Search

OBJECTIVE The objective of this study was to describe the demographic characteristics of patients with idiopathic normal pressure hydrocephalus (iNPH) through an analysis of 3000 consecutive, surgically treated Swedish patients and a systematic review of the literature. METHODS Data on age, sex, comorbidities, diagnostic delay, initial symptoms, and severity of symptoms at diagnosis were extracted from the Swedish Hydrocephalus Quality Registry. In addition, a systematic PRISMA-based review of the literature published from database inception until August 2019 was performed using the PubMed, Cochrane, and Scopus databases on the basis of two concepts: normal pressure hydrocephalus and demography and their association with related terms. Of 1020 unique articles, 16 were eligible for study inclusion and were assessed for quality using the Newcastle-Ottawa Scale. Mean and weighted mean values were calculated. RESULTS The mean patient age at the time of surgery was 74.4 years, 79% of patients were in their 70s, and 60% of the patients were men. Almost 50% of the patients had symptoms from four main domains (i.e., balance, gait, cognition, and urinary dysfunction) at disease onset. Patients aged < 60 years (2%) reported more headaches and fewer balance problems than those aged ≥ 60. Women were more impaired in function than men at the time of diagnosis. Dementia (Mini-Mental State Examination score < 25) was found in 47% of the patients. Men had more diabetes, heart disease, hypertension, and stroke than women, and comorbidity correlated with increased impairment. The incidence of surgery for iNPH was 20%–40% of the disease incidence according to survey and operation-based studies. CONCLUSIONS Most iNPH patients undergo surgery in their 70s. Those aged < 60 years show slightly different symptomatology and probably present with a specific disease entity, indicating that the lower age limit for iNPH should be 60 years. iNPH patients have severe impairment preceded by a long diagnostic delay. Even though the included study designs differed, the systematic review showed that the disorder has a very low treatment incidence. The importance of diagnosing and treating iNPH is further emphasized by the fact that iNPH may account for a considerable part of all cases of dementia.

Background and purpose To examine the effect of delayed compared to early planning of shunt surgery on survival, in patients with idiopathic normal pressure hydrocephalus (iNPH), a long‐term follow‐up case–control study of patients exposed to a severe delay of treatment was performed. Methods In 2010–2011 our university hospital was affected by an administrative and economic failure that led to postponement of several elective neurosurgical procedures. This resulted in an unintentional delay of planning of treatment for a group of iNPH patients, referred to as iNPHDelayed (n = 33, waiting time for shunt surgery 6–24 months). These were compared to patients treated within 3 months, iNPHEarly (n = 69). Primary outcome was mortality. Dates and underlying causes of death were provided by the Cause of Death Registry. Survival was analysed by Kaplan–Meier plots and a Cox proportional hazard model adjusted for potential confounders. Results Median follow‐up time was 6.0 years. Crude 4‐year mortality was 39.4% in iNPHDelayed compared to 10.1% in iNPHEarly (p = 0.001). The adjusted hazard ratio in iNPHDelayed was 2.57; 95% confidence interval 1.13–5.83, p = 0.024. Causes of death were equally distributed between the groups except for death due to malignancy which was not seen in iNPHDelayed but in 4/16 cases in iNPHEarly (p = 0.044). Conclusions The present data indicate that shunt surgery is effective in iNPH and that early treatment increases survival., Patients with idiopathic normal pressure hydrocephalus exposed to 6–24 months delayed planning of shunt surgery had a more than twofold increased mortality compared to patients operated without delay.

BACKGROUND AND PURPOSE: Ventricular enlargement in idiopathic normal pressure hydrocephalus is often estimated using the Evans index. However, the sensitivity of the Evans index to estimate changes in ventricular size postoperatively has been questioned. Here, we evaluated the postoperative change in ventricle size in relation to shunt response in patients with idiopathic normal pressure hydrocephalus, by comparing ventricular volume and the Evans index. MATERIALS AND METHODS: Fifty-seven patients with idiopathic normal pressure hydrocephalus underwent high-resolution MR imaging preoperatively and 6 months after shunt insertion. Clinical symptoms of gait, balance, cognition, and continence were assessed according to the idiopathic normal pressure hydrocephalus scale. The ventricular volume of the lateral and third ventricles and the Evans index were measured using ITK-SNAP software. Semiautomatic volumetric analysis was performed, and postoperative changes in ventricular volume and the Evans index and their relationships to postoperative clinical improvement were compared. RESULTS: The median postoperative ventricular volume decrease was 25 mL (P < .001). The proportional decrease in ventricular volume was greater than that in the Evans index (P < .001). The postoperative decrease in ventricular volume was associated with a postoperative increase in the idiopathic normal pressure hydrocephalus scale score (P = .004). Shunt responders (75%) demonstrated a greater ventricular volume decrease than nonresponders (P = .002). CONCLUSIONS: Clinical improvement after shunt surgery in idiopathic normal pressure hydrocephalus is associated with a reduction of ventricular size. Ventricular volume is a more sensitive estimate than the Evans index and, therefore, constitutes a more precise method to evaluate change in ventricle size after shunt treatment in idiopathic normal pressure hydrocephalus.

