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Objectives Idiopathic normal pressure hydrocephalus (INPH) is a neurodegenerative disorder characterized by excess cerebrospinal fluid (CSF) in the ventricles, which can be diagnosed by invasive CSF drainage test and treated by shunt placement. Here, we aim to investigate the diagnostic and prognostic power of systematic volumetric analysis based on brain structural MRI for INPH. Methods We performed a retrospective study with a cohort of 104 probable INPH patients who underwent CSF drainage tests and another cohort of 41 INPH patients who had shunt placement. High-resolution T1-weighted images of the patients were segmented using an automated pipeline into 283 structures that are grouped into different granularity levels for volumetric analysis. Volumes at multi-granularity levels were used in a recursive feature elimination model to classify CSF drainage responders and non-responders. We then used pre-surgical brain volumes to predict Tinetti and MMSE scores after shunting, based on the least absolute shrinkage and selection operator. Results The classification accuracy of differentiating the CSF drainage responders and non-responders increased as the granularity increased. The highest diagnostic accuracy was achieved at the finest segmentation with a sensitivity/specificity/precision/accuracy of 0.89/0.91/0.84/0.90 and an area under the curve of 0.94. The predicted post-surgical neurological scores showed high correlations with the ground truth, with r = 0.80 for Tinetti and r = 0.88 for MMSE. The anatomical features that played important roles in the diagnostic and prognostic tasks were also illustrated. Conclusions We demonstrated that volumetric analysis with fine segmentation could reliably differentiate CSF drainage responders from other INPH-like patients, and it could accurately predict the neurological outcomes after shunting. Key Points • We performed a fully automated segmentation of brain MRI at multiple granularity levels for systematic volumetric analysis of idiopathic normal pressure hydrocephalus (INPH) patients. • We were able to differentiate patients that responded to CSF drainage test with an accuracy of 0.90 and area under the curve of 0.94 in a cohort of 104 probable INPH patients, as well as to predict the post-shunt gait and cognitive scores with a coefficient of 0.80 for Tinetti and 0.88 for MMSE. • Feature analysis showed the inferior lateral ventricle, bilateral hippocampus, and orbital cortex are positive indicators of CSF drainage responders, whereas the posterior deep white matter and parietal subcortical white matter were negative predictors.

Background Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer’s disease (AD) pathology (amyloid-β [Aβ 42/40 ], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOE ε4 status, and plasma amyloid-β status modified these associations. Methods Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. Results Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aβ 42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aβ 42/40 (higher Aβ burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOE ε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aβ burden, as was the association of higher GFAP with memory decline. Conclusions Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.

•A novel MRI technique was developed to provide a non-invasive assessment of oxygen extraction fraction in the medial temporal lobe (MTL-OEF) in less than 5 minutes.•MTL-OEF was measured to be 23.9±3.6% in healthy adults and was significantly lower (P<0.0001) than the OEF of 33.3±2.9% in superficial cortical tissues.•In caffeine ingestion challenges, MTL-OEF was elevated by 9.1±4.0%.•MTL-OEF increased with age (MTL-OEF=20.997+0.100 × age; P=0.02). The medial temporal lobe (MTL) is a key area implicated in many brain diseases, such as Alzheimer's disease. As a functional biomarker, the oxygen extraction fraction (OEF) of MTL may be more sensitive than structural atrophy of MTL, especially at the early stages of diseases. However, there is a lack of non-invasive techniques to measure MTL-OEF in humans. The goal of this work is to develop an MRI technique to assess MTL-OEF in a clinically practical time without using contrast agents. The proposed method measures venous oxygenation (Yv) in the basal veins of Rosenthal (BVs), which are the major draining veins of the MTL. MTL-OEF can then be estimated as the arterio-venous difference in oxygenation. We developed an MRI sequence, dubbed arterial-suppressed accelerated T2-relaxation-under-phase-contrast (AS-aTRUPC), to quantify the blood T2 of the BVs, which was then converted to Yv through a well-established calibration model. MTL-OEF was calculated as (Ya−Yv)/Ya × 100%, where Ya was the arterial oxygenation. The feasibility of AS-aTRUPC to quantify MTL-OEF was evaluated in 16 healthy adults. The sensitivity of AS-aTRUPC in detecting OEF changes was assessed by a caffeine ingestion (200 mg) challenge. For comparison, T2-relaxation-under-spin-tagging (TRUST) MRI, which is a widely used global OEF technique, was also acquired. The dependence of MTL-OEF on age was examined by including another seven healthy elderly subjects. The results showed that in healthy adults, MTL-OEF of the left and right hemispheres were correlated (P=0.005). MTL-OEF was measured to be 23.9±3.6% (mean±standard deviation) and was significantly lower (P<0.0001) than the OEF of 33.3±2.9% measured in superior sagittal sinus (SSS). After caffeine ingestion, there was an absolute percentage increase of 9.1±4.0% in MTL-OEF. Additionally, OEF in SSS measured with AS-aTRUPC showed a strong correlation with TRUST OEF (intra-class correlation coefficient=0.94 with 95% confidence interval [0.91, 0.96]), with no significant bias (P=0.12). MTL-OEF was found to increase with age (MTL-OEF=20.997+0.100 × age; P=0.02). In conclusion, AS-aTRUPC MRI provides non-invasive assessments of MTL-OEF and may facilitate future clinical applications of MTL-OEF as a disease biomarker.

