RESUMO
BACKGROUND AND PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) pathogenesis is multifactorial. Systemic inflammation might have a role in gathering clinical-pathological trajectories. We aimed to shape the peripheral immune profile of iNPH and establish correlations with cerebrospinal fluid (CSF) markers, ventricular enlargement, and clinical outcomes. METHODS: We conducted a single-center retrospective-longitudinal study, including 38 iNPH patients and 38 controls. Baseline iNPH Grading Scale and modified Rankin Scale (mRS) scores were collected with peripheral blood cell count, CSF amyloid-ß42 (Aß42), total tau (t-tau), phosphorylated-181-tau, and Evans index. Depending on 5-year outcome, iNPH patients were grouped into "poor outcome" (PO; mRS ≥ 5) and "favorable outcome" (FO; mRS < 5). Biomarkers were compared and correlated with each other. Receiver operating characteristic analysis was performed. RESULTS: iNPH patients compared to controls had higher neutrophil-to-lymphocyte ratio (NLR; 2.43 ± 1.04 vs. 1.61 ± 0.47, p < 0.001), higher neutrophils (4.22 ± 0.86 1000/mL vs. 3.48 ± 1.34, p = 0.033), and lower lymphocytes (1.45 ± 0.55 1000/mL vs. 2.07 ± 0.86, p = 0.038), with the expected CSF biomarkers signature. In the patients' cohort, NLR was associated directly with t-tau and inversely with Aß42. NLR directly correlated with Evans index. PO patients compared to those with FO had higher NLR (3.25 ± 1.40 vs. 2.01 ± 0.77, p = 0.035) and higher t-tau (274.76 ± 114.39 pg/mL vs. 150.28 ± 72.62, p = 0.017), with an area under the curve of 0.786 and 0.793, respectively. CONCLUSIONS: iNPH patients present a proinflammatory state associated with neurodegeneration and predicting poor clinical outcome. Systemic inflammation represents a factor in the clinical-pathological progression of iNPH, and the NLR emerges as a potential prognostic index.
Assuntos
Hidrocefalia de Pressão Normal , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Estudos Retrospectivos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos Longitudinais , Proteínas tau/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , InflamaçãoRESUMO
Idiopathic normal pressure hydrocephalus is a disorder of unknown pathophysiology whose diagnosis is paradoxically made by a positive response to its proposed treatment with cerebrospinal fluid diversion. There are currently no idiopathic normal pressure hydrocephalus disease genes or biomarkers. A systematic analysis of familial idiopathic normal pressure hydrocephalus could aid in clinical diagnosis, prognosis, and treatment stratification, and elucidate disease patho-etiology. In this 2-part analysis, we review literature-based evidence for inheritance of idiopathic normal pressure hydrocephalus in 22 pedigrees, and then present a novel case series of 8 familial idiopathic normal pressure hydrocephalus patients. For the case series, demographics, familial history, pre- and post-operative symptoms, and cortical pathology were collected. All novel familial idiopathic normal pressure hydrocephalus patients exhibited improvement following shunt treatment and absence of neurodegenerative cortical pathology (amyloid-beta and hyperphosphorylated tau), in contrast to many sporadic cases of idiopathic normal pressure hydrocephalus with variable clinical responses. Analysis of the 30 total familial idiopathic normal pressure hydrocephalus cases reported herein is highly suggestive of an autosomal dominant mechanism of inheritance. This largest-ever presentation of multiply affected idiopathic normal pressure hydrocephalus pedigrees provides strong evidence for Mendelian inheritance and autosomal dominant transmission of an idiopathic normal pressure hydrocephalus trait in a subset of patients that positively respond to shunting and lack neurodegenerative pathology. Genomic investigation of these families may identify the first bona fide idiopathic normal pressure hydrocephalus disease gene.