IntroductionMost patients with idiopathic normal pressure hydrocephalus (iNPH) improve gait after surgery. However, knowledge on physical capacity and activity after shunt surgery is limited. One of the aims of this study was to evaluate the effect of shunt surgery in patients with iNPH on short-distance walking, functional exercise capacity, functional strength, and variables of activity and sleep, 3 and 6 months postoperatively. Another aim was to evaluate the effect of a physical exercise program. Additionally, we studied how changes in short-distance walking were correlated with functional exercise capacity and voluntary walking.MethodsIn total, 127 patients were consecutively included and randomized to the exercise group (n = 62) or the control group (n = 65). Participants in the exercise group underwent the supervision of a 12-week exercise program. All patients were assessed before surgery, at 3 and 6 months postoperatively with the 10-m walk test (10MWT), the 6-min walk test (6MWT), 30-s chair stand test (30sCST), and with the actigraphic recordings of activity variables measured for a total of 24 h/day for at least 3 days.ResultsAll patients improved at 3 months postoperatively in the 10MWT (p < 0.001), 6MWT (p < 0.001), and 30sCST (p < 0.001). These results were maintained after 6 months. Actigraphic recordings for voluntary walking (steps per minute) were improved and nighttime sleep (%) increased after 6 months (p = 0.01, p = 0.04). There were no significant differences between the exercise group and the control group, except for the postoperative change in the proportion of daytime sleep after 3 months, which was slightly more reduced compared to baseline in the exercise group (p = 0.04). Changes after 3 months in the 10MWT and 6MWT were moderately correlated (ρ= −0.49, p = 0.01) whereas the correlation between the 10MWT and voluntary walking was weak (ρ = −0.34, p = 0.01).ConclusionShunt surgery improved short-distance walking, functional exercise capacity, functional strength, and voluntary walking. An exercise program did not affect these outcomes. Short-distance walking was weakly correlated with voluntary walking, indicating improved physical capacity does not directly translate to increased physical activity. Further research should address how interventions should be tailored to promote physical activity after shunt surgery.Trial Registrationclinicaltrials.gov, Id: NCT02659111.

In this study, we examine similarities and differences between 52 patients with idiopathic normal pressure hydrocephalus (iNPH) and 17 patients with subcortical small vessel disease (SSVD), in comparison to 28 healthy controls (HCs) by a panel of cerebrospinal fluid (CSF) biomarkers.We analyzed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ isoforms -38, -40, and -42, neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), matrix metalloproteinases (MMP -1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinase 1 (TIMP1). Radiological signs of white matter damage were scored using the age-related white matter changes (ARWMC) scale.All amyloid fragments were reduced in iNPH and SSVD (The results indicate that patients with iNPH and SSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response. The reduction in all APP-derived proteins characterizing iNPH patients is also present, indicating that SSVD encompasses similar pathophysiological phenomena as iNPH.

Background Brevican, neurocan, tenascin-C and tenascin-R are extracellular matrix proteins present in brain that show increased expression in experimental animal models of brain injury. However, little is known about the dynamics of these proteins in human body fluids, such as cerebrospinal fluid (CSF) and serum, after traumatic brain injury (TBI). The aims of this study were to investigate if matrix proteins in CSF and serum are associated with functional outcome following traumatic brain injury, if their concentrations change over time and to compare their levels between brain injured patients to controls. Methods In total, 42 traumatic brain injury patients, nine healthy controls and a contrast group consisting of 38 idiopathic normal pressure hydrocephalus patients were included. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the concentrations of proteins. Results Increased concentrations of brevican, tenascin-C and tenascin-R in CSF correlated with unfavourable outcome, with stronger outcome prediction ability compared to other biomarkers of brain tissue injury. CSF brevican, tenascin-R and serum neurocan gradually decreased with time (p = 0.04, p = 0.008, p = 0.005, respectively), while serum tenascin-C (p = 0.01) increased. CSF concentrations of brevican, neurocan and tenascin-R (only in time point 3) after TBI were lower than in the idiopathic normal pressure hydrocephalus group (p Conclusions These findings indicate that levels of extracellular matrix proteins are associated with clinical outcome following TBI and may act as markers for different pathophysiology than currently used protein biomarkers.

Altered levels of two extracellular matrix (ECM) proteoglycans, brevican and neurocan, have been found in brain injury models; however, their proteolytic processing in traumatic brain injury (TBI) remains unexplored. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a possible contributor to ECM remodelling following TBI. The aims of this study were to evaluate proteolytic brevican/neurocan patterns and ADAMTS-like activity in cerebrospinal fluid (CSF) in the context of TBI.Forty-two acute TBI patients and 37 idiopathic normal pressure hydrocephalus (iNPH) patients were included in the analysis of tryptic brevican and neurocan peptides in CSF using parallel reaction monitoring mass spectrometry. Twenty-nine TBI and 36 iNPH patients were analysed for ADAMTS-like activity in CSF using a quenched fluorescent substrate.The majority of CSF concentrations of brevican peptides significantly decreased in TBI patients compared with the iNPH group (p ≤ 0.002), while ADAMTS-like activity increased (p 0.0001). Two C-terminal brevican peptides strongly correlated with unfavourable outcome of TBI patients (rho = 0.85-0.93, p ≤ 0.001).The decreased CSF concentrations of brevican peptides in TBI are associated with their increased degradation by ADAMTS enzymes. Furthermore, the N- and C-terminal parts of brevican are differentially regulated following TBI and may serve as outcome markers.

BACKGROUND AND PURPOSE: Several studies have evaluated the use of MR imaging markers for the prediction of outcome after shunt surgery in idiopathic normal pressure hydrocephalus with conflicting results. Our aim was to investigate the predictive value of a number of earlier proposed morphologic MR imaging markers in a large group of patients with idiopathic normal pressure hydrocephalus. MATERIALS AND METHODS: One hundred sixty-eight patients (mean age, 70 ± 9.3 years) with idiopathic normal pressure hydrocephalus, subjected to standardized quantification of clinical symptoms before and after shunt surgery, were included in the study. Outcome was calculated using a composite score. Preoperative T1, FLAIR, and flow-sensitive images were analyzed regarding the presence of 13 different morphologic MR imaging markers. RESULTS: The median Evans index was 0.41 (interquartile range, 0.37–0.44). All patients had an aqueductal flow void sign present and white matter hyperintensities. The median callosal angle was 68.8° (interquartile range, 57.7°–80.8°). Dilated Sylvian fissures were found in 69%; focally dilated sulci, in 25%; and widening of the interhemispheric fissure, in 55%. Obliteration of the sulci at the convexity was found in 36%, and 36% of patients were characterized as having disproportionately enlarged subarachnoid space hydrocephalus. Sixty-eight percent of patients improved after surgery. None of the investigated MR imaging markers were significant predictors of improvement after shunt surgery. CONCLUSIONS: Disproportionately enlarged subarachnoid space hydrocephalus, a small callosal angle, and the other MR imaging markers evaluated in this study should not be used to exclude patients from shunt surgery. These markers, though they may be indicative of idiopathic normal pressure hydrocephalus, do not seem to be a part of the mechanisms connected to the reversibility of the syndrome.

