Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus

BACKGROUND: Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ) and α- and β-cleaved soluble forms of amyloid precursor protein (sAPPα and sAPPβ). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery. METHODS: Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month follow-up after surgery using the iNPH scale. Lumbar puncture was performed pre-operatively. CSF samples were analyzed for neurofilament light (NFL), Aβ isoforms Aβ38, Aβ40 and Aβ42, sAPPα, sAPPβ, APLP1 β-derived peptides APL1β25, APL1β 27 and APL1β 28 and YKL40 by immunochemical methods. RESULTS: The concentrations of all soluble forms of APP, all Aβ isoforms and APL1β28 were lower, whilst APL1β25 and APL1β27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged. CONCLUSIONS: The reduced CSF concentrations of Aβ38, Aβ40, Aβ42, sAPPα and sAPPβ suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1β25 and APL1β27 in combination with a slight decreased APL1β28 could be caused by more available γ-secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness

Shared CSF Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus and Subcortical Small Vessel Disease

Introduction: 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. Methods: 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. Results: All amyloid fragments were reduced in iNPH and SSVD (p < 0.05), although more in iNPH than in SSVD in comparison to HC. iNPH and SSVD showed comparable elevations of NFL, MBP, and GFAP (p < 0.05). MMPs were similar in all three groups except for MMP-10, which was increased in iNPH and SSVD. Patients with iNPH had larger ventricles and fewer WMCs than patients with SSVD. Conclusion: 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

Plasma and cerebrospinal fluid concentrations of neurofilament light protein correlate in patients with idiopathic normal pressure hydrocephalus

BACKGROUND: Neurofilament light chain protein (NFL), a marker of neuronal axonal degeneration, is increased in cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH). Assays for analysis of NFL in plasma are now widely available but plasma NFL has not been reported in iNPH patients. Our aim was to examine plasma NFL in iNPH patients and to evaluate the correlation between plasma and CSF levels, and whether NFL levels are associated with clinical symptoms and outcome after shunt surgery. METHODS: Fifty iNPH patients with median age 73 who had their symptoms assessed with the iNPH scale and plasma and CSF NFL sampled pre- and median 9 months post-operatively. CSF plasma was compared with 50 healthy controls (HC) matched for age and gender. Concentrations of NFL were determined in plasma using an in-house Simoa method and in CSF using a commercially available ELISA method. RESULTS: Plasma NFL was elevated in patients with iNPH compared to HC (iNPH: 45 (30-64) pg/mL; HC: 33 (26-50) (median; Q1-Q3), p = 0.029). Plasma and CSF NFL concentrations correlated in iNPH patients both pre- and postoperatively (r = 0.67 and 0.72, p < 0.001). We found only weak correlations between plasma or CSF NFL and clinical symptoms and no associations with outcome. A postoperative NFL increase was seen in CSF but not in plasma. CONCLUSIONS: Plasma NFL is increased in iNPH patients and concentrations correlate with CSF NFL implying that plasma NFL can be used to assess evidence of axonal degeneration in iNPH. This finding opens a window for plasma samples to be used in future studies of other biomarkers in iNPH. NFL is probably not a very useful marker of symptomatology or for prediction of outcome in iNPH

Before and After Shunt Surgery A Controlled Study Using Computerized Dynamic Posturography (EquiTest)

Postural function in idiopathic normal pressure hydrocephalus before and after shunt surgery: a controlled study using computerized dynamic posturography (EquiTest

Postural function in idiopathic normal pressure hydrocephalus before and after shunt surgery : a controlled study using computerized dynamic posturography (EquiTest)

Introduction Postural dysfunction is one of the major features of idiopathic normal pressure hydrocephalus (iNPH). With computerized dynamic posturography (CDP) balance can be assessed objectively. The primary aim of this study was to describe the postural function in iNPH patients pre- and post-operatively in comparison with healthy individuals (HI) using CDP. Subjects and methods Thirty-five patients (16 M, 19 F) with a mean age of 73 (range 49–81) with iNPH, and sixteen HI (7 M, 9 F) aged 73 (62–89) were included. iNPH patients were operated on with a ventriculo-peritoneal shunt. Patients and HI were tested regarding motor function, balance and cognition. CDP, EquiTest (NeuroCom International, Clackamas, OR), was performed before and three months after shunt surgery and twice in HI, with a three-month interval. Results Pre-operatively, the 35 patients had poorer balance measured with the Sensory Organizing Test (SOT) score in every condition (p = 0.01 in SOT 1 and p &lt; 0.001 in SOT 2–6) compared to the HI. The greatest difference was in test conditions measuring mainly vestibular function, where loss of balance (LOB) was frequent. Twenty patients were evaluated three months after shunt surgery and 18/20 (90%) of them were considered shunt responders, with a mean improvement of motor score of 26% (range 5–67%). There was an improvement post-operatively in the weighted composite SOT score (p &lt; 0.05) but no significant change in any of the SOT conditions. LOB was not significantly reduced in any of the test conditions. Conclusion CDP showed that the patients had a poorer balance than the HI. The greatest difference was in SOT 5–6, indicating that the postural disturbance is of primarily central vestibular origin. There was a slight improvement of balance post-operatively

Ventriculoperitoneal shunt complications in the european idiopathic normal pressure hydrocephalus multicenter study

BACKGROUND Ventriculoperitoneal shunt (VP-shunt) is the standard of treatment for idiopathic normal pressure hydrocephalus (iNPH). However, a thorough investigation of VP-shunt complications in this population is lacking. OBJECTIVE To present the analysis and the rates of complications progressively occurring during the first year after shunt surgery in the patients with iNPH included in the European multicenter (EU-iNPH) study. METHODS Patients (n=142) were prospectively included in the EU-iNPH study by 13 institutions. All patients received a programmable VP-shunt. One hundred fifteen patients completed the 12-mo follow-up. Reexaminations were performed 1, 3, and 12 mo after surgery. Data regarding symptomatic over- or underdrainage, infections, malposition, subdural collections, and shunt surgery were collected and analyzed. RESULTS Thirty patients (26%) experienced symptoms due to shunt underdrainage. Symptomatic overdrainage was reported in 10 (9%). Shunt adjustments were made in 43 (37%). Shunt malposition was recognized as the primary cause of shunt malfunction in 8 (7%), while only 1 infection (0.9%) occurred. Subdural hematoma was diagnosed in 7 (6%) and was treated by increasing the opening pressure of the valve in 5 patients. Hygroma was diagnosed in 10 (9%), requiring surgery in 1 patient. Overall, 17 patients (15%) underwent 19 shunt surgeries. CONCLUSION The advances in valve technology, a careful opening pressure setting, and rigorous follow-up allow a significant reduction of complications, which can be usually managed nonsurgically within the first 3 to 6 mo