MRI Indices of Glymphatic Function Correlate With Disease Duration in Idiopathic Intracranial Hypertension.

BACKGROUND: The glymphatic system represents an extravascular network of astrocytic channels responsible for interstitial fluid and solute transit through the brain parenchyma. Its dysfunction has been considered as a possible cause of idiopathic intracranial hypertension (IIH). METHODS: We enrolled participants with active IIH, treated or cured IIH, and controls. The active IIH group was divided into untreated participants with recently developed (<6 mo) and chronic (6+ mo) disease. Glymphatic function was assessed using diffusion tensor imaging along the paravascular space (DTI-ALPS) to generate an ALPS-index, hypothesized to measure glymphatic function. Participants were imaged before lumbar puncture (LP) if IIH was suspected and following LP when possible. RESULTS: ALPS indices were higher in participants with chronically present, active IIH than in those either with recently developed IIH or control participants. ALPS-indices correlated with papilledema but did not correlate significantly with age, BMI, or intracranial pressure (ICP). CONCLUSIONS: Our findings suggest that DTI-ALPS-indices of glymphatic function may be influenced by the chronicity of intracranial hypertension but do not support the hypothesis that glymphatic dysfunction causes IIH. Though these findings are preliminary, glymphatic imaging may be a useful radiographic biomarker in IIH.

Predicting Gait Speed Improvement in Idiopathic Normal Pressure Hydrocephalus Patients: The Role of Evans Index and Ventricular Volume.

Objective This study aims to investigate the association between specific imaging parameters, namely, the Evans index (EI) and ventricular volume (VV), and the variation in gait speed observed in patients with idiopathic normal pressure hydrocephalus (iNPH) before and after cerebrospinal fluid (CSF) removal/lumbar drain (LD). Furthermore, it seeks to identify which imaging parameters are the most reliable predictors for significant improvements in gait speed post procedure. Methods In this retrospective analysis, the study measured the gait speed of 35 patients diagnosed with idiopathic normal pressure hydrocephalus (iNPH) before and after they underwent CSF removal. Before lumbar drain (LD), brain images were segmented to calculate the Evans index and ventricular volume. The study explored the relationship between these imaging parameters (the Evans index and ventricular volume) and the improvement in gait speed following CSF removal. Patients were divided into two categories based on the degree of improvement in gait speed, and we compared the imaging parameters between these groups. Receiver operating characteristic (ROC) curve analysis was employed to determine the optimal imaging parameter thresholds predictive of gait speed enhancement. Finally, the study assessed the predictive accuracy of these thresholds for identifying patients likely to experience improved gait speed post-LD. Results Following CSF removal/lumbar drain, the participants significantly improved in gait speed, as indicated by a paired sample t-test (p-value = 0.0017). A moderate positive correlation was observed between the imaging parameters (EI and VV) and the improvement in gait speed post-LD. Significant differences were detected between the two patient groups regarding EI, VV, and a composite score (statistical test value = 3.1, 2.8, and 2.9, respectively; p-value < 0.01). Receiver operating characteristic (ROC) curve analysis identified the optimal thresholds for the EI and VV to be 0.39 and 110.78 cm³, respectively. The classification based on these thresholds yielded significant associations between patients displaying favorable imaging parameters and those demonstrating improved gait speed post-LD, with chi-square (χ²) values of 8.5 and 7.1, respectively, and p-values < 0.01. Furthermore, these imaging parameter thresholds had a 74% accuracy rate in predicting patients who would improve post-LD. Conclusion The study demonstrates that ventricle volume and the Evans index can significantly predict gait speed improvement after lumbar drain (LD) in patients with iNPH.

Statistical Parametric Mapping in Amyloid Positron Emission Tomography.

Alzheimer's disease (AD), the most common cause of dementia, has limited treatment options. Emerging disease modifying therapies are targeted at clearing amyloid-ß (Aß) aggregates and slowing the rate of amyloid deposition. However, amyloid burden is not routinely evaluated quantitatively for purposes of disease progression and treatment response assessment. Statistical Parametric Mapping (SPM) is a technique comparing single-subject Positron Emission Tomography (PET) to a healthy cohort that may improve quantification of amyloid burden and diagnostic performance. While primarily used in 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-PET, SPM's utility in amyloid PET for AD diagnosis is less established and uncertainty remains regarding optimal normal database construction. Using commercially available SPM software, we created a database of 34 non-APOE ε4 carriers with normal cognitive testing (MMSE > 25) and negative cerebrospinal fluid (CSF) AD biomarkers. We compared this database to 115 cognitively normal subjects with variable AD risk factors. We hypothesized that SPM based on our database would identify more positive scans in the test cohort than the qualitatively rated [11C]-PiB PET (QR-PiB), that SPM-based interpretation would correlate better with CSF Aß42 levels than QR-PiB, and that regional z-scores of specific brain regions known to be involved early in AD would be predictive of CSF Aß42 levels. Fisher's exact test and the kappa coefficient assessed the agreement between SPM, QR-PiB PET, and CSF biomarkers. Logistic regression determined if the regional z-scores predicted CSF Aß42 levels. An optimal z-score cutoff was calculated using Youden's index. We found SPM identified more positive scans than QR-PiB PET (19.1 vs. 9.6%) and that SPM correlated more closely with CSF Aß42 levels than QR-PiB PET (kappa 0.13 vs. 0.06) indicating that SPM may have higher sensitivity than standard QR-PiB PET images. Regional analysis demonstrated the z-scores of the precuneus, anterior cingulate and posterior cingulate were predictive of CSF Aß42 levels [OR (95% CI) 2.4 (1.1, 5.1) p = 0.024; 1.8 (1.1, 2.8) p = 0.020; 1.6 (1.1, 2.5) p = 0.026]. This study demonstrates the utility of using SPM with a "true normal" database and suggests that SPM enhances diagnostic performance in AD in the clinical setting through its quantitative approach, which will be increasingly important with future disease-modifying therapies.

