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.

Cerebral oxygen extraction fraction declines with ventricular enlargement in patients with normal pressure hydrocephalus.

OBJECTIVE: Normal pressure hydrocephalus (NPH) is a neurodegenerative disease that is potentially reversible by shunt surgery in approximately 60% of patients. Imaging may provide a means to investigate brain tissue viability and oxygen metabolism in NPH patients. METHODS: Oxygen extraction fraction (OEF) mapping was generated from 3D multi-echo gradient echo MRI (mGRE) data using QQ-CCTV algorithm and cerebral blood flow (CBF) using 3D arterial spin labeling (ASL) MRI data, thereby calculating the cerebral metabolic rate of oxygen (CMRO2 = CBF × OEF × [H]a) in 16 NPH patients. Regression analyses using cortical gray matter and deep gray matter regions were conducted with age, gender, CSF stroke volume and normalized ventricular volume as independent variables. RESULTS: OEF showed significant negative correlations with normalized brain ventricular volumes in the whole brain (p = 0.004, q = 0.01), cortical gray matter (p = 0.004, q = 0.01), caudate (p = 0.02, q = 0.04), and pallidum (p = 0.03, q = 0.04), but no significant correlation with CSF stroke volume (q > 0.05). There was no significant finding with CBF or CMRO2. CONCLUSION: In NPH patients, low OEF in several regions was significantly correlated with large ventricular volumes, indicating decreased tissue oxygen metabolism with increased NPH severity. OEF mapping may provide a functional understanding of neurodegeneration in NPH and may improve monitoring of disease course and treatment outcomes.

Increased interstitial fluid in periventricular and deep white matter hyperintensities in patients with suspected idiopathic normal pressure hydrocephalus.

Periventricular white matter changes are common in patients with idiopathic normal pressure hydrocephalus (iNPH) and considered to represent focally elevated interstitial fluid. We compared diffusion measures in periventricular hyperintensities in patients with imaging features of iNPH to patients without. The hypothesis is that periventricular hyperintensities in patients with presumed iNPH show higher water content than in patients without imaging features of iNPH. 21 patients with iNPH Radscale 7-12 ("high probability of iNPH") and 10 patients with iNPH Radscale 2-4 ("low probability of iNPH") were examined with a neurodegeneration imaging protocol including a diffusion microstructure imaging sequence. Periventricular hyperintensities and deep white matter hyperintensities were segmented and diffusion measures were compared. In patients with imaging features of iNPH, the free water content in periventricular hyperintensities was significantly higher compared to the control group (p = 0.005). This effect was also detectable in deep white matter hyperintensities (p = 0.024). Total brain volumes and total gray or white matter volumes did not differ between the groups. Periventricular cap free water fraction was highly discriminative regarding patients with presumed iNPH and controls with an ROC AUC of 0.933. Quantitative diffusion microstructure imaging shows elevated water content in periventricular hyperintensities in patients with imaging features of iNPH, which could be the imaging correlate for pathologic fluid accumulation and may be used as an imaging biomarker in the future.

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Participants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [123I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. RESULTS: We enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery (p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 (p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery (p < 0.01). CONCLUSIONS: This prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH.

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood.

BACKGROUNDMethodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism and for diagnostic workup of CSF disturbances.METHODSThe MRI contrast agent gadobutrol (Gadovist) was used as a CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the CNS and is eliminated along extravascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at the level of the cisterna magna in parallel with obtaining blood samples through 48 hours.RESULTSIn a reference patient cohort (n = 29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n = 4), idiopathic normal pressure hydrocephalus dementia (n = 7), pineal cysts (n = 8), and idiopathic intracranial hypertension (n = 4).CONCLUSIONAssessment of CSF tracer clearance is clinically feasible and may provide a way to predict extravascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hours) was preceded by far peak tracer enhancement at MRI in extracranial lymphatic structures (at about 24 hours), as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.FUNDINGThe work was supported by the Department of Neurosurgery, Oslo University Hospital; the Norwegian Institute for Air Research; and the University of Oslo.

In vivo Characterization of Biochemical Variants of Amyloid-ß in Subjects with Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease Neuropathological Change.