Assuntos
Hidrocefalia de Pressão Normal , Humanos , Hidrocefalia de Pressão Normal/genética , Hidrocefalia de Pressão Normal/cirurgia , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Prognóstico , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidianoRESUMO
AIM OF THE STUDY: Neuronal pentraxin-2 (NPTX2) is a synaptic protein responsible for modulating plasticity at excitatory synapses. While the role of NPTX2 as a novel synaptic biomarker in cognitive disorders has been elucidated recently, its role in idiopathic normal pressure hydrocephalus (iNPH) is not yet understood. CLINICAL RATIONALE FOR STUDY: To determine if NPTX2 predicts cognition in patients with iNPH, and whether it could serve as a predictive marker for shunt outcomes. MATERIAL AND METHODS: 354 iNPH patients underwent cerebrospinal fluid drainage (CSF) as part of the tap test or extended lumbar drainage. Demographic and clinical measures including age, Evans Index (EI), Montreal Cognitive Assessment (MoCA) score, Functional Activities Questionnaire (FAQ) score, and baseline and post-shunt surgery Timed Up and Go (TUG) test scores were ascertained. CSF NPTX2 concentrations were measured using an ELISA. CSF ß-amyloid 1-40 (Aß1-40), ß-amyloid 1-42 (Aß1-42), and phosphorylated tau-181 (pTau-181) were measured by chemiluminescent assays. Spearman's correlation was used to determine the correlation between CSF NPTX2 concentrations and age, EI, MoCA and FAQ, TUG, Aß1-40/Aß1-42 ratio, and pTau-181 concentrations. Logistic regression was used to determine if CSF NPTX2 values were a predictor of short-term improvement post-CSF drainage or long-term improvement post-shunt surgery. RESULTS: There were 225 males and 129 females with a mean age of 77.7 years (± 7.06). Average CSF NPTX2 level in all iNPH patients was 559.97 pg/mL (± 432.87). CSF NPTX2 level in those selected for shunt surgery was 505.61 pg/mL (± 322.38). NPTX2 showed modest correlations with pTau-181 (r = 0.44, p < 0.001) with a trend for Aß42/Aß40 ratio (r = -0.1, p = 0.053). NPTX2 concentrations did not correlate with age (r = -0.012, p = 0.83) or MoCA score (r = 0.001, p = 0.87), but correlated negatively with FAQ (r = -0.15, p = 0.019). CONCLUSIONS: While CSF NPTX2 values correlate with neurodegeneration, they do not correlate with cognitive or functional measures in iNPH. CSF NPTX2 cannot serve as a predictor of either short-term or long-term improvement after CSF drainage. CLINICAL IMPLICATIONS: These results suggest that synaptic degeneration is not a core feature of iNPH pathophysiology.
Assuntos
Proteína C-Reativa , Hidrocefalia de Pressão Normal , Proteínas do Tecido Nervoso , Masculino , Feminino , Humanos , Idoso , Hidrocefalia de Pressão Normal/cirurgia , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , CogniçãoRESUMO
OBJECTIVES: To examine the relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and tap test response to elucidate the effects of comorbidity of AD in idiopathic normal-pressure hydrocephalus (iNPH). DESIGN: Case-control study. SETTING: Osaka University Hospital. PARTICIPANTS: Patients with possible iNPH underwent a CSF tap test. MEASUREMENTS: Concentrations of amyloid beta (Aß) 1-40, 1-42, and total tau in CSF were measured. The response of tap test was judged using Timed Up and Go test (TUG), 10-m reciprocation walking test (10MWT), Mini-Mental State Examination (MMSE), and iNPH grading scale. The ratio of Aß1-42 to Aß1-40 (Aß42/40 ratio) and total tau concentration was compared between tap test-negative (iNPH-nTT) and -positive (iNPH-pTT) patients. RESULTS: We identified 27 patients as iNPH-nTT and 81 as iNPH-pTT. Aß42/40 ratio was significantly lower (mean [SD] = 0.063 [0.026] vs. 0.083 [0.036], p = 0.008), and total tau in CSF was significantly higher (mean [SD] = 385.6 [237.2] vs. 293.6 [165.0], p = 0.028) in iNPH-nTT than in iNPH-pTT. Stepwise logistic regression analysis revealed that low Aß42/40 ratio was significantly associated with the negativity of the tap test. The response of cognition was significantly related to Aß42/40 ratio. The association between Aß42/40 ratio and tap test response, especially in cognition, remained after adjusting for disease duration and severity at baseline. CONCLUSIONS: A low CSF Aß42/40 ratio is associated with a poorer cognitive response, but not gait and urinary response, to a tap test in iNPH. Even if CSF biomarkers suggest AD comorbidity, treatment with iNPH may be effective for gait and urinary dysfunction.
