Idiopathic Normal pressure hydrocephalus (iNPH) is a form of adult hydrocephalus that is clinically characterized by progressive gait impairment, cognitive dysfunction, and urinary incontinence. The ...current standard method of treatment involves surgical installation of a CSF diversion shunt. However, only a fraction of patients shows an alleviation of symptoms from shunt surgery. Thus, the purpose of this prospective explorative proteomic study was to identify prognostic CSF biomarkers to predict shunt responsiveness in iNPH patients. Further, we evaluated the ability of the core Alzheimer's disease (AD) CSF biomarkers phosphorylated (p)-tau, total (t)-tau, and amyloid-β 1-42 (Aβ
) to serve as predictors of shunt response.
We conducted a tandem mass tag (TMT) proteomic analysis of lumbar CSF from 68 iNPH patients, sampled pre-shunt surgery. Tryptic digests of CSF samples were labelled with TMTpro reagents. The TMT multiplex samples were fractionated in 24 concatenated fractions by reversed-phase chromatography at basic pH and analysed by liquid chromatography coupled to mass spectrometry (LC-MS) on an Orbitrap Lumos mass spectrometer. The relative abundances of the identified proteins were correlated with (i) iNPH grading scale (iNPHGS) and (ii) gait speed change 1 year after surgery from baseline to identify predictors of shunt responsiveness.
We identified four CSF biomarker candidates which correlated most strongly with clinical improvement on the iNPHGS and were significantly changed in shunt-responsive compared to shunt-unresponsive iNPH patients 1 year post-surgery: FABP3 (R = - 0.46, log
(fold change (FC)) = - 0.25, p < 0.001), ANXA4 (R = 0.46, log
(FC) = 0.32, p < 0.001), MIF (R = -0.49, log
(FC) = - 0.20, p < 0.001) and B3GAT2 (R = 0.54, log
(FC) = 0.20, p < 0.001). In addition, five biomarker candidates were selected based on their strong correlation with gait speed change 1 year after shunt installation: ITGB1 (R = - 0.48, p < 0.001), YWHAG (R = - 0.41, p < 0.01), OLFM2 (R = 0.39, p < 0.01), TGFBI (R = - 0.38, p < 0.01), and DSG2 (R = 0.37, p < 0.01). Concentrations of the CSF AD core biomarkers did not differ significantly with shunt responsiveness.
FABP3, MIF, ANXA4, B3GAT2, ITGB1, YWHAG, OLFM2, TGFBI and DSG2 in CSF are promising prognostic biomarker candidates to predict shunt responsiveness in iNPH patients.
Abstract
BACKGROUND
Idiopathic normal pressure hydrocephalus (iNPH) is a progressive and potentially treatable neurodegenerative disease affecting elderly people, characterized by gait impairment and ...ventricular enlargement in brain imaging. Similar findings are seen in some patients with schizophrenia (SCZ).
OBJECTIVE
To determine the prevalence of SCZ among patients suffering from probable or possible iNPH and the specific effects of comorbid SCZ on the outcome of the cerebrospinal fluid (CSF) shunting.
METHODS
All medical records of the 521 iNPH patients in the NPH registry were retrospectively analyzed from 1991 until 2017. The prevalence of comorbidity of SCZ was determined and compared to that of general aged (≥65 yr) population in Finland.
RESULTS
We identified a total of 16 (3.1%) iNPH patients suffering from comorbid SCZ. The prevalence of SCZ among the iNPH patients was significantly higher compared to the general population (3.1% vs 0.9%, P < .001). All iNPH patients with comorbid SCZ were CSF shunted and 12 (75%) had a clinically verified shunt response 3 to 12 mo after the procedure. The CSF shunt response rate did not differ between patients with and without comorbid SCZ.
CONCLUSION
SCZ seems to occur 3 times more frequently among iNPH patients compared to the general aged population in Finland. The outcome of the treatment was not affected by comorbid SCZ and therefore iNPH patients suffering from comorbid SCZ should not be left untreated. These results merit validation in other populations. In addition, further research towards the potential connection between these chronic conditions is warranted.