BACKGROUND: Stepwise occurrence of biochemically modified amyloid-ß (Aß) in the brain of subjects with Alzheimer's disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aß is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aß are indeed also suffering from AD. OBJECTIVE: We assessed the occurrence of biochemically modified Aß variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia. METHODS: We assessed Aß proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry. RESULTS: The pyroglutamylated Aß (pyAß) precedes the aggregation of phosphorylated Aß (pAß) during the AD neuropathological change progression; moreover, these modified variants of Aß correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aß aggregation that might be of significance for neurodegeneration leading to cognitive impairment. CONCLUSION: The observation that both pyAß and pAß are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aß in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aß is observed in the biopsy, the biochemical characterization is of interest.

Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH), the most common type of adult-onset hydrocephalus, is a potentially reversible neuropsychiatric entity characterized by dilated ventricles, cognitive deficit, gait apraxia, and urinary incontinence. Despite its relatively typical imaging features and clinical symptoms, the pathogenesis and pathophysiology of iNPH remain unclear. In this review, we summarize current pathogenetic conceptions of iNPH and its pathophysiological features that lead to neurological deficits. The common consensus is that ventriculomegaly resulting from cerebrospinal fluid (CSF) dynamics could initiate a vicious cycle of neurological damages in iNPH. Pathophysiological factors including hypoperfusion, glymphatic impairment, disturbance of metabolism, astrogliosis, neuroinflammation, and blood-brain barrier disruption jointly cause white matter and gray matter lesions, and eventually lead to various iNPH symptoms. Also, we review the current treatment options and discuss the prospective treatment strategies for iNPH. CSF diversion with ventriculoperitoneal or lumboperitonealshunts remains as the standard therapy, while its complications prompt attempts to refine shunt insertion and develop new therapeutic procedures. Recent progress on advanced biomaterials and improved understanding of pathogenesis offers new avenues to treat iNPH.

Cortical metabolic changes and clinical outcome in normal pressure hydrocephalus after ventriculoperitoneal shunt: Our preliminary results. / Cambios metabólicos corticales y resultado clínico en la hidrocefalia normotensiva después de la derivación ventrículo-peritoneal: nuestros resultados preliminares.

INTRODUCTION: Our objective was to evaluate the cortical metabolic changes and clinical outcome in patients affected by idiopathic normal pressure hydrocephalus (iNPH) after a placement of ventriculoperitoneal (VP) shunt. MATERIALS AND METHODS: 10 patients affected by suspected iNPH underwent a CSF hydrodynamics evaluation based on a lumbar infusion test (LIT). The main selection criterion for surgery was based on intracranial elasticity (IE)>0.30. All subjects with an IE>0.30 underwent a PET scan with 18 fluorodeoxiglucose (18F-FDG) at baseline (PET1) and 1 month after surgery (PET2). Furthermore, the same patients were submitted to clinical evaluation before and 1 month after surgery through neuropsychological tests and gait analysis. RESULTS: An overall number of 20 18F-FDG PET scans were performed in all the enrolled patients. As compared to PET1, PET2 showed an increase in glucose consumption in the left frontal and left parietal lobe in PET2 as compared to PET1 (P<.001). All the enrolled patients presented a significant increase in neuropsychological scores (i.e Frontal Assessment Battery and Montreal Cognitive Assessment) and have clinically improved at gait analysis. A significant correlation was found between the increase of cortical glucose consumption in the left parietal area and the cognitive improvement as detectable by neuropsychological assessment. CONCLUSIONS: Improvement in 18F FDG PET glucose metabolism could be considered a useful imaging marker for the assessment of iNPH response to VP shunting.

Detailed visual assessment of striatal dopaminergic depletion in patients with idiopathic normal pressure hydrocephalus: unremarkable or not?

BACKGROUND: Dopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated. METHODS: In this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis. RESULTS: Striatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved. CONCLUSION: Striatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders.

Glymphatic System Impairment in Alzheimer's Disease and Idiopathic Normal Pressure Hydrocephalus.

Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer's disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-ß (Aß) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia-lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics.

Cholinergic transmission is impaired in patients with idiopathic normal-pressure hydrocephalus: a TMS study.