Assuntos
Doença de Alzheimer , Hidrocefalia de Pressão Normal , Humanos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/complicações , Estudos de Casos e Controles , Proteínas tau/líquido cefalorraquidiano , Equilíbrio Postural , Estudos de Tempo e Movimento , Doença de Alzheimer/complicações , Biomarcadores/líquido cefalorraquidiano , CogniçãoRESUMO
BACKGROUND: The etiology of enlarged subarachnoid spaces of infancy is unknown; however, there is radiologic similarity with normal pressure hydrocephalus. Adults with normal pressure hydrocephalus have been shown to have altered cerebrospinal (CSF) flow through the cerebral aqueduct. OBJECTIVE: To explore potential similarity between enlarged subarachnoid spaces of infancy and normal pressure hydrocephalus, we compared MRI-measured CSF flow through the cerebral aqueduct in infants with enlarged subarachnoid spaces of infancy to infants with normal brain MRIs. MATERIALS AND METHODS: This was an IRB approved retrospective study. Clinical brain MRI examinations including axial T2 imaging and phase contrast through the aqueduct were reviewed for infants with enlarged subarachnoid spaces of infancy and for infants with a qualitatively normal brain MRI. The brain and CSF volumes were segmented using a semi-automatic technique (Analyze 12.0) and CSF flow parameters were measured (cvi42, 5.14). All data was assessed for significant differences while controlling for age and sex using analysis of covariance (ANCOVA). RESULTS: Twenty-two patients with enlarged subarachnoid spaces (mean age 9.0 months, 19 males) and 15 patients with normal brain MRI (mean age 18.9 months, 8 females) were included. Volumes of the subarachnoid space (P < 0.001), lateral (P < 0.001), and third ventricles (P < 0.001) were significantly larger in infants with enlarged subarachnoid spaces of infancy. Aqueductal stroke volume significantly increased with age (P = 0.005), regardless of group. CONCLUSION: CSF volumes were significantly larger in infants with enlarged subarachnoid spaces of infancy versus infants with a normal MRI; however, there was no significant difference in CSF flow parameters between the two groups.
Assuntos
Hidrocefalia de Pressão Normal , Hidrocefalia , Masculino , Adulto , Feminino , Humanos , Lactente , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Espaço Subaracnóideo/diagnóstico por imagem , Ventrículos Cerebrais/diagnóstico por imagem , Aqueduto do Mesencéfalo/diagnóstico por imagem , Hidrocefalia/diagnóstico por imagemRESUMO
BACKGROUND: The commonly used cerebrospinal fluid (CSF) drainage system remains the manual drip-chamber drain. The LiquoGuard (Möller Medical GmbH, Germany) is an automated CSF management device with dual functionality, measuring intracranial pressure and automatic pressure- or volume-led CSF drainage. There is limited research for comparison of devices, particularly in the neurosurgical field, where it has potential to reshape care. OBJECTIVE: This study aims to compare manual drip-chamber drain versus LiquoGuard system, by assessing accuracy of drainage, associated morbidity and impact on length of stay. METHOD: Inclusion criteria consisted of suspected normal pressure hydrocephalus (NPH) patients undergoing extended lumbar drainage. Patients were divided into manual drain group versus automated group. RESULTS: Data was analysed from 42 patients: 31 in the manual group versus 11 in the LiquoGuard group. Volumetric over-drainage was seen in 90.3% (n = 28) versus 0% (p < 0.05), and under-drainage in 38.7% (n = 12) versus 0% (p < 0.05), in the manual and automatic group, respectively. Symptoms of over-drainage were noted in 54.8% (n = 17) of the manual group, all of which had episodes of volumetric over-drainage, versus 18.2% (n = 2) in automated group, of which neither had actual over-drainage (p < 0.05). Higher over-drainage symptoms of manual drain is likely due to increased fluctuation of CSF drainage, instead of smooth CSF drainage seen with LiquoGuard system. An increased length of stay was seen in 38.7% (n = 12) versus 9% (n = 1) (p < 0.05) in the manual and LiquoGuard group, respectively. CONCLUSION: The LiquoGuard device is a more superior way of CSF drainage in suspected NPH patients, with reduced morbidity and length of stay.