Objective To assess the predictive value of common measures validated to predict falls in other geriatric populations in patients presenting with suspected Normal Pressure Hydrocephalus (NPH). Methods One hundred ninety-five patients over the age of 60 who received the Fall Risk Questionnaire were retrospectively recruited from the CSF Disorders clinic within the departments of Neurosurgery and Neurology. Multiple logistic regression was used to create a model to predict falls for patients with suspected NPH using common measures: Timed Up & Go, Dual Timed Up & Go, 10 Meter Walk, MiniBESTest, 6-Minute Walk, Lower Extremity Function (Mobility), Fall Risk Questionnaire, and Functional Activities Questionnaire. Results The Fall Risk Questionnaire and age were shown to be the best predictors of falls. The model was 95.92% (Positive predictive value: 83.93%) sensitive and 47.92% specific (Negative predictive value: 77.78%). Conclusion Patients presenting with suspected NPH are at an increased fall risk, 75% of the total patients and 89% of patients who responded to a temporary drain of CSF had at least one fall in the past 6 months. The Fall Risk Questionnaire and age were shown to be predictive of falls for patients with suspected NPH. The preliminary evidence indicates measures that have been validated to assess fall risk in other populations may not be valid for patients presenting with suspected NPH.

Several models have been proposed for the evolution of Alzheimer's disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD. We examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset. All nine measures had significant changepoints, all of which preceded symptom onset, however, the timing of these changepoints varied considerably. A single measure, CSF t-tau, had an early changepoint (34 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF Abeta and phosphorylated tau) and all cognitive tests had changepoints 10-15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a 6-year time difference between the right and left side (respectively nine and 3 years prior to symptom onset). These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance.

To examine the prospective association between blood biomarkers of immune functioning (i.e., innate immune activation, adaptive immunity, and inflammation) and subsequent cognitive decline and clinical progression to mild cognitive impairment (MCI) in cognitively normal individuals. The BIOCARD study is an observational cohort study of = 191 initially cognitively healthy participants (mean age 65.2 years). Blood plasma samples were assayed for markers of chronic inflammation (TNFR1, IL-6), adaptive immunity (CD25), and innate immune activation (CD14 and CD163). Participants were followed annually for ongoing clinical assessment and cognitive testing for up to 7.3 years. Primary study outcomes were progression to MCI and cognitive change over time, as measured by a global factor score encompassing multiple cognitive domains. Higher levels of plasma TNFR1 were associated with greater risk of progression from normal cognition to MCI (HR: 3.27; 95% confidence interval, CI: 1.27, 8.40). Elevated levels of TNFR1 were also associated with steeper rate of cognitive decline on follow-up but not with baseline cognitive performance. Baseline IL-6 levels and markers of innate and adaptive immune activation showed no relationship with MCI risk or cognitive decline. Inflammation, mediated by TNF signaling, may play a selective role in the early phase of AD. Accordingly, plasma TNFR1 may facilitate improved prediction of disease progression for individuals in the preclinical stage of AD.

INTRODUCTION The factors that influence the progression of Alzheimer's disease (AD) after individuals become amyloid‐positive are poorly understood. This study examines how sex influences the longitudinal trajectories of plasma AD and neurodegenerative biomarkers in the years following a person's estimated onset of amyloid‐β. METHODS Linear mixed‐effects modeling investigated overall and sex‐specific longitudinal trajectories of plasma biomarkers, brain volumes, and cognition relative to the estimated age of amyloid onset in a cohort of 78 amyloid‐positive Baltimore Longitudinal Study of Aging (BLSA) participants (n = 45 male; follow‐up time: 6.8 years [SD 3.31]). Amyloid status was ascertained with 11C‐Pittsburgh compound B (PiB) PET imaging. RESULTS After amyloid onset, men displayed steeper increases in pTau181, pTau231, and neurofilament light (NfL) compared to women. In this same period, men demonstrated steeper declines in brain volume and cognitive performance. DISCUSSION These findings suggest that sex influences the trajectory of AD pathology, neuronal injury, and symptom progression after individuals become amyloid‐positive. Highlights Steeper rates of increase in pTau and GFAP among amyloid‐positive individuals. After amyloid onset, steeper increases in pTau and NfL concentrations in men than in women. Steeper declines in brain volume and cognition in men corroborate biomarker results.