The pathophysiological mechanisms of cognitive and gait disturbances in subjects with normal-pressure hydrocephalus (NPH) are still unclear. Cholinergic and other neurotransmitter abnormalities have been reported in animal models of NPH. The objective of this study was to evaluate the short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain, in subjects with idiopathic NPH (iNPH). We applied SAI technique in twenty iNPH patients before ventricular shunt surgery. Besides SAI, also the resting motor threshold and the short intracortical inhibition to paired stimulation were assessed. A significant reduction of the SAI (p = 0.016), associated with a less pronounced decrease of the resting motor threshold and the short latency intracortical inhibition to paired stimulation, were observed in patients with iNPH at baseline evaluation. We also found significant (p < 0.001) correlations between SAI values and the gait function tests, as well as between SAI and the neuropsychological tests. These findings suggest that the impairment of cholinergic neurons markedly contributes to cognitive decline and gait impairment in subjects with iNPH.

[11C]PIB PET Is Associated with the Brain Biopsy Amyloid-ß Load in Subjects Examined for Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-ß (Aß) pathology. OBJECTIVE: To compare the [11C]PIB PET uptake in the patients with suspected iNPH to Aß and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aß, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD). METHODS: Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aß and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [11C]PIB PET. Aß, total tau, and Pτ181 were measured by ELISA from the ventricular (n = 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1). RESULTS: [11C]PIB uptake in the right frontal cortex (ρ= 0.60, p < 0.01) and the combined neocortical [11C]PIB uptake score (ρ= 0.61, p < 0.01) were associated with a higher Aß load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11C]PIB uptake was also associated with the ventricular CSF Aß (ρ= -0.58, p = 0.03). CONCLUSIONS: The findings show that [11C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aß pathology in the patients with iNPH might also warrant treatment with current AD drugs.

Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of dementia that may be successfully treated with cerebrospinal fluid (CSF) diversion. Recently, magnetic resonance imaging (MRI) using a MRI contrast agent as a CSF tracer revealed impaired clearance of the CSF tracer from various brain regions such as the entorhinal cortex of iNPH patients. Hampered clearance of waste solutes, for example, soluble amyloid-ß, may underlie neurodegeneration and dementia in iNPH. The goal of the present study was to explore whether iNPH is associated with altered subcellular distribution of aquaporin-4 (AQP4) water channels, which is reported to facilitate CSF circulation and paravascular glymphatic drainage of metabolites from the brain parenchyma. Cortical brain biopsies of 30 iNPH patients and 12 reference individuals were subjected to AQP4 immunogold cytochemistry. Electron microscopy revealed significantly reduced density of AQP4 water channels in astrocytic endfoot membranes along cortical microvessels in patients with iNPH versus reference subjects. There was a significant positive correlation between density of AQP4 toward endothelial cells (perivascular) and toward parenchyma, but the reduced density of AQP4 toward parenchyma was not significant in iNPH. We conclude that perivascular AQP4 expression is attenuated in iNPH, potentially contributing to impaired glymphatic circulation, and waste clearance, and subsequent neurodegeneration. Hence, restoring normal perivascular AQP4 distribution may emerge as a novel treatment strategy for iNPH.

Dopaminergic imaging separates normal pressure hydrocephalus from its mimics.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) and iNPH mimics (i.e., Parkinson's disease, progressive supranuclear palsy or dementia with Lewy bodies) share similar clinical features, and discrimination between both conditions relies on invasive time-consuming investigations. This study aims to compare [123I]FP-CIT SPECT imaging-visual rating and semiquantitative values-between iNPH and iNPH mimics. METHODS: Among 56 patients with a suspicion of iNPH (76.5 ± 6.1 years; 23.2% women), 26 fulfilled the iNPH diagnostic criteria and the remaining 30 were classified as iNPH mimics. Patients were visually categorized as having normal or abnormal [123I]FP-CIT SPECT; and for the quantification of the [123I]FP-CIT SPECT imaging, we calculated striatal binding ratios (SBR) using BRASS™ automated brain analysis while applying locally established reference limits (adjusted for age). Logistic regressions were used to assess the association between [123I]FP-CIT SPECT and diagnostic groups. RESULTS: A normal SBR [123I]FP-CIT SPECT was present in 69.2% of iNPH and 37.9% of mimics (p value = .020), while visual rating did not differ between the two groups. Normal SBR [123I]FP-CIT SPECT values were associated with the diagnosis of iNPH, even after adjusting for white matter changes and comorbidities (adjusted odds ratio: 4.17; 95% CI 1.26-13.80). CONCLUSION: Semi-quantitative [123I]FP-CIT SPECT evaluation, but not visual assessment, discriminates iNPH patients from their mimics. [123I]FP-CIT SPECT represents an interesting neuroimaging biomarker to improve the selection of patients with iNPH for invasive shunt surgery.