Assuntos
Hidrocefalia de Pressão Normal , Humanos , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/cirurgia , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Pressão Intracraniana , Vazamento de Líquido Cefalorraquidiano , AlemanhaRESUMO
BACKGROUND: Diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is based on clinical, radiological, and hydrodynamic data of cerebrospinal fluid (CSF) obtained by invasive methods such as lumbar infusion test, which is used to determine the resistance to CSF outflow (Rout). However, Rout has limitations, and its value as predictor of valve response is questioned. Other variables can be obtained by lumbar infusion test, such as the time to reach the plateau (TRP) and the slope until reaching the plateau (SRP). The objectives were to determine if SRP could be a predictor of response to ventriculoperitoneal shunt (VPS) and what variable (Rout versus SRP) would have greater predictive value. METHOD: Patients with probable iNPH who underwent a lumbar infusion test and were indicated for a VPS were retrospectively studied. Two groups were established, responders and non-responders. Rout, TRP (period between the start of infusion until reaching the plateau measured in seconds) and SRP ((plateau pressure-opening pressure)/TRP) were obtained. For Rout and SRP, the receiver operating curves (ROC) with its areas under the curve (AUC) were calculated. RESULTS: One hundred ten patients were included, being 86 responders (78.20%). Shunt responders had a significantly greater Rout (17.02 (14.45-20.23) versus 13.34 (12.10-16.28) mmHg/ml/min, p = 0.002) and SRP (0.049 (0.043-0.054) versus 0.031 (0.026-0.036) mmHg/sec, p < 0.001) and smaller TRP (641.28 (584.83-697.73) versus 777.65 (654.03-901.27) sec, p = 0.028) than non-responders. The AUC for SRP was greater than the AUC for Rout (0.763 (95 % CI 0.655-0.871, p < 0.001) versus 0.673 (95 % CI 0.595-0.801, p = 0.008), respectively), but the differences were not significant (p = 0.180). CONCLUSIONS: SRP could be considered predictor of response to VPS, and its accuracy tends to be better than Rout. So, this variable may be a useful tool to select shunt candidates among patients with probable iNPH.
Assuntos
Hidrocefalia de Pressão Normal , Humanos , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/cirurgia , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Estudos Retrospectivos , Derivações do Líquido Cefalorraquidiano/métodos , Próteses e Implantes , CatéteresRESUMO
OBJECTIVE: The aim of this study was to investigate the diagnostic accuracy of the pulsatility curve to predict shunt response in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Lumbar cerebrospinal fluid dynamics were derived from an automatic lumbar infusion test (LIT) protocol. All patients were treated with ventriculoperitoneal shunting and re-examined 6 months after shunting. Patient demographics and outcomes were gathered in a prospective, electronic database that spanned from January 2012 to January 2020. A validated iNPH scale was used to assess patients preoperatively and 6 months postoperatively. The relationship of the relative pulse pressure coefficient (RPPC), delta amplitude, successful lowering of amplitude, and the pressure-value at a hypothetical amplitude of zero (P0), resistance to outflow (Rout), and outcome, were assessed using receiver operating characteristic (ROC) curves. RESULTS: We included 38 patients. The RPPC, delta amplitude, successful lowering of amplitude, and P0 parameters did not predict shunt response. Mean P0 was 0.5 (IQR 0.4-0.9) in improved patients and 0.4 (IQR 0-1.2) in non-improved patients. The delta amplitude was 0.16 kPa (IQR 0.10-0.23) in improved patients and 0.18 kPa (IQR 0.11-0.24) in non-improved patients. Furthermore, we found a technical failure rate of pulsatility curve measurements of 32%. CONCLUSION: Pulsatility curve results were not suitable in predicting shunt response in our cohort. The diagnostic value of LIT in case of normal pressure hydrocephalus should be subject to more rigorous research.
Assuntos
Hidrocefalia de Pressão Normal , Derivações do Líquido Cefalorraquidiano/métodos , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/cirurgia , Procedimentos Neurocirúrgicos , Estudos Prospectivos , Derivação VentriculoperitonealRESUMO
BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease and dementia subtype involving disturbed cerebrospinal fluid (CSF) homeostasis. Patients with iNPH may improve clinically following CSF diversion through shunt surgery, but it remains a challenge to predict which patients respond to shunting. It has been proposed that CSF and blood biomarkers may be used to predict shunt response in iNPH. OBJECTIVE: To conduct a systematic review and meta-analysis to identify which CSF and venous biomarkers predict shunt-responsive iNPH most accurately. METHODS: Original studies that investigate the use of CSF and venous biomarkers to predict shunt response were searched using the following databases: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR. Included studies were assessed using the ROBINS-I tool, and eligible studies were evaluated utilising univariate meta-analyses. RESULTS: The study included 13 studies; seven addressed lumbar CSF levels of amyloid-ß 1-42, nine studies CSF levels of Total-Tau, six studies CSF levels of Phosphorylated-Tau, and seven studies miscellaneous biomarkers, proteomics, and genotyping. A meta-analysis of six eligible studies conducted for amyloid-ß 1-42, Total-Tau, and Phosphorylated-Tau demonstrated significantly increased lumbar CSF Phosphorylated-Tau (- 0.55 SMD, p = 0.04) and Total-Tau (- 0.50 SMD, p = 0.02) in shunt-non-responsive iNPH, though no differences were seen between shunt responders and non-responders for amyloid-ß 1-42 (- 0.26 SMD, p = 0.55) or the other included biomarkers. CONCLUSION: This meta-analysis found that lumbar CSF levels of Phosphorylated-Tau and Total-Tau are significantly increased in shunt non-responsive iNPH compared to shunt-responsive iNPH. The other biomarkers, including amyloid-ß 1-42, did not significantly differentiate shunt-responsive from shunt-non-responsive iNPH. More studies on the Tau proteins examining sensitivity and specificity at different cut-off levels are needed for a robust analysis of the diagnostic efficiency of the Tau proteins.
