Proteomic profiling in idiopathic normal-pressure hydrocephalus
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Junming Zhu
PROVIDER: PXD059796 | iProX | Tue Jan 14 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:Idiopathic normal pressure hydrocephalus (iNPH) is a common, yet enigmatic form of dementia characterized by cerebral ventriculomegaly. In contrast to other types of hydrocephalus, iNPH exhibits normal or even reduced intracranial pressures and infrequent reductions in ventricular size after CSF shunting. Here, we generated the first single-cell RNA sequencing atlas of the peripheral blood and ventricular CSF in elderly iNPH patients totaling 140,207 transcriptomes. Integrated analyses identified a pro-inflammatory signature in peripheral blood and CSF monocytes that was significantly enriched in iNPH subgroups with lower cognitive function. We also identified novel CSF cell populations likely representing the periventricular sloughing of degenerating neuroglial cells. Our findings suggest that immune dysregulation detectable in peripheral blood monocytes contributes to CSF space inflammation, neurodegeneration, and associated cognitive deficits in iNPH. These data shift the paradigm of iNPH from a primary disorder of impaired “brain plumbing” and highlight the potential for non-invasive, immune-based diagnostic and treatment strategies.
2025-04-23 | GSE292141 | GEO
Project description:ObjectivesThe aim of this study was to determine the prevalence of idiopathic normal-pressure hydrocephalus (iNPH) in elderly persons in a large population-based sample using radiologic and clinical examinations.MethodsWe examined representative elderly populations aged 70 years and older that had undergone neuropsychiatric evaluations and CT of the brain between 1986 and 2000 (n = 1,238). Gait was evaluated by clinical examination and history of walking difficulty. Cognitive function was evaluated with the Mini-Mental State Examination and urinary incontinence by self-report. iNPH was diagnosed in concordance with the American-European iNPH guidelines. Exclusion criteria were history of meningitis, severe head trauma, and subarachnoid hemorrhage.ResultsThe prevalence of probable iNPH was 0.2% in those aged 70-79 years (n = 2) and 5.9% (n = 24) in those aged 80 years and older, with no difference between men and women. Only 2 of these persons had been treated for iNPH. Hydrocephalic ventricular enlargement, i.e., a CT image consistent with NPH, was found in 56 persons (4.5%). An Evans Index >0.3 was found in 256 (20.7%) and occluded sulci at the high convexity in 67 persons (5.4%). All of these findings were more common in the older age groups.ConclusionsMany elderly possess clinical and imaging features of iNPH, especially those older than 80 years. The number of persons with iNPH is probably much higher than the number of persons currently treated.
| S-EPMC4001197 | biostudies-literature
Project description:The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.
| S-EPMC5841149 | biostudies-literature
Project description:Single-cell elderly blood-CSF atlas implicates peripherally-influenced neuroinflammatory degeneration in normal pressure hydrocephalus
| PRJNA1237269 | ENA
Project description:Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6-fold and 2.7-fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol-anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol-anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.
| S-EPMC7933959 | biostudies-literature
Project description:IntroductionAmyloid plaque has been reported in brain biopsies from patients with idiopathic normal-pressure hydrocephalus (iNPH) and proposed as a significant feature of the pathophysiology. Presence of the apolipoprotein E ε4 (APOE ε4) allele is associated with increased risk of Alzheimer's disease (AD).AimsTo compare the distribution of APOE genotype in iNPH patients with an age-matched population-based control group and with Alzheimer's disease (AD) patients.MethodsAPOE genotype frequencies were determined in 77 iNPH patients (50 men and 27 women, mean age 71.7 years) diagnosed with iNPH, a sample of 691 AD patients and 638 age-matched population controls (299 men and 339 women) from the INTERGENE cohort.ResultsThe APOE distribution did not differ significantly between the iNPH patients and the control population. The per e4-allele odds-ratio (OR) of iNPH was given by OR = 0.90, 95% confidence interval (CI) = (0.50, 1.60) that was considerably smaller than the per-allele OR of AD, OR = 5.34 (4.10, 7.00).ConclusionThe results suggest that the APOE-related risk of AD in patients with iNPH is not higher than in the general population.
| S-EPMC4956274 | biostudies-literature
Project description:A vascular disease could be involved in pathophysiology of normal pressure hydrocephalus (INPH). If so, there should be an association between INPH and cerebral microbleeds (CMB). This study aims to analyze if CMB are associated with INPH.In this case-control study we included 14 patients with INPH (mean age 76 years, 60 % female) and 41 healthy controls (HeCo; mean age 71 years, 60 % female). All were investigated with magnetic resonance imaging (MRI) using a T2*-sequence. The MRI exams were reviewed by two neuroradiologists for the presence of CMBs; the prevalence of findings of two or more CMBs was compared between INPH group and control group. After investigation, INPH patients underwent shunt surgery.Two or more CMB were detected more frequently in the INPH group compared to HeCo (n = 6, 43 % vs. n = 4, 10 %; p = 0.01). Among the participants where MRI revealed CMB, the number of CMB was higher among the INPH patients than the HeCo (median 8; IQR 2-34 vs. median 1; IQR 1-2; p = 0.005).This study supports a vascular component to the pathophysiology of INPH.
| S-EPMC4748449 | biostudies-other
Project description:Idiopathic normal pressure hydrocephalus (iNPH) is a highly prevalent condition in the elderly population; however, the underlying pathophysiology in relation to the aging process remains unclear. To investigate the effect of removal of cerebrospinal fluid by lumbar "tap test" on the cerebral circulation in patients with iNPH, 14 patients with "probable" iNPH were studied using a novel blood tracking technique based on blood oxygenation level-dependent (BOLD) magnetic resonance signal intensity. By tracking the propagation of the low-frequency component of the BOLD signal, extended venous drainage times were observed in the periventricular region of the patients, which was reversed by tap test. Interestingly, the venous drainage time in the periventricular region exhibited an age-related prolongation in the healthy control group. Additional regression analyses involving 81 control subjects revealed a dissociation of deep and superficial venous systems with increasing age, presumably reflecting focal inefficiency in the deep system. Our results not only provide insights into the etiology of iNPH, but also point to a potential non-invasive biomarker for screening iNPH.
| S-EPMC5703706 | biostudies-literature
Project description:Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer's disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (n = 69) and the other with Alzheimer's disease (n = 178). In the second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer's disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real-life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity.
| S-EPMC9897186 | biostudies-literature
Project description:BackgroundGait analysis objectively quantifies gait impairment in idiopathic normal pressure hydrocephalus (iNPH), may improve diagnosis and evaluation for surgical candidacy.ObjectivesThis meta-analysis aims to understand which objective gait parameters improve after tap-test (TT) and CSF shunt surgery (CSS), also comparing responders (R) with non-responders (NR) and to assess if gait restores within the range of healthy controls after procedures.MethodsStudies enrolling iNPH with at least one instrumented gait measure were selected. Three time points of gait assessment were defined: PRE, POST-TT, and POST-CSS. Gait velocity, cadence, step length, stride length, and double limb support time were evaluated. Patients were categorized based on responsiveness to CSF diversion procedures.ResultsSeventeen studies including 527 patients were selected. iNPH improved significantly in almost all gait parameters POST-TT, and to a greater extent POST-CSS. Gait parameters consistently discriminated iNPH from healthy controls. Despite the aforementioned improvements, iNPH's gait did not completely normalize after CSF diversion procedures. Meta-regression analysis also revealed that TT's effect on gait velocity plateaus after 24-48 hr and returns to baseline in 90-100 hr.ConclusionsGait analysis is a reliable quantitative instrument to assess gait impairment in iNPH, demarking a net differentiation from healthy controls, according to the notion that the iNPH CSF dynamic alteration also leads to an irreversible damage. Specific gait parameters improve among TT-R, providing an opportunity to select patients that will respond to CSS. Future studies validating a standardized reporting method including criteria of responsiveness, specific gait parameters, and timeframe of assessment are needed.
| S-EPMC10654838 | biostudies-literature