Rapid increase of 'brain-type' transferrin in cerebrospinal fluid after shunt surgery for idiopathic normal pressure hydrocephalus: a prognosis marker for cognitive recovery.

Idiopathic normal pressure hydrocephalus (iNPH) is a dementia-inducing disorder. Primary cause of iNPH is speculated to be a reduction of cerebrospinal fluid (CSF) absorption, which secondarily induces hydrocephalus, compression of brain, and reduction of CSF production. Patients are treated by surgically inserting a shunt to deliver excess CSF to the abdominal cavity. The prognosis for cognitive improvement after shunt surgery has been difficult to predict. We therefore investigated various CSF proteins, hoping to find a biomarker predictive of cognitive performance one to two years after shunt surgery. CSF proteins of 34 iNPH and 15 non-iNPH patients were analysed by Western blotting, revealing two glycan isoforms of transferrin (Tf); 'brain-type' Tf with N-acetylglucosaminylated glycans and 'serum-type' Tf with α2, 6-sialylated glycans. Brain-type Tf levels decreased in iNPH but rapidly returned to normal levels within 1-3 months after shunt surgery. This change was positively correlated with recovery from dementia, per Mini-Mental State Examination and Frontal Assessment Battery scores at 11.8 ± 7.7 months post-operation, suggesting that brain-type Tf is a prognostic marker for recovery from dementia after shunt surgery for iNPH. Histochemical staining with anti-Tf antibody and an N-acetylglucosamine-binding lectin suggests that brain-type Tf is secreted from choroid plexus, CSF-producing tissue.

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.

Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus.

AIMS: Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). METHODS: The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. RESULTS: iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. CONCLUSIONS: Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH.

PTPRQ as a potential biomarker for idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is caused by the accumulation of cerebrospinal fluid (CSF) and is characterized by gait disturbance, urinary incontinence, and dementia. iNPH dementia is treatable by shunt operation; however, since the cognitive symptoms of iNPH are often similar to those of other dementias, including Alzheimer's disease (AD), accurate diagnosis of iNPH is difficult. To overcome this problem, the identification of novel diagnostic markers to distinguish iNPH and AD is warranted. Using comparative proteomic analysis of CSF from patients with iNPH and AD, protein tyrosine phosphatase receptor type Q (PTPRQ) was identified as a candidate biomarker protein for discriminating iNPH from AD. ELISA analysis indicated that the PTPRQ concentration in the CSF was significantly higher in patients with iNPH compared with those with AD. In addition, the PTPRQ concentration in the CSF of non­responders to shunt operation (SNRs) tended to be relatively lower compared with that in the responders. PTPRQ may be a useful biomarker for discriminating between patients with iNPH and AD, and may be a potential companion biomarker to identify SNRs among patients with iNPH. Additional large­scale analysis may aid in understanding the novel aspects of iNPH.

mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease.

A major obstacle to presymptomatic diagnosis and disease-modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid-ß oligomers (AßOs) and tau, the precursors of plaques and tangles. We now report that CCR results from AßO-induced activation of the protein kinase complex, mTORC1, at the plasma membrane and mTORC1-dependent tau phosphorylation, and that CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. AßOs were also shown previously to reduce neuronal insulin signaling. Our data therefore indicate that the decreased insulin signaling provoked by AßOs unleashes their toxic potential to cause neuronal CCR, and by extension, neuron death.

Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer's Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus: A New/Old Potential Target.

As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies.