The Compartmentalization of Amyloid-ß in Idiopathic Normal Pressure Hydrocephalus Brain Biopsies.

Background: Amyloid-ß (Aß) is one of the hallmark lesions of Alzheimer's disease (AD). During the disease process, Aß undergoes biochemical changes, producing toxic Aß variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different Aß variants in their brain biopsies, obtained during shunting. Objective: To study the cellular compartmentalization of different Aß variants in brain biopsies from iNPH subjects. Methods: We studied the cellular localization of different proteoforms of Aß using antibodies towards different amino acid sequences or post-translational modifications of Aß, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated- (N3pE), phosphorylated-(1E4E11) Aß and Aß protein precursor (AßPP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM). Results: In LM all Aß variants were detected. In LMst and EM, the Aß 4G8, 6F/3D, and the pyroglutamylated Aß were detected. The AßPP was visualized by all methods. The Aß labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the AßPP was seen both intra- and extracellularly. Conclusions: The Aß markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of Aß in the human brain. No intracellular Aß pathology was seen. AßPP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles.

Cystoventricular Drainage of Intracranial Arachnoid Cysts in Adults.

BACKGROUND: Intracranial arachnoid cysts (ACs) are generally benign fluid-filled cysts with a prevalence of 0.5%-2.7%. They can be treated through craniotomy with cyst removal, endoscopic fenestration, or cystoperitoneal or ventriculoperitoneal shunting. However, the outcome of these treatments has not been completely satisfactory. Cystoventricular shunting was described as an alternative method for the treatment of intracranial ACs in children in 2003. In the present report, we have described the outcomes of cystoventricular shunting in adults with symptomatic intracranial ACs. METHODS: A total of 24 patients with symptomatic ACs underwent cystoventricular drainage from 2012 to 2019. The most common symptom preoperatively was headache, followed by dysphasia, motor weakness, memory loss, seizures, and balance disturbances. After radiological evaluation, a ventricular catheter was placed in the AC and another in one of the lateral ventricles and connected extracranially after subgaleal tunneling using a straight metal connector. RESULTS: At 3-6 months of postoperative follow-up, 21% of patients were asymptomatic and 42% showed improvement in clinical symptoms. No patient had experienced impairment or progression of symptoms postoperatively. Three patients had required revision of the catheters and one patient had developed a postoperative superficial skin infection without signs of deeper infection. CONCLUSIONS: Cystoventricular drainage seems to be an effective, reliable, and safe procedure to treat intracranial ACs when fenestration to the basal cisterns is not possible.

Increase in callosal angle and decrease in ventricular volume after shunt surgery in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE Postoperative decrease in ventricle size is usually not detectable either by visual assessment or by measuring the Evans index in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of the present study was to investigate whether the angle between the lateral ventricles (the callosal angle [CA]) increases and ventricular volume decreases after shunt surgery in patients with iNPH. METHODS Magnetic resonance imaging of the brain was performed before and 3 months after shunt surgery in 18 patients with iNPH. The CA and Evans index were measured on T1-weighted 3D MR images, and ventricular volume contralateral to the shunt valve was measured with quantitative MRI. RESULTS The CA was larger postoperatively (mean 78°, 95% CI 69°-87°) than preoperatively (mean 67°, 95% CI 60°-73°; p < 0.001). The volume of the lateral ventricle contralateral to the shunt valve decreased from 73 ml (95% CI 66-80 ml) preoperatively to 63 ml (95% CI 54-72 ml) postoperatively (p < 0.001). The Evans index was 0.365 (95% CI 0.35-0.38) preoperatively and 0.358 (95% CI 0.34-0.38) postoperatively (p < 0.05). Postoperative change of CA showed a negative correlation with change of ventricular volume (r = -0.76, p < 0.01). CONCLUSIONS In this sample of patients with iNPH, the CA increased and ventricular volume decreased after shunt surgery. The relative difference was most pronounced for the CA, indicating that this accessible, noninvasive radiological marker should be evaluated further as an indirect method to determine shunt function in patients with iNPH.

Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus.

We had an opportunity to assess the change observed in the brain regarding Alzheimer's disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-ß (Aß, Aß40, Aß42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aß42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aß42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

Brain tissue Aß42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus.

OBJECTIVE: The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aß) reflect the propensity of cortical Aß aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment. METHODS: Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aß40, Aß42, and neurotoxic Aß oligomers/protofibrils, associated with Aß aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aß species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale. RESULTS: The brain tissue levels of Aß42 were negatively correlated with CSF Aß42 (Spearman's r = -0.53, p < 0.05). The Aß40, Aß42, and Aß oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aß aggregates (p < 0.05). The preoperative CSF Aß42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aß aggregates and high brain tissue Aß42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05). CONCLUSIONS: Brain tissue measurements of soluble Aß species are feasible. Since high Aß42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aß species may be associated with the clinical response to shunt treatment.

Correlations between mini-mental state examination score, cerebrospinal fluid biomarkers, and pathology observed in brain biopsies of patients with normal-pressure hydrocephalus.

