Antti Johannes Luikku

Background: Idiopathic normal pressure hydrocephalus (iNPH) primarily affects older adults, often overlapping with Alzheimer's disease (AD). Amyloid pathology in frontal cortex biopsies predicts future AD and relates to reduced shunt responsiveness in iNPH. Cerebrospinal fluid (CSF) biomarkers and positron emission tomography imaging detect amyloid but are invasive, costly, or hard to access. Magnetic resonance imaging (MRI) is more available but usually reveals amyloid changes only in later disease stages. Objective: To assess whether MRI-derived 3D geometry and curvature features of the lateral ventricles, combined with demographic, genetic, and CSF biomarker data, can predict amyloid pathology in frontal cortex biopsies from iNPH patients. Methods: The main cohort included 178 iNPH patients; the CSF cohort, 155. Inclusion required an iNPH diagnosis, APOE genotyping, preoperative MRI, and frontal cortex biopsy during shunt surgery. 3D meshes of the lateral ventricles were reconstructed from volumetric segmentations of T1-weighted MRI, followed by extraction of geometric and curvature features. A calibrated linear Support Vector Classifier with LASSO penalty performed joint feature selection and classification, with performance evaluated via nested stratified cross-validation. Results: A classifier using curvature, demographic, and APOE genotype features predicted amyloid pathology with an AUC of 0.817 (SD = 0.053) in the main cohort. Adding CSF biomarker ratios in the CSF cohort increased the AUC to 0.835 (SD = 0.065). Conclusions: MRI-based lateral ventricle curvature features are effective markers of amyloid pathology in iNPH, performing comparably to CSF biomarkers. Combining these features with demographic, APOE , and CSF data enhances prediction, supporting the value of 3D MRI-based features for amyloid assessment in iNPH.

BACKGROUND AND OBJECTIVES: Idiopathic normal pressure hydrocephalus is a condition with gait impairment, incontinence, and cognitive decline, treated with shunt surgery. The Gothenburg scale (GBS) provides comprehensive assessment of symptoms and outcomes. The cerebrospinal fluid tap test (CSF-TT) is used as a prognostic tool, but its predictive value remains inconsistent. This study aimed to evaluate the clinical utility of CSF-TT and its association with postoperative outcomes measured using GBS, a rarely applied multidomain outcome measure in CSF-TT evaluation. METHODS: A prospective, population-based cohort of consecutive patients with suspected idiopathic normal pressure hydrocephalus was examined. Shunt surgery was recommended based on clinical and radiological criteria, with CSF-TT serving as prognostic support. Outcomes were assessed using GBS preoperatively, at 3 and 12 months. Linear mixed-effects models were applied to evaluate shunt outcomes and receiver operating characteristic analysis assessed classification accuracy. RESULTS: A total of 218 patients underwent shunt surgery, 181 completed follow-up (median age 74.6, 56% female). Mean GBS scores increased by 13.6 (95% CI: 11.5-15.6) at 3 months and 13.7 (95% CI: 11.4-16.1) at 12 months. Patients without CSF-TT improvement showed no response (mean change 5.3 [95% CI: −0.6 to 11.2] at 3 months; 2.9 [95% CI: −3.9 to 9.6] at 12 months). Classification accuracy of CSF-TT was low (3 months: area under the curve 0.56; 12 months: area under the curve 0.59). At 12 months, positive predictive value was 76% and negative predictive value 45%. CONCLUSION: CSF-TT is associated with shunt outcomes when assessed with GBS. Strict reliance on CSF-TT thresholds may inappropriately exclude patients who could benefit from shunt surgery.

Background: Plasma phosphorylated tau isoforms 181 (pTau181) and 217 (pTau217) are promising Alzheimer's disease (AD) biomarkers. Objective: We evaluated the performance of pTau181 and pTau217 in the differential diagnostics between AD, other neurodegenerative diseases and non-neurodegenerative participants. Methods: We included 104 patients with neurodegenerative diseases (37 with AD, 21 with synucleinopathies [SYNU], 24 with frontotemporal dementia [FTD] and 22 with idiopathic normal-pressure hydrocephalus [iNPH]) and 50 participants without neurodegenerative disorders (33 individuals undergoing knee arthroplasty and 17 with psychiatric diagnoses). pTau181 and pTau217 were measured via single-molecule array. Results: pTau181 differentiated AD patients from psychiatric patients with an area under the curve (AUC) of 0.879 and AD patients from all other participants with an AUC of 0.685. pTau181 was higher in patients with AD compared to FTD, iNPH, and non-neurodegenerative (ND) patients. pTau217 differentiated AD patients from psychiatric patients, with an AUC of 0.998, and AD patients from all other groups, with an AUC of 0.835. pTau217 was higher in AD patients compared to ND, FTD, and SYNU patients, but it did not differ between AD and iNPH patients without adjustment for age as a covariate. Conclusions: Our prospective cohort data indicate that pTau217 differentiates AD patients from psychiatric patients, with an excellent AUC value in receiver operating characteristic analysis. Our study supports the use of pTau217 rather than pTau181 as a minimally invasive tool to differentiate AD from non-neurodegenerative diseases (e.g., psychiatric disorders). Further studies are needed to determine the nature of pTau217 in iNPH.