Idiopathic Normal Pressure Hydrocephlaus (iNPH) is, despite a vastly improved knowledge of the disorder since its first description still underdiagnosed and undertreated. Because of this, there is a need for further large studies describing the typical symptomatology and reversibility of symptoms in iNPH, which was the aim of this study.In all, 429 patients (mean age 71 years) were included. Detailed pre- and postoperative examinations of symptoms and signs were analyzed. A composite outcome measure was constructed.Sixty-eight % improved after surgery. Preoperatively, 72% exhibited symptoms from three or four of the assessed domains (gait, balance, neuropsychology and continence) while 41% had symptoms from all four domains. Ninety % had gait disturbances, of which 75% had broad-based gait, 65% shuffling gait and 30% freezing of gait. These disturbances coexisted in most patients preoperatively, but were more likely to appear as isolated findings after surgery. Impaired balance was seen in 53% and retropulsion in 46%. MMSE25 was seen in 53% and impaired continence in 86%. Improvements were seen in all symptom domains postoperatively.The iNPH phenotype is characterized by a disturbance in at least 3/4 symptom domains in most patients, with improvements in all domains after shunt surgery. Most patients present with a broad-based and shuffling gait as well as paratonia. Present symptoms in all domains and a shuffling gait at the time of diagnosis seem to predict a favorable postoperative outcome, whereas symptom severity does not.

Objective To explore relationships between clinical improvement and relative cerebral blood flow (rCBF) changes after shunt-insertion in idiopathic normal pressure hydrocephalus (iNPH) as measured by dynamic susceptibility contrast magnetic resonance imaging. Methods In 20 idiopathic normal pressure hydrocephalus patients rCBF was measured preoperatively and 3 months postoperatively. Because of shunt-induced right-sided artefacts, evaluation was restricted to 12 left-sided cortical, subcortical, and periventricular regions of interest. Correlations between rCBF and clinical symptoms were analyzed in shunt responders. Results In responders, the postoperative regions of interest-based rCBF increase of 2% to 9% was significant in the parenchyma, the hippocampus, and the anterior periventricular white matter. Perfusion improvement in the cingulus, caudate head, and thalamus correlated with decreased disturbance in one or more of the domains neuropsychology, gait, balance, and total performance. Conclusions Apparently, dynamic susceptibility contrast magnetic resonance imaging can measure postoperative perfusion changes in responders. Postoperatively, perfusion increase in some grey matter structures seems to determine the degree of clinical improvement.

Neuropathologically, Alzheimer's disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-β (Aβ42) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of Aβ42, increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively.To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in CSF volumes, CSF production rate, and intracranial pressure in healthy individuals.CSF concentrations of Aβ42, P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years).Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, Aβ38, and Aβ40), and ventricular CSF volume, but apart from this finding, no significant correlations were observed.These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field.

Purpose To demonstrate in idiopathic normal pressure hydrocephalus (iNPH) patients by dynamic susceptibility contrast MRI a reduced preoperative cerebral blood flow (CBF) which correlates with the severity of clinical symptoms and predicts shunt outcome. Materials and Methods In cortical, subcortical, periventricular regions and along peri-and paraventricular profiles absolute perfusion values were estimated by multi-slice DSC MRI in 21 iNPH patients and 16 age-matched healthy individuals (HI). Relative CBF (rCBF), calculated with the occipital cortex as internal reference, was used for comparison between groups and for correlation analysis between regional rCBF and symptoms or outcome. Results iNPH patients showed significantly decreased rCBF in the basal medial frontal cortex, hippocampus, lentiform nucleus, periventricular white matter (PVWM), central grey matter and the global parenchyma as compared to HI. iNPH patients with higher preoperative rCBF in the PVWM performed better in clinical tests. A lower overall preoperative function resulted in a more obvious recovery after shunt insertion. Shunt-responders had higher rCBF values in the basal medial frontal cortex than non-responders. Conclusion DSC MRI perfusion is a potentially useful diagnostic tool in iNPH and perfusion based criteria might be possible predictors of shunt response. J. Magn. Reson. Imaging 2014;39:1533–1542. © 2013 Wiley Periodicals, Inc.

Introduction Amyloid 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). Aims To compare the distribution of APOE genotype in iNPH patients with an age-matched population-based control group and with Alzheimer’s disease (AD) patients. Methods APOE 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. Results The 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). Conclusion The results suggest that the APOE-related risk of AD in patients with iNPH is not higher than in the general population.

Object Patients with idiopathic normal pressure hydrocephalus (iNPH) often present with impaired gait and cognition together with ventricular enlargement and normal intracranial pressure. Many have vascular risk factors as well as periventricular and deep white matter changes on MR imaging. Abnormal CSF dynamics, that is, high resistance to outflow or improvement after CSF drainage, indicate good effects of shunt surgery. The authors examined whether the worst-case iNPH patients with extensive vascular white matter disease and normal CSF dynamics would benefit from shunt surgery. These patients also fulfilled the criteria for Binswanger disease. Therefore, a randomized controlled double-blind study was performed. Methods Fourteen consecutive patients fulfilling the above criteria were randomized to receive either open or closed shunts. At 3 months after surgery, the patients with initially ligated shunts had their shunts opened. Clinical evaluation consisting of 7 quantitative psychometric and 6 continuous gait tests was performed preoperatively and 3 and 6 months after surgery. Results Patients randomized to receive open shunts had improved motor (30% increase) and psychometric (23% increase) scores 3 months after shunt placement. There were no significant changes between the 3- and 6-month follow-up in these same patients. Conversely, those with initially ligated shunts were unchanged during the first 3-month period, although they improved in both motor (28%) and cognitive (18%) functions following removal of the ligature. Conclusions Patients with enlarged ventricles, hydrocephalic symptoms, and extensive vascular white matter changes benefit from shunt surgery.

