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.

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.

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.

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.

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.

Longitudinal Metabolite Profiling of Cerebrospinal Fluid in Normal Pressure Hydrocephalus Links Brain Metabolism with Exercise-Induced VEGF Production and Clinical Outcome.

Idiopathic normal pressure hydrocephalus is a neurological disease caused by abnormal cerebrospinal fluid flow and presents with symptoms such as dementia. Current therapy involves the removal of excess cerebrospinal fluid by shunting. Not all patients respond to this therapy and biomarkers are needed that could facilitate the characterization of patients likely to benefit from this treatment. Here, we measure brain metabolism in normal pressure hydrocephalus patients by performing a novel longitudinal metabolomic profiling study of cerebrospinal fluid. We find that the levels of brain metabolites correlate with clinical parameters, the amount of vascular endothelial growth factor in the cerebrospinal fluid, and environmental stimuli such as exercise. Metabolomic analysis of normal pressure hydrocephalus patients provides insight into changes in brain metabolism that accompany cerebrospinal fluid disorders and may facilitate the development of new biomarkers for this condition.

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.

Preoperative and postoperative 1H-MR spectroscopy changes in frontal deep white matter and the thalamus in idiopathic normal pressure hydrocephalus.

BACKGROUND: In a previous study we found significantly decreased N-acetyl aspartate (NAA) and total N-acetyl (tNA) groups in the thalamus of patients with idiopathic normal pressure hydrocephalus (iNPH) compared with healthy individuals (HI). No significant difference between the groups could be found in the frontal deep white matter (FDWM). OBJECTIVE: The primary aim of this study was to investigate if these metabolites in the thalamus were normalised after shunt surgery. The secondary aim was to investigate postoperative metabolic changes in FDWM. SUBJECTS AND METHODS: Fourteen patients with iNPH, mean age 74 years, and 15 HI, also mean age 74 years, were examined. Assessment of a motor score (MOSs) was performed before and after shunt surgery. Absolute quantitative (1)H-MR spectroscopy (1.5 T, volumes of interest 2.5-3 ml) was performed on the patients in the FDWM and in the thalamus, before and 3 months after shunt surgery, and also once on the HI. The following metabolites were analysed: tNA, NAA, total creatine, total choline (tCho), myo-inositol (mIns), glutamate and lactate concentrations. MRI volumetric calculations of the lateral ventricles were also performed. RESULTS: At 3 months postoperatively, we found no significant changes of tNA or NAA in the thalamus. In contrast, in the FDWM, there was a significant increase of tCho (p=0.01) and a borderline significant decrease of mIns (p=0.06). 12/14 patients were shunt responders (motor function). Median reduction of the lateral ventricle was 16%. A weak correlation between MOS and ventricular reduction was seen. CONCLUSIONS: Normalisation of thalamic tNA and NAA could not be detected postoperatively. The increased tCho and decreased mIns in the FDWM postoperatively might relate to clinical improvement.

Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.

BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical biopsy. METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain. RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-ß levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003). CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-ß in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-ß pathology, both in patients with possible NPH and among the wider population.

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.

α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system.

The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (Q(aSyn)) to the albumin quotient (Q(albumin)) to evaluate its relation to blood-CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, ß-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that Q(aSyn) did not rise or fall with Q(albumin) values, a relative measure of blood-CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and ß-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.

Reduced thalamic N-acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled 1H-magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification.

INTRODUCTION: Patients with idiopathic normal pressure hydrocephalus (INPH) frequently have a reduction in cerebral blood flow in the subcortical frontal lobe/basal ganglia/thalamic areas. With magnetic resonance spectroscopy, the metabolism in the brain can be examined. The aim of this study was to investigate if there was a compromised metabolism in the thalamus and in the subcortical frontal areas in INPH patients. This was done by measuring total creatine, myo-inositol, total choline, N-acetylaspartate (NAA), total N-acetylaspartate (tNA), glutamate and lactate levels. A comparison was made with healthy individuals (HI). SUBJECTS AND METHODS: 16 patients (nine males, seven females, mean age 74 years, range 49-83) diagnosed as INPH and 15 HI (nine males, six females, mean age 74 years, range 62-89) were examined. (1)H magnetic resonance spectroscopy (1.5 T, point-resolved spectroscopy, echo time/relaxation time 30/3000 ms, volume of interest 2.5-3 ml) was performed in frontal deep white matter and in the thalamus. Absolute quantification with internal water as a reference was used. RESULTS: INPH patients had lower NAA (p=0.02) and lower tNA (p=0.05) concentrations in the thalamus compared with HI. NAA and tNA in the frontal deep white matter did not differ between patients and HI. The absolute metabolic concentrations of total creatine, myo-inositol total choline, tNA, lactate and Cr ratios in frontal deep white matter and in the thalamus were similar in INPH patients and HI. CONCLUSION: Reduced thalamic NAA and tNA in INPH patients suggest a compromised metabolic neuronal function in these regions. Thus, the thalamus might have an important role in the pathogenesis of INPH.

Cognitive, biochemical, and imaging profile of patients suffering from idiopathic normal pressure hydrocephalus.

INTRODUCTION: It has still not been clearly established whether the cognitive deficits of idiopathic normal pressure hydrocephalus (iNPH) are caused by a disturbance in cerebrospinal fluid (CSF) dynamics or an underlying metabolic disturbance. OBJECTIVE: To identify the possible associations between biochemical markers, the neuroimaging characteristics, and cognitive deficits of patients undergoing investigations for possible iNPH. METHODS: A CSF sample obtained during a lumbar puncture from 10 patients with iNPH was analyzed for several biochemical markers (lactate, 8-isoprostane, vascular endothelial growth factor [VEGF], neurofilament heavy protein, glial fibrillary acidic protein, amyloid beta 1-42, and total tau). All patients underwent a battery of neuropsychological testing and imaging as part of their selection process for their suitability for CSF diversion surgical procedure. Volumetric analysis of imaging was carried out measuring the ventricular volume (VV), intracranial volume (ICV), periventricular lucencies, deep white matter hyperintensities, and white matter (WM) volume, as well as their ratios. RESULTS: A significant negative correlation of preoperative symptom duration and total tau levels (R = -0.841, P = .002) was found. There was a significant positive correlation (R = 0.648, P = .043) between the levels of VEGF and the VV/ICV ratio. There was a significant positive correlation of the levels of glial fibrillary acidic protein and the VV/deep white matter hyperintensities ratio (R = 0.828, P = .006). A significant negative correlation was observed between the levels of neurofilament heavy protein and the VV/ICV ratio (R = -0.657, P = .039) and the WM volume (R = -0.778, P = .023). Lactate levels were lower for patients performing in the normal range on the Recognition Memory Test for faces. Patients who performed better in the Recognition Memory Test words test had higher ICV volumes. All the patients in this study showed below normal performance when the subcortical function was assessed. CONCLUSION: The positive correlation of VEGF with the severity of ventriculomegaly may indicate that this is because of the transmantle pressure gradient; this response may not be because of hypoxia but represents an attempt at neuroregeneration. The degree of reactive gliosis correlates inversely with the severity of WM lesions. Neuronal degeneration is negatively correlated with the volume of the WM in these patients. The small association of volumetry and the cognitive profile of these patients may be consistent with a direct biochemical disturbance being responsible for the cognitive deficit observed. Ongoing studies with set protocols for neuropsychological assessment and volumetric analysis are warranted to further elucidate on the preliminary results of the current study.

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.

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 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.

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.

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.

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.

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.