Objective Ventricular collapse is a prevalent yet poorly understood complication of ventriculo-peritoneal shunting (VPS) in idiopathic intracranial hypertension (IIH). By identifying the risk factors of ventricular collapse (VC), this study aims to characterize the clinical progression and treatment of IIH and its complications. The relationships between ventricular area, symptoms and treatments were assessed longitudinally with ventricular segmentation on MRI/CT imaging, and correlated with other risk factors of IIH and VC. Methods We retrospectively reviewed 147 patients who underwent VPS for IIH at our Institution, and identified 73 shunt-naïve subjects. Manual segmentation of CT/MRI scans was performed at each clinical stage (baseline, post-shunting, post-collapse and after each intervention). Variables collected included valve type and opening-pressure, shunt revisions, use of anti-siphoning devices (ASD), comorbidities, venous sinus hypoplasia/stenosis, stenting, general demographics. Linear univariate regression models were used to determine the association between individual risk factors and VC, and quantitatively assess the effect of treatment. Two multivariate models were tested, including Pre-Shunting and Post-Shunting variables, to quantify their association with VC. Results Of 73 IIH patients with new shunts, 32 experienced collapse (uni- or bilateral, 26.5% of the total). In shunt-naïve patients, collapse was associated with pre-shunting (rho = −0.36; p  = 0.001) and post-shunting ventricular area (rho = 0.62; p  = 0.0002). Both collapse and ventricular area were correlated with shunt-related symptoms at 6 months (rho = −0.29; p  = 0.01). Shunt adjustment, addition of ASDs, valve replacement proved to be effective strategies to re-expand the ventricles and reduce symptoms. Nonetheless, a significant fraction of patients remained symptomatic after multiple treatments, suggesting a complex etiology for VC. On univariate analysis, catheter revisions were more common in the VC group, while the multivariate model with Post-Shunting factors was significantly associated with VC. Conclusions In newly VP-shunted IIH patients, small ventricular area predisposes to collapse and headaches, while higher valve settings and ASDs may reduce the risk of collapse and promote symptomatic improvement. Within the restraints of a retrospective analysis, this study is the first to analyze the risk factors of VC in IIH patients, longitudinally integrating the clinical progression with ventricular imaging. Further studies are warranted to better understand the clinical progression of collapse.

We aimed to define the prevalence of objective cognitive impairment in a group of chronic migraineurs, and to define how migraineurs with cognitive impairment differed from those without impairment, and in doing so to compare cognitive impairment in chronic migraine to another chronic headache-related disorder already associated with cognitive impairment (i.e. pseudotumor cerebri syndrome). Cognitive impairment in migraine, especially chronic migraine, has been too little studied. Only a few studies have been done, demonstrating that cognitive impairment exists in chronic migraineurs. It is not known how this compares to other headache-related conditions. We administered a cognitive battery consisting of the National Adult Reading Test, Mini-Mental Status Examination, Digit Span, Boston Naming Test, Rey Auditory Verbal Learning Test, Trail Making Test, Controlled Oral Word Association, and Category Fluency. Cognitive impairment was defined as mild single-domain with one test score, and mild multi- -domain with two scores more than two standard deviations below the mean for age-, gender-, and education-adjusted norms. The data from this study was compared to our previously published population of patients with pseudotumor cerebri syndrome. One hundred prospectively recruited patients with chronic migraine were enrolled. Fifty-seven patients had normal cognitive profiles. Forty-three patients demonstrated mild cognitive impairment, and more than half (n = 24) showed impairment in multiple cognitive domains. Migraineurs with multi-domain impairment had higher pain intensity, shorter duration of disease, were taking narcotics, had more impaired vision-related mental health scores, and worse social health scores. We found an association between objective cognitive impairment and subjective perception of impairment only when controlling for pain. We found no associations with depression and topiramate use. The mean composite cognitive Z score was no different in chronic migraineurs and patients with pseudotumor cerebri. Most chronic migraineurs have normal cognitive profiles, but a large proportion of them do experience mild cognitive impairment, especially in multiple domains. The impairment seen in migraine is similar to that in pseudotumor cerebri syndrome, which has already been associated with mild cognitive impairment. Cognitively impaired migraineurs are different from non-impaired/less impaired migraineurs in several ways, which may be an important factor in influencing their migraine treatment.