Quantitative Water Permeability Mapping of Blood-Brain-Barrier Dysfunction in Aging.

Blood-brain-barrier (BBB) dysfunction is a hallmark of aging and aging-related disorders, including cerebral small vessel disease and Alzheimer's disease. An emerging biomarker of BBB dysfunction is BBB water exchange rate (kW) as measured by diffusion-weighted arterial spin labeling (DW-ASL) MRI. We developed an improved DW-ASL sequence for Quantitative Permeability Mapping and evaluated whole brain and region-specific kW in a cohort of 30 adults without dementia across the age spectrum. In this cross-sectional study, we found higher kW values in the cerebral cortex (mean = 81.51 min-1, SD = 15.54) compared to cerebral white matter (mean = 75.19 min-1, SD = 13.85) (p < 0.0001). We found a similar relationship for cerebral blood flow (CBF), concordant with previously published studies. Multiple linear regression analysis with kW as an outcome showed that age was statistically significant in the cerebral cortex (p = 0.013), cerebral white matter (p = 0.033), hippocampi (p = 0.043), orbitofrontal cortices (p = 0.042), and precunei cortices (p = 0.009), after adjusting for sex and number of vascular risk factors. With CBF as an outcome, age was statistically significant only in the cerebral cortex (p = 0.026) and precunei cortices (p = 0.020). We further found moderate negative correlations between white matter hyperintensity (WMH) kW and WMH volume (r = -0.51, p = 0.02), and normal-appearing white matter (NAWM) and WMH volume (r = -0.44, p = 0.05). This work illuminates the relationship between BBB water exchange and aging and may serve as the basis for BBB-targeted therapies for aging-related brain disorders.

Heuristic scoring method utilizing FDG-PET statistical parametric mapping in the evaluation of suspected Alzheimer disease and frontotemporal lobar degeneration.

Distinguishing frontotemporal lobar degeneration (FTLD) and Alzheimer Disease (AD) on FDG-PET based on qualitative review alone can pose a diagnostic challenge. SPM has been shown to improve diagnostic performance in research settings, but translation to clinical practice has been lacking. Our purpose was to create a heuristic scoring method based on statistical parametric mapping z-scores. We aimed to compare the performance of the scoring method to the initial qualitative read and a machine learning (ML)-based method as benchmarks. FDG-PET/CT or PET/MRI of 65 patients with suspected dementia were processed using SPM software, yielding z-scores from either whole brain (W) or cerebellar (C) normalization relative to a healthy cohort. A non-ML, heuristic scoring system was applied using region counts below a preset z-score cutoff. W z-scores, C z-scores, or WC z-scores (z-scores from both W and C normalization) served as features to build random forest models. The neurological diagnosis was used as the gold standard. The sensitivity of the non-ML scoring system and the random forest models to detect AD was higher than the initial qualitative read of the standard FDG-PET [0.89-1.00 vs. 0.22 (95% CI, 0-0.33)]. A categorical random forest model to distinguish AD, FTLD, and normal cases had similar accuracy than the non-ML scoring model (0.63 vs. 0.61). Our non-ML-based scoring system of SPM z-scores approximated the diagnostic performance of a ML-based method and demonstrated higher sensitivity in the detection of AD compared to qualitative reads. This approach may improve the diagnostic performance.

Sensitization of rapid dopamine signaling in the nucleus accumbens core and shell after repeated cocaine in rats.

Repeated cocaine exposure and withdrawal leads to long-term changes, including behavioral and dopamine sensitization to an acute cocaine challenge, that are most pronounced after long withdrawal periods. However, the changes in dopamine neurotransmission after short withdrawal periods are less well defined. To study dopamine neurotransmission after 1-day withdrawal, we used fast-scan cyclic voltammetry (FSCV) to determine whether repeated cocaine alters rapid dopamine release and uptake in the nucleus accumbens (NAc) core and shell. FSCV was performed in urethane anesthetized male Sprague-Dawley rats that had previously received one or seven daily injections of saline or cocaine (15 mg/kg, ip). In response to acute cocaine, subjects showed increased dopamine overflow that resulted from both increased dopamine release and slowed dopamine uptake. One-day cocaine pre-exposure, however, did not alter dopaminergic responses to a subsequent cocaine challenge. In contrast, 7-day cocaine-treated subjects showed a potentiated rapid dopamine response in both the core and shell after an acute cocaine challenge. In addition, kinetic analysis during the cocaine challenge showed a greater increase in apparent K(m) of 7-day cocaine exposed subjects. Together, the data provide the first in vivo demonstration of rapid dopamine sensitization in the NAc core and shell after a short withdrawal period. In addition, the data clearly delineate cocaine's release and uptake effects and suggest that the observed sensitization results from greater uptake inhibition in cocaine pre-exposed subjects.