Assuntos
Hidrocefalia de Pressão Normal , Doenças Neurodegenerativas , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/cirurgia , Proteínas tau/líquido cefalorraquidianoRESUMO
Idiopathic Normal Pressure Hydrocephalus (iNPH)-the leading cause of reversible dementia in aging-is characterized by ventriculomegaly and gait, cognitive and urinary impairments. Despite its high prevalence estimated at 6% among the elderlies, iNPH remains underdiagnosed and undertreated due to the lack of iNPH-specific diagnostic markers and limited understanding of pathophysiological mechanisms. INPH diagnosis is also complicated by the frequent occurrence of comorbidities, the most common one being Alzheimer's disease (AD). Here we investigate the resting-state functional magnetic resonance imaging dynamics of 26 iNPH patients before and after a CSF tap test, and of 48 normal older adults. Alzheimer's pathology was evaluated by CSF biomarkers. We show that the interactions between the default mode, and the executive-control, salience and attention networks are impaired in iNPH, explain gait and executive disturbances in patients, and are not driven by AD-pathology. In particular, AD molecular biomarkers are associated with functional changes distinct from iNPH functional alterations. Finally, we demonstrate a partial normalization of brain dynamics 24 hr after a CSF tap test, indicating functional plasticity mechanisms. We conclude that functional changes involving the default mode cross-network interactions reflect iNPH pathophysiological mechanisms and track treatment response, possibly contributing to iNPH differential diagnosis and better clinical management.
Assuntos
Conectoma , Rede de Modo Padrão/fisiopatologia , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/fisiopatologia , Rede Nervosa/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Rede de Modo Padrão/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagemRESUMO
OBJECTIVE: The aim was to investigate whether neurodegenerative biomarkers in cerebrospinal fluid (CSF) differentiate patients with suspected normal pressure hydrocephalus (NPH) who respond to CSF drainage from patients who do not respond. METHODS: Data from 62 consecutive patients who presented with magnetic resonance imaging changes indicative of NPH were studied with regard to cognitive and gait functions before and after drainage of 40-50ml of CSF. Additionally, S100 protein, neuron-specific enolase, ß-amyloid protein, tau protein and phospho-tau were determined in CSF. Statistical analyses were carried out with ANOVA and multiple linear regression. RESULTS: Patients with CSF constellations typical for Alzheimer's disease (n = 28) improved significantly in cognitive and gait-related functions after CSF drainage. In contrast, those patients without a CSF constellation typical for Alzheimer's disease (n = 34) did not improve in cognitive and gait-related functions after CSF drainage. In addition, positive CSF biomarkers for Alzheimer's disease predicted these improvements. INTERPRETATION: Our data suggest an association between Alzheimer's disease and NPH changes, supporting the recently suggested dichotomy of a neurodegenerative NPH and a true idiopathic NPH, with the latter appearing to be rare. ANN NEUROL 2020;88:703-711.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/etiologia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Hidrocefalia de Pressão Normal/complicações , Masculino , Punção EspinalRESUMO
BACKGROUND: Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. OBJECTIVES: To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. SEARCH METHODS: We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. SELECTION CRITERIA: We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. DATA COLLECTION AND ANALYSIS: Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. MAIN RESULTS: We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. AUTHORS' CONCLUSIONS: Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.
Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Alcoolismo/complicações , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Viés , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Intervalos de Confiança , Síndrome de Creutzfeldt-Jakob/sangue , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Demência Vascular/sangue , Demência Vascular/líquido cefalorraquidiano , Demência Vascular/diagnóstico , Diagnóstico Diferencial , Demência Frontotemporal/sangue , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/diagnóstico , Humanos , Hidrocefalia de Pressão Normal/sangue , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Funções Verossimilhança , Sensibilidade e EspecificidadeRESUMO
Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disease, causing motor and cognitive dysfunction and dementia. iNPH and Alzheimer's disease (AD) share similar molecular characteristics, including amyloid deposition, t-tau and p-tau dysregulation; however, the disease is under-diagnosed and under-treated. The aim was to identify a panel of sphingolipids and proteins in CSF to diagnose iNPH at onset compared to aged subjects with cognitive integrity (C) and AD patients by adopting multiple reaction monitoring mass spectrometry (MRM-MS) for sphingolipid quantitative assessment and advanced high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomic analysis. The results indicated that iNPH are characterized by an increase in very long chains Cer C22:0, Cer C24:0 and Cer C24:1 and of acute-phase proteins, immunoglobulins and complement component fragments. Proteins involved in synaptic signaling, axogenesis, including BACE1, APP, SEZ6L and SEZ6L2; secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and LCAT) were statistically lower in iNPH. In conclusion, at the disease onset, several factors contribute to maintaining cell homeostasis, and the protective role of very long chains sphingolipids counteract overexpression of amyloidogenic and neurotoxic proteins. Monitoring specific very long chain Cers will improve the early diagnosis and can promote patient follow-up.
Assuntos
Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Proteínas do Tecido Nervoso/líquido cefalorraquidiano , Proteômica , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esfingolipídeos/líquido cefalorraquidianoRESUMO
PURPOSE: The aim of this study was to investigate correlations between clinical symptoms, cerebrospinal fluid flow metrics, hydrocephalus index, small-vessel disease, and white matter (WM) changes in normal pressure hydrocephalus (NPH). METHODS: Aquaductal stroke volumes (ASVs), Z Evans index, Fazekas grading (FG), and diffusion tensor imaging measurements from WM bundles of 37 patients with NPH were retrospectively evaluated. Mann-Whitney U test between clinical symptoms and other variables and Spearman ρ correlations for relationships between variables and Kruskal-Wallis to correlate FG with nonclinical variables were used. RESULTS: Patients with NPH had increased ASV (median 53 µL). No correlation was found between Z Evans index and ASV. Three groups of patients with dementia or ataxia or incontinence had increased ASV values than their counterparts without symptoms (55 vs 48.5 µL, 75 vs 47 µL, 64 vs 49.5 µL, respectively). Patients having 2 common symptoms of dementia and ataxia and patients having all 3 symptoms of dementia, ataxia, and incontinence were compared with ASV values of 63.5 versus 78 µL, respectively. Patients with FG 1 had median ASV values of 45 µL; FG 2, 82.5 µL; and FG 3, 59 µL. Patients with dementia had significantly higher apparent diffusion coefficient (ADC) values of corona radiata (CR) on both sides. There were no significant WM changes in patients with ataxia and incontinence. The Z Evans index was positively correlated with ADC values of CR on both sides and genu of corpus callosum. Fazekas grading was found positively correlated with ADC and negatively correlated with FA values of CR. CONCLUSIONS: Patients with NPH, regardless of stages of the diseases, have increased ASV values and could benefit from shunting. Decreasing ASV values of patients with FG 3 comparing with those with FG 2 support the hypothesis of decreasing compliance of brain with aging and increasing severity of small-vessel disease.
Assuntos
Líquido Cefalorraquidiano/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Idoso de 80 Anos ou mais , Angiografia por Tomografia Computadorizada , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer's disease-related amyloid ß (Aß) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. METHODS: The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson's disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer's disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPß), Aß species (Aß38, Aß40 and Aß42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1). RESULTS: Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aß40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aß40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers. CONCLUSIONS: The combination of the CSF biomarkers T-tau, Aß40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.