Objectives – To explore diagnostic differences in periventricular white matter (PWM) and deep white matter (DWM) diffusion patterns in patients diagnosed with Binswanger disease (BD) and in patients diagnosed with probable idiopathic normal pressure hydrocephalus (INPH) using diffusion-weighted imaging (DWI). Materials and methods – Apparent diffusion coefficient (ADC) values were calculated in the PWM and DWM in patients with INPH (n = 14) and BD (n = 9) and in controls (n = 10) using an spin echo echo planar imaging single-shot diffusion sequence and region of interest (ROI) analysis. Results – Patients with BD had higher ADC values than patients with INPH in the PWM and DWM in the frontal and occipital regions (P

OBJECTIVE: To prospectively evaluate the effects of shunting on the neuropsychological performance of patients with idiopathic normal pressure hydrocephalus (INPH), to compare their performance with that of healthy individuals, and to estimate the predictive utility of putatively important factors. METHODS: A consecutive series of 47 patients with INPH underwent neurological, radiological, and neuropsychological examinations before and 3 months after shunt surgery. The same neuropsychological tests, measuring simple and target reaction times, dexterity, memory and learning, working memory, and aspects of executive functioning, were also administered to 159 healthy individuals. RESULTS: Performance on all neuropsychological tests, except Simple Reaction Time and Digit Span, significantly improved after surgery, with more severe functional deficits showing greatest improvement. Age, education, duration, vascular comorbidity, sex, and onset symptom all failed to predict the neuropsychological effects of treatment. Despite improvement 3 months after shunt surgery, INPH patients were still outperformed by healthy individuals. CONCLUSION: Most of the wide range of neuropsychological functions that are affected by INPH are markedly improved by shunt treatment, but not completely restored.

Normal pressure hydrocephalus (NPH) is characterized by disturbed cerebrospinal fluid (CSF) dynamics and white matter lesions (WML). Although the morphology of these lesions is described, little is known about the biochemistry. Our aim was to explore the relationship between ventricular CSF markers, periventricular WML and postoperative clinical outcome in patients with NPH. We analysed lumbar and ventricular concentrations of 10 CSF markers, 12 clinical symptoms and signs, magnetic resonance imaging (MRI) periventricular white matter hyperintensities (PVH) and ventricular size before and 3 months after shunt surgery in 35 patients with NPH. Higher ventricular CSF neurofilament protein (NFL), an axonal marker, correlated with more extensive PVH. A larger postoperative reduction in NFL correlated with larger reduction in PVH and a more pronounced overall improvement. Albumin ratio, HMPG, NPY, VIP and GD3 increased postoperatively whereas NFL, tau and HVA decreased. Variations in ventricular size were not associated with CSF concentrations of any marker. We conclude that NPH is characterized by an ongoing periventricular neuronal dysfunction seen on MRI as PVH. Clinical improvement after shunt surgery is associated with CSF changes indicating a restitution of axonal function. Other biochemical effects of shunting may include increased monoaminergic and peptidergic neurotransmission, breakdown of blood brain barrier function, and gliosis.

Objective – To evaluate if impaired wakefulness (IW) in normal pressure hydrocephalus (NPH) is associated with reduced blood flow in regions associated with the brain arousal system. Method – NPH (n = 28) patients were studied before and after surgery. Wakefulness was assessed using a new developed scale. Relative regional cerebral blood flow (rrCBF) was quantified using SPECT and rectangular regions of interest analysis. Results – Sixteen patients presented with IW at baseline and in 14 of these, IW vanished after surgery. Patients presenting with IW had reduced rrCBF in the anterior cingulate cortex compared with those without. After surgery, rrCBF increased significantly in thalamic, frontal and hippocampal grey matter regions. Increased hippocampal rrCBF correlated with increased basal frontal rrCBF (r = 0.64). In patients where IW vanished after surgery, rrCBF increased in the mesencephalon, hippocampus and the frontal association cortex. The postoperative increase in wakefulness correlated with increased rrCBF in frontal (r = 0.74) and parietal (r = 0.65) association cortex areas. Conclusion – IW in NPH is associated with reduced rrCBF in the anterior cingulate cortex. Improved wakefulness following surgery corresponds to rrCBF increments in the frontal association cortex. This study provides support for a functional coupling between frontal, hippocampal, thalamic and mesencephalic rrCBF in NPH at large.

Objective: To analyze the effect of white matter lesions in different brain regions on regional cortical glucose metabolism, regional cortical atrophy, and cognitive function in a sample with a broad range of cerebrovascular disease and cognitive function. Methods: Subjects (n = 78) were recruited for a study of subcortical ischemic vascular disease (SIVD) and Alzheimer disease (AD) contributions to dementia. A new method was developed to define volumes of interest from high-resolution three-dimensional T1-weighted MR images. Volumetric measures of MRI segmented white matter signal hyperintensities (WMH) in five different brain regions were related to regional PET glucose metabolism (rCMRglc) in cerebral cortex, MRI measures of regional cortical atrophy, and neuropsychological assessment of executive and memory function. Results: WMH was significantly higher in the prefrontal region compared to the other brain regions. In all subjects, higher frontal and parietal WMH were associated with reduced frontal rCMRglc, whereas occipitotemporal WMH was only marginally associated with frontal rCMRglc. These associations were stronger and more widely distributed in nondemented subjects where reduced frontal rCMRglc was correlated with WMH for all regions measured. In contrast, there was no relationship between WMH in any brain region and rCMRglc in either parietal or occipitotemporal regions. WMHs in all brain regions were associated with low executive scores in nondemented subjects. Conclusions: The frontal lobes are most severely affected by SIVD. WMHs are more abundant in the frontal region. Regardless of where in the brain these WMHs are located, they are associated with frontal hypometabolism and executive dysfunction.

Objective – To comprehensively describe and compare prospectively (pre/postoperatively) the symptomatology in aqueductal stenosis (AS) vs idiopathic normal pressure hydrocephalus (INPH). Methods – Twenty-seven patients with AS and 39 patients with INPH were consecutively included. Postural functions, gait, wakefulness, cognitive functions, urinary continence and headache were examined before and 3 months after treatment with shunt operation or endoscopic ventriculostomy. Results – The AS patients had better postural functions, walked faster, performed better cognitively and had a higher wakefulness than INPH patients, but these differences were explained by age differences between groups. The frequency of incontinence was similar in the two patients groups. Headache occurred more frequently in AS, but independently of the other symptoms. Most symptoms and signs improved after surgery. Conclusion – Patients with AS had a higher frequency of headaches than INPH patients, but otherwise the symptomology of the two groups was not found to differ after correcting for age differences.

Objectives– To analyse the diagnostic and prognostic value of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) magnetic resonance imaging (MRI) changes and their relation to symptoms and cerebrospinal fluid (CSF) markers of demyelination (sulphatide) and axonal degeneration [neurofilament triplet protein (NFL)] in a large series of patients with normal pressure hydrocephalus (NPH) and Binswanger disease (BD). Materials and methods– PVH and DWMH were determined by a semi-automatic segmentation method on T2-weighted images in 29 patients with NPH and 17 patients with BD. CSF analyses, psychometric testing and quantification of balance, gait and continence were performed in all patients and also postoperatively in NPH patients. Results– No MRI variable could identify NPH or BD patients. Abundant PVH and DWMH preoperatively correlated with improvement in gait, balance and psychometric performance after shunt surgery (P

BACKROUND—Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES—To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS—Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS—Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p

The postural function in 52 patients with normal pressure hydrocephalus (NPH) and in 19 patients with subcortical arteriosclerotic encephalopathy (SAE) was analysed bedside and in 17 of the NPH, 10 of the SAE and 23 healthy individuals (HI) also examined with a force platform. At the bedside examination, no differences in postural functions between NPH and SAE patients were found. The NPH patients improved more in the postural than in motor functions after shunt surgery. The NPH patients had a larger sway area and a higher backward directed velocity of centre of pressure than HI. The direction of the inclination in the sagittal plane was neutral or forward in the NPH and the SAE patients while it was backward in HI. The postural function was better in positions with open eyes in all 3 groups, but significantly less in the NPH patients, indicating a misinterpretation of afferent visual stimuli in the brainstem postural centre.

The present study was designed to replicate previously reported findings of abnormal frontal and/or temporal cerebral blood flow in violent offenders and to control for the influence of major mental disorder (MMD), substance abuse, and current medication. HMPAO-SPECT-CBF and MRI scans from pretrial forensic psychiatric investigations of 21 subjects convicted of impulsive violent crimes were retrospectively re-evaluated. In 16/21 subjects, visual assessment of SPECT scans showed some hypoperfusion in the temporal and/or frontal lobes. MRI showed no corresponding structural damage. Quantified regional cerebral blood flow (rCBF) in defined regions of interest was compared between index cases and 11 healthy control subjects. Index subjects had significant reductions in the right angular gyrus and the right medial temporal gyrus, bilaterally in the hippocampus, and in the left white frontal matter, but they had significantly increased rCBF in the parietal association cortex bilaterally. The aberrations were as frequent and severe among the subjects without MMD, substance abuse, and current medication (n=7) as in the entire group of index subjects.

Objective To evaluate the long-term efficacy of third ventriculostomies for adult patients with hydrocephalus caused by primary aqueductal stenosis. Methods Eighteen of 64 patients who underwent endoscopic third ventriculostomies (ETVs) between June 1991 and July 1995 were treated because of primary aqueductal stenosis. All of these patients accepted follow-up investigations, which were performed 3 months to 5 years after surgery. If hydrocephalic symptoms persisted, the patency of the ventriculostomy was investigated; in cases of open ventriculostomies, the patients were offered shunt surgery. The effects of the shunt surgery were evaluated after 3 months. Results After ETV, nine of the patients exhibited excellent improvements, two exhibited slight improvements, one displayed no change, and six demonstrated temporary improvements. The ventriculostomies were patent in all nine patients who experienced less than excellent results. Subsequent ventriculoperitoneal shunt placement produced improvements for all seven patients who accepted the surgery. Conclusion In our experience, the long-term effectiveness of ETVs for adult patients with noncommunicating hydrocephalus was sufficient in only 50% of the cases. One-third of the patients exhibited temporary improvements, lasting 1 to 12 months (average duration, 5 mo) after the ETVs, and then demonstrated deterioration to even worse clinical conditions, despite patent ventriculostomies. All patients who did not exhibit permanent improvements after the ETVs benefited from shunt surgery. Efforts should be made to establish methods for the selection of patients for ETV or ventriculoperitoneal shunt surgery.

To demonstrate in idiopathic normal pressure hydrocephalus (iNPH) patients by dynamic susceptibility contrast MRI a reduced preoperative cerebral blood flow (CBF) which correlates with the severity of clinical symptoms and predicts shunt outcome.In cortical, subcortical, periventricular regions and along peri-and paraventricular profiles absolute perfusion values were estimated by multi-slice DSC MRI in 21 iNPH patients and 16 age-matched healthy individuals (HI). Relative CBF (rCBF), calculated with the occipital cortex as internal reference, was used for comparison between groups and for correlation analysis between regional rCBF and symptoms or outcome.iNPH patients showed significantly decreased rCBF in the basal medial frontal cortex, hippocampus, lentiform nucleus, periventricular white matter (PVWM), central grey matter and the global parenchyma as compared to HI. iNPH patients with higher preoperative rCBF in the PVWM performed better in clinical tests. A lower overall preoperative function resulted in a more obvious recovery after shunt insertion. Shunt-responders had higher rCBF values in the basal medial frontal cortex than non-responders.DSC MRI perfusion is a potentially useful diagnostic tool in iNPH and perfusion based criteria might be possible predictors of shunt response.