Alzheimer disease (AD)-related pathology was assessed in cortical biopsy samples of 111 patients with idiopathic normal-pressure hydrocephalus. Alzheimer disease hallmark lesions-ß-amyloid (Aß) and hyperphosphorylated tau (HPtau)-were observed in 47% of subjects, a percentage consistent with that for whole-brain assessment reported postmortem in unselected cohorts. Higher-immunostained area fraction of AD pathology corresponded with lower preoperative mini-mental state examination scores. Concomitant Aß and HPtau pathology, reminiscent of that observed in patients with AD, was observed in 22% of study subjects. There was a significant correlation between Aß-immunostained area fraction in tissue and Aß42 (42-amino-acid form of Aß) in cerebrospinal fluid (CSF). Levels of Aß42 were significantly lower in CSF in subjects with concomitant Aß and HPtau pathology compared with subjects lacking pathology. Moreover, a significant correlation between HPtau-immunostained area fraction and HPtau in CSF was noted. Both HPtau and total tau were significantly higher in CSF in subjects with concomitant Aß and HPtau pathology compared with subjects lacking pathology. The 42-amino-acid form of Aß (Aß42) and HPtau in CSF were the most significant predictors of the presence of AD pathology in cortical biopsies. Long-term follow-up studies are warranted to assess whether all patients with idiopathic normal-pressure hydrocephalus with AD pathology progress to AD and to determine the pathologic substrate of idiopathic normal-pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus: cerebral perfusion measured with pCASL before and repeatedly after CSF removal.

Pseudo-continuous arterial spin labeling (pCASL) measurements were performed in 20 patients with idiopathic normal pressure hydrocephalus (iNPH) to investigate whether cerebral blood flow (CBF) increases during the first 24 hours after a cerebrospinal fluid tap test (CSF TT). Five pCASL magnetic resonance imaging (MRI) scans were performed. Two scans were performed before removal of 40 mL CSF, and the other three at 30 minutes, 4 hours, and 24 hours, respectively after the CSF TT. Thirteen different regions of interest (ROIs) were manually drawn on coregistered MR images. In patients with increased CBF in lateral and frontal white matter after the CSF TT, gait function improved more than it did in patients with decreased CBF in these regions. However, in the whole sample, there was no significant increase in CBF after CSF removal compared with baseline investigations. The repeatability of CBF measurements at baseline was high, with intraclass correlation coefficients of 0.60 to 0.90 for different ROIs, but the median regional variability was in the range of 5% to 17%. Our results indicate that CBF in white matter close to the lateral ventricles plays a role in the reversibility of symptoms after CSF removal in patients with iNPH.

The callosal angle measured on MRI as a predictor of outcome in idiopathic normal-pressure hydrocephalus.

OBJECT: Different neuroimaging biomarkers have been studied to find a tool for prediction of response to CSF shunting in idiopathic normal-pressure hydrocephalus (iNPH). The callosal angle (CA) has been described as useful in discriminating iNPH from ventricular dilation secondary to atrophy. However, the usefulness of the CA as a prognostic tool for the selection of shunt candidates among patients with iNPH is unclear. The aim of this study was to compare the CA in shunt responders with that in nonresponders and clarify whether the CA can serve as a predictor of the outcome. METHODS: Preoperative MRI brain scans were evaluated in 109 patients who had undergone shunt surgery for iNPH during 2006-2010. Multiplanar reconstruction was performed interactively to obtain a coronal image through the posterior commissure, perpendicular to the anterior-posterior commissure plane. The CA was measured as the angle between the lateral ventricles on the coronal image. The patients were examined clinically before surgery and at 12 months postoperatively. RESULTS: Shunt responders had a significantly smaller mean preoperative CA compared with nonresponders: 59° (95% CI 56°-63°) versus 68° (95% CI 61°-75°) (p < 0.05). A CA cutoff value of 63° showed the best prognostic accuracy. CONCLUSIONS: The preoperative CA is smaller in patients whose condition improves after shunt surgery and may be a useful tool in the selection of shunt candidates among patients with iNPH.

Patients with spontaneous subarachnoid haemorrhage - presentation of a 10-year hospital series.

In this study we present the population-based patient material with spontaneous SAH, treated in our Neurosurgical unit during the 10 years (1997-2006) after the introduction of endovascular treatment of aneurysms (EVT) in our hospital. All patients that had a spontaneous SAH and a potential to survive were admitted. The present study comprises 1471 patients. 72 % had one or more aneurysms. AVM or other vascular pathological findings where found in 2%. Angiography was judged as normal in 21% and was not performed in 5%. 664 of the patients with aneurysms were treated by endovascular means, 333 were operated and 31 were treated with both methods. Thirty-five received no treatment. The main difference in admission parameters between the coiled and clipped aneurysms was the location of the aneurysm, with posterior circulation aneurysm exclusively being coiled and MCA aneurysms mainly clipped. The highest 6-month mortality for aneurysms presented in the untreated group (71.4%), and the lowest (3.2%) in the group treated with both clip and coil. Six-month mortality was 3.5% for the patients with a normal angiography. Of these, no one with Fisher grade 1 and 2/120 patients with Fisher 2 died. The mortality was high (89%) for those patients where angiography was not performed. The present patient group was compared to an earlier published a 12-year patient series from our clinic. The patients with aneurysmal SAH in the present series were older and had a lower 6-month mortality in our material compared to the published data from our clinic from 1981-1992. More patients were admitted in a good clinical condition in the present series, but there was also a higher proportion of patients from the worst clinical groups. The percentage of aneurysms treated had increased from 80% to 97% after EVT was introduced.