Assuntos
Doença de Alzheimer/diagnóstico , Demência Vascular/diagnóstico , Diagnóstico Diferencial , Degeneração Lobar Frontotemporal/diagnóstico , Hidrocefalia de Pressão Normal/diagnóstico , Atrofia de Múltiplos Sistemas/diagnóstico , Doença de Parkinson/diagnóstico , Paralisia Supranuclear Progressiva/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Quimiocina CCL2/líquido cefalorraquidiano , Demência Vascular/líquido cefalorraquidiano , Feminino , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosfoproteínas/líquido cefalorraquidiano , Sensibilidade e Especificidade , Paralisia Supranuclear Progressiva/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
PURPOSE: To identify if specific findings on magnetic resonance imaging (MRI) cerebrospinal fluid (CSF) flow studies can be utilised to identify which patients with idiopathic normal pressure hydrocephalus (iNPH) will have improved gait following a CSF tap test (TT). METHODS: Prospective study of patients undergoing a CSF TT for iNPH. Functional gait was assessed using the timed up and go (TUG) test before and after the CSF TT. MRI CSF flow studies accompanied the CSF TT. The minimum clinically important difference for the TUG (3.63 s) was used as a cutoff value to categorise patients as responders to the CSF TT. RESULTS: Fifty-three patients underwent CSF TT and MRI CSF flow studies. Significant differences were identified between groups for (non-responder vs responder) superior sagittal sinus flow (47.10% vs 40.41%), sagittal sinus stroke volume (274 vs 176.5 µl), sagittal sinus to arterial stroke volume ratio (0.203 vs 0.164), sagittal sinus area (42.2 mm2 vs 36.2 mm2) and circumference (27.7 mm vs 24.95 mm). No differences were present for aqueduct stroke volume, arterial stroke volume or aqueduct net flow. CONCLUSION: A link between gait improvement resulting from CSF drainage and sagittal sinus measurements indicates that the sagittal sinus may play a role in the manifestation of symptoms in iNPH. This may have implications for the diagnosis of iNPH and potentially inform clinical decision making regarding surgical intervention.
Assuntos
Derivações do Líquido Cefalorraquidiano , Transtornos Neurológicos da Marcha/líquido cefalorraquidiano , Transtornos Neurológicos da Marcha/terapia , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/terapia , Imageamento por Ressonância Magnética/métodos , Seio Sagital Superior/diagnóstico por imagem , Idoso , Feminino , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Hidrocefalia de Pressão Normal/fisiopatologia , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate which clinical assessments are suitable for differentiating patients who fall from patients who do not fall in patients with idiopathic normal pressure hydrocephalus (iNPH). DESIGN: Prospective observational study. SETTING: Osaka Medical College Hospital. PARTICIPANTS: Patients with a cerebrospinal fluid tap test (TT) result meeting the diagnosis criteria for iNPH (N=68). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were assessed before the TT based on the following: timed Up and Go (TUG), 10-meter walk test (10MWT), Functional Gait Assessment (FGA), Berg Balance Scale (BBS), isometric quadriceps strength (QS), and a history of falls within the past 6 months. RESULTS: The full area under the curve (AUC) of the receiver operating characteristic curves and 95% confidence interval were found to be 0.651 (95% confidence interval, 0.503-0.775) for the TUG, 0.692 (95% confidence interval, 0.540-0.812) for the 10MWT, 0.869 (95% confidence interval, 0.761-0.933) for the FGA, and 0.796 (95% confidence interval, 0.663-0.886) for the BBS; except for QS, they all were identified as statistically significant predictive variables. In the TUG<20 seconds group (n=47), the FGA (AUC 0.849 [95% confidence interval, 0.698-0.932]) and BBS (AUC 0.734 [95% confidence interval, 0.550-0.862]) were found to be statistically significant predictive variables; however, the other assessments were not. In the TUG<15 seconds group (n=34), the FGA was found to be the only statistically significant predictive variable (AUC 0.842 [95% confidence interval, 0.640-0.942]), whereas the other assessments were not. The AUC of the FGA was statistically significantly greater than those of the other assessments. CONCLUSIONS: Our findings indicate that patients with iNPH who fall experience falls due to dynamic balance dysfunction during gait rather than lower limb muscle strength. The FGA may be more suitable than other assessments for differentiating patients who fall from patients who do not fall in patients with mild iNPH.
