Previously, mean stump pressure and CBF were confirmed to have a correlation coefficient of 0.497 in studies measuring both variables simultaneously in patients with BTO undergoing SPECT. In those studies, mean stump pressure and CBF measurements were obtained during room-to-room transfer of patients with a balloon catheter remaining inside the patients. Venous phase delay, however, cannot be detected during SPECT or other perfusion studies, and therefore the true correlation between venous phase delay and CBF is unknown, although the correlation between venous phase delay before the transfer and CBF after the transfer has been found to have a high correlation coefficient (0.94340).  A novel perfusion technique, x-ray angiography perfusion (XAP) analysis, uses only diagnostic DSA equipment to estimate CBF, venous phase delay, and mean stump pressure completely simultaneously. Through such simultaneous quantification, this study aims to compare various interpretation methods for VPD and mean stump pressure as to their potential to predict CBF and to introduce widely available methods to any institution with no expensive software or CBF-measuring apparatus such as SPECT.

This analysis was applied to 17 patients and resulted in successful estimation of all 3 parameters in each case. The average venous phase delay of several cortical veins had a strong correlation with relative CBF (rCBF) between bilateral hemispheres with a correlation coefficient of 0.89443, a correlation as strong as that (0.90357) of the “approximate VPD,” which is interpreted based on the trend line of the scatterplot of the time to peak contrast opacification in cortical veins and their spatial positioning from the median sagittal plane. Mean stump pressure and classic visual determination of venous phase delay have weaker correlation coefficients with rCBF (0.56119 and 0.70048, respectively). Overall, subjective visual determination in combination with the calculation of the trend line to estimate VPD provided a considerably strong correlation with rCBF (R = 0.86660) without any dedicated software or hardware.

4 figures, 1 table

9. Freund P, Seif M, Weiskopf N, et al. MRI in traumatic spinal cord injury: from clinical assessment to neuroimaging biomarkers. Lancet Neurol. 2019;18(12):1123-1135. doi:10.1016/S1474-4422(19)30138-3

In this review, the authors evaluate findings from conventional MRI and discuss the insights they have provided concerning the primary pathological features of the injury epicenter. They then assess developments in quantitative MRI imaging studies that have revealed new information on secondary pathological changes affecting the entire neuraxis. They discuss the relevance and implications of these advances in quantitative MRI for improving the ability to predict recovery are discussed, and they follow that discussion with an assessment of their application as biomarkers in spinal cord injury trials. They review studies assessing cortical and spinal functional plasticity by means of fMRI and rs-fMRI are reviewed before discussing the application of MRI protocols in clinical and research settings.

The most prominent features on sagittal T2-weighted MRI scans include hemorrhage, cytotoxic edema, and spinal cord swelling. Serial quantification of the sagittal T2-weighted hyperintensity revealed that the intramedullary damage dynamically expands rostrally and caudally, with injury severity substantially affecting the rate of expansion. On the basis of T2-weighted signal abnormalities, a five-point ordinal MRI score—referred to as the BASIC score (brain and spinal cord injury score)—has been proposed for MRI-based diagnostic and prognostic classification in patients with spinal cord injury in the first days after injury. The BASIC score quantifies five distinct patterns of intramedullary T2-weighted signal abnormality in the axial plane at the injury epicenter of the spinal cord. These patterns range from no abnormalities to the most severe abnormalities, consisting of a mix of hemorrhage and edema. The feasibility and prognostic validity of the BASIC score have been demonstrated for patients with acute cervical and thoracic spinal cord injury, in whom MRI had been performed within days after injury. Moreover, the intramedullary lesion size, measured on sagittal T2-weighted scans, might be a good predictor of recovery as its size is influenced by injury severity and the outcome of surgical decompression.

BASIC O

No appreciable intramedullary cord signal abnormality

BASIC 1

Intramedullary T2 hyperintensity is approximately confined to central grey matter

BASIC 2

Intramedullary T2 hyperintensity extends beyond expected grey matter margins to involve spinal white matter, but does not involve the entire transverse extent of the spinal cord

BASIC 3

Intramedullary T2 hyperintensity involves entire transverse extent of spinal cord

BASIC 4

Grade 3 injury plus discrete T2 hypointense foci, consistent with macrohemorrhage