Patients with idiopathic normal pressure hydrocephalus (iNPH) often present with impaired gait and cognition together with ventricular enlargement and normal intracranial pressure. Many have vascular risk factors as well as periventricular and deep white matter changes on MR imaging. Abnormal CSF dynamics, that is, high resistance to outflow or improvement after CSF drainage, indicate good effects of shunt surgery. The authors examined whether the worst-case iNPH patients with extensive vascular white matter disease and normal CSF dynamics would benefit from shunt surgery. These patients also fulfilled the criteria for Binswanger disease. Therefore, a randomized controlled double-blind study was performed.Fourteen consecutive patients fulfilling the above criteria were randomized to receive either open or closed shunts. At 3 months after surgery, the patients with initially ligated shunts had their shunts opened. Clinical evaluation consisting of 7 quantitative psychometric and 6 continuous gait tests was performed preoperatively and 3 and 6 months after surgery.Patients randomized to receive open shunts had improved motor (30% increase) and psychometric (23% increase) scores 3 months after shunt placement. There were no significant changes between the 3- and 6-month follow-up in these same patients. Conversely, those with initially ligated shunts were unchanged during the first 3-month period, although they improved in both motor (28%) and cognitive (18%) functions following removal of the ligature.Patients with enlarged ventricles, hydrocephalic symptoms, and extensive vascular white matter changes benefit from shunt surgery.

To improve the reproducibility of arterial input function (AIF) registration and absolute cerebral blood flow (CBF) quantification in dynamic-susceptibility MRI-perfusion (MRP) at 1.5T, we rescaled the AIF by use of a venous output function (VOF). We compared CBF estimates of 20 healthy, elderly volunteers, obtained by computed tomography (CT)-perfusion (CTP) and MRP on two consecutive days. MRP, calculated without the AIF correction, did not result in any significant correlation with CTP. The rescaled MRP showed fair to moderate correlation with CTP for the central gray matter (GM) and the whole brain. Our results indicate that the method used for correction of partial volume effects (PVEs) improves MRP experiments by reducing AIF-introduced variance at 1.5T. Magn Reson Med, 2009. (Less)

Background The aim of this study was to explore biochemical changes in the cerebrospinal fluid (CSF) induced by shunt surgery and the relationship between these changes and clinical improvement. Methods We measured clinical symptoms and analysed lumbar CSF for protein content, neurodegeneration and neurotransmission markers in patients with secondary (SNPH, n = 17) and idiopathic NPH (INPH, n = 18) before and 3 months after shunt surgery. Patients were divided into groups according to whether or not there was improvement in clinical symptoms after surgery. Results Preoperatively, the only pathological findings were elevated neurofilament protein (NFL), significantly more so in the SNPH patients than in the INPH patients, and elevated albumin content. Higher levels of NFL correlated with worse gait, balance, wakefulness and neuropsychological performance. Preoperatively, no differences were seen in any of the CSF biomarkers between patients that improved after surgery and those that did not improve. Postoperatively, a greater improvement in gait and balance performance correlated with a more pronounced reduction in NFL. Levels of albumin, albumin ratio, neuropeptide Y, vasoactive intestinal peptide and ganglioside GD3 increased significantly after shunting in both groups. In addition, Gamma amino butyric acid increased significantly in SNPH and tau in INPH. Conclusion We conclude that a number of biochemical changes occur after shunt surgery, but there are no marked differences between the SNPH and INPH patients. The results indicate that NFL may be a marker that can predict a surgically reversible state in NPH.

Normal pressure hydrocephalus (NPH) is the most frequent form of chronic hydrocephalus in adults. NPH remains underdiagnosed although between 5% and 10% of all demented patients may suffer from this disorder. As dementia is an increasing demographic problem, treatable forms such as in NPH have become a central issue in neurology. Despite the traditional perception of hydrocephalus being a disorder of disturbed CSF dynamics, in NPH metabolic impairment seems at least as important. So far, the only valid animal model of NPH is chronic adult kaolin hydrocephalus. In this model, opening of alternative CSF outflow pathways leads to normal or near-normal intracranial pressure and CSF outflow resistance. Yet, various metabolic disturbances cause ongoing ventricular enlargement and characteristic symptoms including cognitive decline and gait ataxia. Delayed hippocampal neuronal death, accumulation of beta-amyloid and disturbed cholinergic neurotransmission may contribute to memory dysfunction. Compromised periventricular blood flow, decreased dopamine levels in the substantia nigra and damaged striatal GABAergic interneurons may reflect basal ganglia symptoms. At least in human hydrocephalus cerebrovascular co-morbidity of the white matter plays an important role as well. It seems that in hydrocephalus from a certain 'point of no return' metabolic impairment becomes decoupled from CSF dynamics and, at least partly, self-sustained. This is probably the reason why despite restored CSF circulation by shunting many patients with chronic hydrocephalus still suffer from severe neurological deficits. The present paper offers a comprehensive review of the experimental and clinical data suggesting metabolic disturbances in chronic hydrocephalus.