Assuntos
Acidentes por Quedas/estatística & dados numéricos , Avaliação da Deficiência , Transtornos Neurológicos da Marcha/fisiopatologia , Hidrocefalia de Pressão Normal/fisiopatologia , Equilíbrio Postural/fisiologia , Idoso , Feminino , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Masculino , Força Muscular/fisiologia , Estudos Prospectivos , Fatores de RiscoRESUMO
OBJECTIVE: To assess the value of phase contrast magnetic resonance imaging cerebrospinal fluid flowmetry in differentiating between normal pressure hydrocephalus and involutional atrophy. METHODS: The descriptive case-control study was conducted at the Al-Yarmouk Teaching Hospital, Baghdad, Iraq, from April to December 2017, and comprised patients with normal pressure hydrocephalus and involutional brain changes. Healthy volunteers were included as controls. Demographic data was recorded and the patients were divided according to age. Conventional magnetic resonance imaging of the brain was performed followed by the assessment of cerebrospinal fluid flow dynamics, was done at the level of the aqueduct of Sylvius. Data was analysed using SPSS 25. RESULTS: Of the 23 subjects with a mean age of 52.3}16.8 years (range: 25-75 years), There were 13(56.5%) males and 10(43.5%) were females. Also, there were 17(74%) patients and 6(26%) controls. Among the patients, 8(47%) had brain atrophic changes based on magnetic resonance imaging, and 9(53%) had normal pressure hydrocephalus signs clinically and scanning criteria. Flowmetry showed mean systolic velocity 1.5}0.3 cm\sec, peak systolic velocity 1.5}0.3 cm\sec and systolic stroke volume 28.5}4.7µLin the control group which was significantly different from the patients (p<0.001). CONCLUSIONS: Phase-contrast magnetic resonance imaging was found to be a useful tool to differentiate between normal pressure hydrocephalus and age-related brain atrophy.
Assuntos
Encéfalo/patologia , Líquido Cefalorraquidiano/diagnóstico por imagem , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Reologia , Adulto , Idoso , Atrofia , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Pressão do Líquido Cefalorraquidiano , Diagnóstico Diferencial , Feminino , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: Alzheimer's disease (AD) pathology is highly prevalent in patients with idiopathic normal pressure hydrocephalus (iNPH), and the presence of AD pathology may involve regional cerebral blood flow (rCBF). In this study, we examined the relationship between rCBF and AD-related biomarkers in the cerebrospinal fluid of iNPH patients. METHODS: Patients with iNPH (n = 39) were classified into groups with (iNPH/AD+) (n=15) and without (iNPH/AD-) (n=24) high biomarker probability of AD (i.e. combined low amyloid ß 42 and high total tau in the cerebrospinal fluid). rCBF was quantified in 17 regions of interest by N-isopropyl-p-[123 I]iodoamphetamine single-photon emission computed tomography with the autoradiography method. We compared rCBF between the iNPH/AD- and iNPH/AD+ groups at baseline using a t-test and then compared changes in rCBF after shunt surgery between the groups using a paired t-test and two-way repeated measures ANOVA. RESULTS: At baseline, there were no significant differences in rCBF between the groups in most regions apart from the putamen. After shunt surgery, a significant increase in rCBF in the putamen, amygdala, hippocampus, and parahippocampal gyrus was observed in iNPH/AD- patients. In iNPH/AD+ patients, no significant improvement in rCBF was observed in any region. In repeated measures analysis of variance, a significant group × shunt interaction was observed in the parietal lobe, frontal lobe, posterior cingulate cortex, precuneus, lateral temporal lobe, amygdala, hippocampus, parahippocampal gyrus, and putamen. CONCLUSIONS: Improvement in rCBF after shunt surgery in iNPH/AD+ patients may be poorer than that in iNPH AD- patients.
Assuntos
Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Circulação Cerebrovascular , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Feminino , Humanos , Hidrocefalia de Pressão Normal/sangue , Hidrocefalia de Pressão Normal/complicações , Hidrocefalia de Pressão Normal/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Proteínas tau/metabolismoRESUMO
Idiopathic normal pressure hydrocephalus (iNPH) is a disabling neurological disorder whose potential treatability is significantly limited by diagnostic uncertainty. In fact, typical clinical presentation occurs at late phases of disease, when CSF shunting could be ineffective. In recent years, measurement of different CSF proteins, whose concentration directly reflects neuropathological changes of CNS, has significantly improved both diagnostic timing and accuracy of neurodegenerative disease. Unfortunately iNPH lacks neuropathological hallmarks allowing the identification of specific disease biomarkers. However, neuropathology of iNPH is so rich and heterogeneous that many processes can be tracked in CSF, including Alzheimer's disease core pathology, subcortical degeneration, neuroinflammation and vascular dysfunction. Indeed, a huge number of CSF biomarkers have been analyzed in iNPH patients, but a unifying profile has not been provided yet. In this brief survey, we thus attempted to summarize the main findings in the field of iNPH CSF biomarkers, aimed at outlining a synthetic model. Although defined cut-off values for biomarkers are not available, a better knowledge of CSF characteristics may definitely assist in diagnosing the disease.