Background The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it ...comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families. Methods Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their greater than or equai to 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher's exact test (two-tailed), the Mann-Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses. Results Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1-12.9, p = 0.030). Conclusions Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH. Keywords: Normal pressure hydrocephalus, Familial, Comorbidities, Diabetes, Depression, Genetics, SFMBT1
Abstract Neuropathologic changes of Alzheimer disease (AD) including Aβ accumulation and neuroinflammation are frequently observed in the cerebral cortex of patients with idiopathic normal pressure ...hydrocephalus (iNPH). We created an automated analysis platform to quantify Aβ load and reactive microglia in the vicinity of Aβ plaques and to evaluate their association with cognitive outcome in cortical biopsies of patients with iNPH obtained at the time of shunting. Aiforia Create deep learning software was used on whole slide images of Iba1/4G8 double immunostained frontal cortical biopsies of 120 shunted iNPH patients to identify Iba1-positive microglia somas and Aβ areas, respectively. Dementia, AD clinical syndrome (ACS), and Clinical Dementia Rating Global score (CDR-GS) were evaluated retrospectively after a median follow-up of 4.4 years. Deep learning artificial intelligence yielded excellent (>95%) precision for tissue, Aβ, and microglia somas. Using an age-adjusted model, higher Aβ coverage predicted the development of dementia, the diagnosis of ACS, and more severe memory impairment by CDR-GS whereas measured microglial densities and Aβ-related microglia did not correlate with cognitive outcome in these patients. Therefore, cognitive outcome seems to be hampered by higher Aβ coverage in cortical biopsies in shunted iNPH patients but is not correlated with densities of surrounding microglia.
Abstract
Background
Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait apraxia, cognitive deterioration and urinary incontinence. Differential diagnosis with other ...neurodegenerative disorders like Alzheimer’s disease (AD) can be challenging. Furthermore, AD‐related brain pathology is frequent comorbidity and can predict subsequent clinical AD. Here we aim to describe a diagnostic and treatment protocol of iNPH optimized for prediction of clinical outcome, especially future AD, and research value on neurodegenerative diseases.
Method
Since 1993 until the end of 2019, 990 patients with possible NPH underwent diagnostic right frontal cortical brain biopsy during intraventricular pressure measurement or CSF shunt surgery. Brain biopsies are routinely evaluated by immunohistochemistry against amyloid‐β (Aβ) and hyperphosphorylated tau (HPτ). Patients are follow‐up until death to gain all available outcome data.
Result
We have found an increased occurrence of clinical AD (up to 25%) in previously shunted iNPH patients as compared with rate of dementia in general population (15%). Cortical biopsy with Aβ pathology (seen in around 40% of all biopsies) during shunt insertion was the best predictor of future comorbid AD. These patients would be ideal for clinical trials of potential preventive therapies.
Conclusion
Diagnostic work‐up of NPH offer large amount of CSF, repeated brain imaging and cognitive testing. Most importantly, CSF shunt surgery open an ethically sustainable window to living brain including various comorbid neuropathological findings by chance. Along with optimized patient care, Kuopio iNPH work‐up (Figure) offer unique platform for biomarker discovery and validation.
Background
Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait apraxia, cognitive deterioration and urinary incontinence. Differential diagnosis with other neurodegenerative ...disorders like Alzheimer’s disease (AD) can be challenging. Furthermore, AD‐related brain pathology is frequent comorbidity and can predict subsequent clinical AD. Here we aim to describe a diagnostic and treatment protocol of iNPH optimized for prediction of clinical outcome, especially future AD, and research value on neurodegenerative diseases.
Method
Since 1993 until the end of 2019, 990 patients with possible NPH underwent diagnostic right frontal cortical brain biopsy during intraventricular pressure measurement or CSF shunt surgery. Brain biopsies are routinely evaluated by immunohistochemistry against amyloid‐β (Aβ) and hyperphosphorylated tau (HPτ). Patients are follow‐up until death to gain all available outcome data.
Result
We have found an increased occurrence of clinical AD (up to 25%) in previously shunted iNPH patients as compared with rate of dementia in general population (15%). Cortical biopsy with Aβ pathology (seen in around 40% of all biopsies) during shunt insertion was the best predictor of future comorbid AD. These patients would be ideal for clinical trials of potential preventive therapies.
Conclusion
Diagnostic work‐up of NPH offer large amount of CSF, repeated brain imaging and cognitive testing. Most importantly, CSF shunt surgery open an ethically sustainable window to living brain including various comorbid neuropathological findings by chance. Along with optimized patient care, Kuopio iNPH work‐up (Figure) offer unique platform for biomarker discovery and validation.