BACKGROUND AND OBJECTIVES: Spinal cord stimulation (SCS) is an established but intricate therapy for neuropathic pain. Chronic pain is associated with increased mortality; however, the impact of successful SCS treatment on mortality remains unreported. In this retrospective case-controlled study, we present survival and cause-specific mortality data for patients trialed for SCS. METHODS: The primary outcome was cause-specific mortality in our cohort of 330 consecutive patients, aged 65 years or younger, referred to Kuopio University Hospital for persistent spinal pain syndrome type 2, complex regional pain syndrome, or other neuropathic pain. An SCS device was implanted in 256 patients but later explanted in 78 cases. To compare mortality, 979 matched controls and causes of death were sourced from a national registry. RESULTS: During a median follow-up of 9.1 years, 28 patients and 39 matched controls died. The 10-year mortality rate was increased in the trial-only group (hazard ratio [HR] = 2.34; CI 1.11-5.09, P = .03) and the explanted SCS group (HR = 3.57; CI 1.83-6.98, P < .001), whereas no increased mortality was observed in the permanent SCS group compared with matched controls (HR = 1.41; CI 0.68-2.91, P = .35). The most frequent causes of death were malignant neoplasms (27%) and external causes (27%). CONCLUSION: Increased mortality was observed in patients with a negative SCS trial or explanted SCS devices, whereas patients with successful SCS treatment experienced no excess mortality.

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.

Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (Aβ) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of Aβ and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:Aβ42, 10% beyond tau PET, and 50% beyond CSF NfL in Aβ positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate in APOE4 carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25 ^th percentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2– individuals (bottom 25 ^th percentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by Aβ and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of Aβ, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

Background: Health-related quality of life (HRQoL) is severely impaired in persons with idiopathic normal pressure hydrocephalus (iNPH). The HRQoL improves in a number of patients after the placement of a cerebrospinal fluid (CSF) shunt, but long-term follow-up of HRQoL is rare.Methods: Extended follow-up (60 months) of a prospective cohort study involving 189 patients with iNPH who underwent shunt surgery. Preoperative variables were used to predict favorable HRQoL outcome (improvement or non-deterioration) measured by the 15D instrument 5 years after shunting.Results: Out of the 189 initially enrolled study participants, 88 had completed 5-year HRQoL follow-up (46%), 64 had died (34%), and 37 (20%) failed to complete the HRQoL follow-up but were alive at the end of the study. After initial post-operative HRQoL improvement, HRQoL deteriorated so that 37/88 participants (42%) had a favorable HRQoL outcome 5 years after shunting. Multivariate binary logistic regression analysis indicated that younger age (adjusted OR 0.86, 95% CI 0.77–0.95;p < 0.005), lower body mass index (adjusted OR 0.87, 95% CI 0.77–0.98;p < 0.05) and better Mini-Mental State Examination performance (adjusted OR 1.16, 95% CI 1.01–1.32;p < 0.05) before surgery predicted favorable 5-year outcome.Conclusions: This extended follow-up showed that the self-evaluated HRQoL outcome is associated with iNPH patients’ pre-operative cognitive status, overweight and age. The post-operative deterioration may reflect the natural progression of iNPH, but also derive from aging and comorbidities. It indicates a need for long-term follow-up.

Background: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer’s disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression

The Kuopio University Hospital (KUH) idiopathic normal pressure hydrocephalus (iNPH) cerebrospinal fluid (CSF) shunting protocol is described together with the initial outcomes of 175 patients with probable iNPH treated according to this protocol from a defined population. Our secondary aim was to display the variety of differential diagnoses referred to the KUH iNPH outpatient clinic from 2010 until 2017. Patients were divided into four groups according to the prognostic tests: tap test (positive or negative) and infusion test (positive or negative). The short-term outcome was compared between groups. The 3-month outcome following shunt surgery was assessed by measuring gait speed improvement, using a 12-point iNPH grading scale (iNPHGS) and the 15D instrument. From 341 patients suspected of iNPH, 88 patients were excluded from further research mostly due to deviation from the protocol’s gait assessment guidelines. Hence 253 patients with suspected iNPH were included in the study, 177/253 (70%) of whom were treated with a CSF shunt. A favorable clinical outcome following surgery was observed in 79–93% of patients depending on the prognostic group. A moderate association (Cramer’s V = 0.32) was found between the gait speed improvement rate and the prognostic group (X2, p = 0.003). Patients with a positive tap test had the highest gait speed improvement rate (75%). In addition, an improvement in walking speed was observed in 4/11 patients who had both a negative tap test and a negative infusion test. Other outcome measures did not differ between the prognostic groups. Conditions other than iNPH were found in 25% of the patients referred to iNPH outpatient clinic, with the most prevalent being Alzheimer’s disease. Our results emphasize the importance of a systematic diagnostic and prognostic workup especially in cases with an atypical presentation of iNPH. Additional diagnostic testing may be required, but should not delay adequate care. Active surgical treatment is recommended in patients with a high clinical probability of iNPH. Other neurological conditions contributed to most of the non iNPH diagnoses.