Objective To compare the neuropsychological performance of patients with idiopathic normal pressure hydrocephalus (INPH) with that of healthy individuals and to examine its relation to neurological signs, vascular comorbidity, and background factors. Methods A consecutive series of 58 patients with INPH underwent neurological, neuroradiological, and neuropsychological examinations. The neuropsychological tests, measuring vigilance, fine movements of the hands, learning, working memory, and aspects of executive functioning, were also administered to 108 healthy individuals. Results Patients performed worse than healthy individuals on all included tests. Significant correlations between test results were more frequent and stronger among patients and the degree of neuropsychological impairment was related to the severity of other signs of INPH. Patients with vascular risk factors performed worse than those without. Conclusion The neuropsychological deficits in INPH are widely distributed, interrelated, associated with neurological signs, and aggravated by vascular comorbidity.

We investigated if tau, microtubular binding protein, in serum and ventricular CSF (vCSF) in patients with severe traumatic brain injury (TBI) during the initial posttraumatic days correlated to 1-year outcome.Patients with severe TBI (n = 39, Glasgow Coma Scale scoreor=8) were included. We measured serum and vCSF total tau on days 0 to 14, using ELISA. vCSF total tau correlated to 1-year Extended Glasgow Outcome Scale (GOSE), the NIH Stroke Scale (NIHSS) neurologic status, and the Bartel Daily Living Index. Patients (n = 20) with normal pressure hydrocephalus (NPH) served as reference.Higher levels of tau were found in TBI patients vs patients with NPH. A correlation was found between initial vCSF total tau and GOSE levels (R = 0.42, p0.001) but not between vCSF total tau and NIHSS or Bartel scores at 1 year. A vCSF total tau level of2,126 pg/mL on days 2 to 3 discriminated between dead and alive (sensitivity of 100% and a specificity of 81%). A vCSF total tau level of702 pg/mL on days 2 to 3 discriminated between bad (GOSE 1 to 4) and good (GOSE 5 to 8) outcome (sensitivity of 83% and a specificity of 69%). Patients with GOSE 1 (dead) had higher vCSF total tau levels on days 2 to 3 (p0.001) vs both surviving patients (GOSE 2 to 8) and those with NPH. Total tau was not detected in serum throughout the study.The increase in ventricular CSF (vCSF) total tau probably reflects axonal damage, known to be a central pathologic mechanism in traumatic brain injury (TBI). These results suggest that vCSF total tau may be an important early biochemical neuromarker for predicting long-term outcome in patients with a severe TBI.

To compare levels of biochemical markers in ventricular cerebrospinal fluid (vCSF) between patients with aqueductal stenosis (AS) and idiopathic normal pressure hydrocephalus (INPH) and relate these results to clinical outcome after surgery. Neurofilament light protein, tau protein, sulfatide, vasoactive intestinal peptide (VIP), neuropeptide PYY (NPY) and CSF/serum albumin ratio were measured in vCSF from 18 consecutive AS and 19 consecutive INPH patients. Clinical outcome was evaluated after surgery by standardized indices. The levels of markers were related to clinical outcome. No differences in any of the markers were found between AS and INPH patients. The concentration of sulfatide and albumin ratio correlated inversely with psychometric improvement, whilst VIP and NPY correlated inversely with improvement in alertness. The similar levels of biochemical markers in vCSF from AS and INPH patients indicate similarities in pathophysiology and turnover rate of vCSF despite differences in CSF dynamics. High albumin ratio and sulfatide concentrations in vCSF in hydrocephalus patients have negative implications for surgical outcome and might indicate concomitant cerebrovascular disorder.

Numerous anatomical and brain imaging studies find substantial differences in brain structure between men and women across the span of human aging. The ability to extend the results of many of these studies to the general population is limited, however, due to the generally small sample size and restrictive health criteria of these studies. Moreover, little attention has been paid to the possible impact of brain infarction on age-related differences in regional brain volumes. Given the current lack of normative data on gender and aging related differences in regional brain morphology, particularly with regard to the impact of brain infarctions, we chose to quantify brain MRIs from more than 2200 male and female participants of the Framingham Heart Study who ranged in age from 34 to 97 years. We believe that MRI analysis of the Framingham Heart Study more closely represents the general population enabling more accurate estimates of regional brain changes that occur as the consequence of normal aging. As predicted, men had significantly larger brain volumes than women, but these differences were generally not significant after correcting for gender related differences in head size. Age explained approximately 50% of total cerebral brain volume differences, but age-related differences were generally small prior to age 50, declining substantially thereafter. Frontal lobe volumes showed the greatest decline with age (approximately 12%), whereas smaller differences were found for the temporal lobes (approximately 9%). Age-related differences in occipital and parietal lobe were modest. Age-related gender differences were generally small, except for the frontal lobe where men had significantly smaller lobar brain volumes throughout the age range studied. The prevalence of MRI infarction was common after age 50, increased linearly with age and was associated with significantly larger white matter hyperintensity (WMH) volumes beyond that associated with age-related differences in these measures. Amongst men, the presence of MRI infarction was associated with significant age-related reductions in total brain volume. Finally, statistically significant associations were found between the volume of MRI infarcts in cubic centimeters and all brain measures with the exception of parietal lobe volume for individuals where the volume of MRI infarctions was measured. These data serve to define age and gender differences in brain morphology for the Framingham Heart Study. To the degree participants of the Framingham Heart Study are representative the general population, these data can serve as norms for comparison with morphological brain changes associated with aging and disease. In this regard, these cross-sectional quantitative estimates suggest that age-related tissue loss differs quantitatively and qualitatively across brain regions with only minor differences between men and women. In addition, MRI evidence of cerebrovascular disease is common to the aging process and associated with smaller regional brain volumes for a given age, particularly for men. We believe quantitative MRI studies of the Framingham community enables exploration of numerous issues ranging from understanding normal neurobiology of brain aging to assessing the impact of various health factors, particularly those related to cerebrovascular disease, that appear important to maintaining brain health for the general population.

It has been shown previously that iNPH patients do exhibit suppressed levels of amyloid-β (Aβ) and the precursors soluble amyloid precursor protein α-, and β- (sAPPα, sAPPβ) in combination with depressed levels of tau proteins, both phosphorylated and total (t-tau, p-tau) and elevated levels of Neurofilament light protein (NFL). Expanding on this knowledge, we wanted to study if the changes seen in the amyloid processing pathways could be expanded to other fragments in the amyloid metabolism pathway.