Background
Alzheimer’s pathologic change is frequently observed among patients with idiopathic normal pressure hydrocephalus (iNPH). Amyloid‐beta (Aβ) plaques and pathologic tau deposits in vivo are ...the hallmarks of neuropathologically verified AD, but correlation of Aβ plaque amount to cognitive decline remains controversial. The microglia reaction related with the brain Aβ pathology is under intense research and may modulate the toxicity of Aβ accumulation. Our aim is to characterize Aβ pathology and load in detail and evaluate microglia reaction related with the plaques and their correlation with clinical outcome.
Method
51 patients were shunted for iNPH between 9/2010 and end of 2017 with frontal cortical biopsy positive for Aβ. Aiforia create‐machine learning (ML) software was used on whole slide images (WSI) of ionized calcium binding adaptor molecule 1 (Iba1)/Aβ stained biopsies. ML was used to recognize Aβ area and Iba1 stained microglia somas. Clinical Dementia Rating global score (CDR‐GS) and Alzheimer’s clinical syndrome (ACS) were evaluated retrospectively at the end of the median follow‐up of 7.6 years (range 4.1‐ 14) during which 40 patients died.
Result
During the follow‐up 19 patients were diagnosed with Alzheimer’s clinical syndrome. Trained image analysis yielded recognition precision for tissue, Aβ and microglia somas with 0.99, 0.98, and 0.96, respectively. Percentage of Aβ area, microglia soma density and reactive microglia within 25 µm of Aβ plaques were acquired. In univariate analysis, preoperative MMSE was significant predictor of CDR‐GS (p < .001) and ACS (p < .01). In multivariate analysis, high preoperative MMSE predicted lower CDR‐GS on follow‐up (OR 0.74 0.63‐0.85) and lesser development of ACS (OR 0.86 0.75‐0.99). Among demented subjects, there was a trend of higher Aβ area density (median 2.4 % for CDR‐GS 0.5 and 10.1 % for CDR‐GS 3), and reactive microglia (median 84 for CDR‐GS 0.5 and 178 for CDR‐GS 3).
Conclusion
Higher Aβ load and reactive microglia might predict worse cognitive outcome and dementia. As additional patients will be analyzed during spring 2021, we will expect this trend to turn significant. Good baseline cognitive performance seems to protect from later development of Alzheimer’s clinical syndrome and dementia among iNPH patients.
The authors set out to study whether autosomal dominant polycystic kidney disease (ADPKD), an established risk factor for intracranial aneurysms (IAs), affects the acute course and long-term outcome ...of aneurysmal subarachnoid hemorrhage (aSAH).
The outcomes of 32 ADPKD patients with aSAH between 1980 and 2015 (median age 43 years; 50% women) were compared with 160 matched (age, sex, and year of aSAH) non-ADPKD aSAH patients in the prospectively collected Kuopio Intracranial Aneurysm Patient and Family Database.
At 12 months, 75% of the aSAH patients with ADPKD versus 71% of the matched-control aSAH patients without ADPKD had good outcomes (Glasgow Outcome Scale score 4 or 5). There was no significant difference in condition at admission. Hypertension had been diagnosed before aSAH in 69% of the ADPKD patients versus 27% of controls (p < 0.001). Multiple IAs were present in 44% of patients in the ADPKD group versus 25% in the control group (p = 0.03). The most common sites of ruptured IAs were the anterior communicating artery (47% vs 29%, p = 0.05) and the middle cerebral artery bifurcation (28% vs 31%), and the median size was 6.0 mm versus 8.0 mm (p = 0.02). During the median follow-up of 11 years, a second aSAH occurred in 3 of 29 (10%) ADPKD patients and in 4 of 131 (3%) controls (p = 0.11). A fatal second aSAH due to a confirmed de novo aneurysm occurred in 2 (6%) of the ADPKD patients but in none of the controls (p = 0.027).
The outcomes of ADPKD patients with aSAH did not differ significantly from those of matched non-ADPKD aSAH patients. ADPKD patients had an increased risk of second aSAH from a de novo aneurysm, warranting long-term angiographic follow-up.
PDF