Studies support a higher proportion of vascular risk factors in iNPH patients than in the general population. Less favorable outcome for patients with, than without, cerebrovascular comorbidity and vascular risk factors has been described, though in smaller studies. We investigate whether this can be confirmed in a large national Quality Registry based study.

The cost-utility analysis of shunt surgery was based on a decision-analytic Markov model adapted to Swedish circumstances. The effectiveness measure was qualityadjusted life years (QALYs) gained per patient. Costs were derived from the European iNPH Multicenter Study and data on costs of dementia disorders in Sweden reported by the National Board of Health and Welfare. Data from thirty-seven patients with iNPH (median age 70 years, range 50-89 years) evaluated before and six months after surgery with the EQ-5D (EuroQol Group-5 Dimension health survey) was used to calculate quality adjusted life years (QALYs). Figures of prevalence, natural course of iNPH and transition probabilities were obtained from the literature. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to investigate the robustness of the model. Results

Objectives: Subcortical vascular dementia (SVD) is associated with white matter lesions and demyelination. The aim of the present study was to examine the cerebrospinal fluid (CSF) levels of TNF-α, a proinflammatory cytokine mediating myelin damage, in SVD patients. The intrathecal TNF-α levels were related to the clinical symptoms of dementia, as well as to intrathecal levels of sulfatide, a marker of white matter degradation, and of neurofilament, a marker of neuronal degeneration. Methods: CSF levels of TNF-a, sulfatide and neurofilament were all analyzed by immunoenzymatic procedures in 17 patients with SVD and in 26 healthy controls. Results: The intrathecal concentration of TNF-α was significantly increased in SVD patients compared to healthy controls (p = 0.0001). The intrathecal levels of TNF-α were significantly correlated (r = 0.6, p = 0.02) to the levels of sulfatide, but not to the levels of neurofilament, (r = 0.08, NS). Conclusions: We have demonstrated intrathecal production of TNF-α in SVD patients. The correlation between TNF-a and sulfatide levels in the CSF suggests that this apoptosis-inducing cytokine leads to the death of oligodendrocytes, thereby contributing to white matter degeneration, a hallmark of SVD.

Several brain-imaging studies have found associations between aberrant functioning in the frontal and temporal lobes and violent offending. We have previously reported decreased frontotemporal perfusion unrelated to psychosis, substance abuse, or current medication in 21 violent offenders. In the present study, we compared the regional cerebral blood flow (rCBF) in a new group of 32 violent offenders to scores on the Psychopathy Checklist-Revised (PCL-R), which rates two aspects of psychopathy: disturbed interpersonal attitudes (Factor 1) and impulsive antisocial behavior (Factor 2). A recently proposed model has split Factor 1 into a new Factor 1 (deceitful interpersonal style), a new Factor 2 (affective unresponsiveness), and a Factor 3, which approximately corresponds to the old Factor 2. The rCBF was assessed by single-photon emission computed tomography (SPECT) with technetium-99m-d,l-hexamethylpropyleneamine oxime (HMPAO) in regions of interest (ROIs) placed in accordance with fusioned magnetic resonance images (MRI) and SPECT scans. Significant negative correlations were found between interpersonal features of psychopathy (the old and especially the new Factor 1) and the frontal and temporal perfusion. The two most clearly associated ROIs were the head of the caudate nuclei and the hippocampi. These findings in a group of violent offenders living under the same conditions, which reduced the number of state-related confounders, add to the evidence indicating that aberrant frontotemporal activity may be a factor in violent behavior.

OBJECTIVES—To examine the CSF concentrations of molecules reflecting demyelination, neuronal and axonal degeneration, gliosis, monoaminergic neuronal function, and aminergic and peptidergic neurotransmission in a large series of patients with normal pressure hydrocephalus (NPH) or subcortical arteriosclerotic encephalopathy (SAE), to elucidate pathogenic, diagnostic, and prognostic features. METHODS—CSF concentrations of glycosphingolipid (sulfatide), proteins (neurofilament triplet protein (NFL), glial fibrillary acidic protein (GFAP)), neuropeptides (vasoactive intestinal peptide (VIP), 4-aminobutyric acid (GABA)), and monoamines (homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenylglycol (HMPG)) were analysed in 43 patients with NPH and 19 patients with SAE. The diagnoses of NPH and SAE were based on strict criteria and patients with NPH were subsequently operated on. Twelve clinical variables, psychometric tests measuring perceptual speed, accuracy, learning, and memory and a psychiatric evaluation were performed in all patients and before and after a shunt operation in patients with NPH. RESULTS—The CSF sulfatide concentration was markedly increased in patients with SAE (mean 766, range 300-3800 nmol/l) compared with patients with NPH (mean 206, range 50-400 nmol/l) (p

We examined CSF levels of markers of neuronal degeneration and astrogliosis-the light subunit of the neurofilament triplet protein (NFL) and the glial fibrillary acidic protein (GFAP)-in 65 patients with normal pressure hydrocephalus (NPH). NFL was increased sixfold (864 +/- 1,538 [mean +/- SD] versus 156 +/- 81 ng/L; por = 0.001) and GFAP twofold (1,116 +/- 1,085 versus 637 +/- 295 ng/L; por = 0.01) in NPH patients compared with neurologically healthy age-matched controls. No correlation was found between any particular symptom or sign and GFAP levels in CSF. The levels of NFL, on the other hand, were higher in patients with severe symptoms compared with those with moderate or no symptoms. Furthermore, there was a correlation between a high level of NFL and gait disturbance, incontinence, psychometric incapability, and social dysfunction. A high preoperative NFL level was associated with favorable outcome after shunt surgery. This indicates that NFL is a marker of ongoing and possibly still-reversible axonal damage in NPH.