Predicting Development of Alzheimer's Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus.

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 of neurodegenerative disorders. OBJECTIVE: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. METHODS: 335 shunted iNPH-patients (median 74 years) were followed until death (n = 185) or 6/2015 (n = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). CONCLUSION: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD.

Incidence, Comorbidities, and Mortality in Idiopathic Normal Pressure Hydrocephalus.

OBJECT: To investigate the incidence, comorbidities, mortality, and causes of death in idiopathic normal pressure hydrocephalus (iNPH). METHODS: A cohort of 536 patients with possible NPH from a defined population with a median follow-up time of 5.1 years, (range 0.04-19.9 years) was included in the study. Patients were evaluated by brain imaging and intraventricular pressure monitoring, with a brain biopsy specimen immunostained against amyloid-ß and hyperphosphorylated τ. Hospital records were reviewed for vascular diseases and type 2 diabetes mellitus (T2DM). Death certificates and yearly population of the catchment area were obtained from national registries. RESULTS: A total of 283 patients had a clinical diagnosis of iNPH, leading to a median annual incidence of 1.58 iNPH patients per 100,000 inhabitants (range, 0.8-4.5). Alzeimer disease-related brain biopsy findings were less frequent in iNPH patients than in non-iNPH patients (P < 0.05). An overrepresentation of hypertension (52% vs. 33%, P < 0.001) and T2DM (23% vs. 13%, P = 0.002) was noted in iNPH patients. Age (hazard ratio [HR] 1.04/year, 95% confidence interval [CI] 1.03-1.06, P < 0.001) and T2DM (HR 1.63, 95% CI 1.23-2.16, P < 0.001) increased the risk of death in the iNPH patients and in the total population. iNPH was associated with decreased risk of death (HR 0.63, 95% CI 0.50-0.78, P < 0.001). The most frequent causes of death were cardiovascular and cerebrovascular disease. Dementia as a cause of death was more common in non-iNPH patients (27% vs. 10%, P < 0.001). CONCLUSIONS: Hypertension and T2DM are common in iNPH and the latter causes excess mortality in the affected patients.

Alzheimer's Disease-Related Polymorphisms in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a late onset, surgically treated progressive brain disease caused by impaired cerebrospinal fluid dynamics and subsequent ventriculomegaly. Comorbid Alzheimer's disease (AD) seems to be frequent in iNPH. OBJECTIVE: We aim to evaluate the role of AD-related polymorphisms in iNPH. METHODS: Overall 188 shunt-operated iNPH patients and 688 controls without diagnosed neurodegenerative disease were included into analysis. Twenty-three single-nucleotide polymorphisms (SNPs FRMD4A [rs7081208_A, rs2446581_A, rs17314229_T], CR1, BIN, CD2AP, CLU, MS4A6A, MS4A4E, PICALM, ABCA7, CD33, INPP5D, HLA_DRB5, EPHA1, PTK2B, CELF1, SORL1, FERMT2, SLC24A, DSG2, CASS4, and NME8) adjusted to APOE were analyzed between groups by using binary logistic regression analysis. Neuroradiological characteristics and AD-related changes in the right frontal cortical brain biopsies were available for further analysis. RESULTS: Logistic regression analysis adjusted to age, gender, and other SNPs indicated allelic variation of NME8 between iNPH patients and non-demented controls (p = 0.014). The allelic variation of NME8 was not related to the neuropathological changes in the brain biopsies of iNPH patients. However, periventricular white matter changes (p = 0.017) were more frequent in the iNPH patients with the AA-genotype, an identified risk factor of AD. CONCLUSIONS: Our findings increase the evidence that iNPH is characterized by genetic and pathophysiological mechanisms independent from AD. Considering that NME8 plays a role in the ciliary function and displays SNP-related diversity in white matter changes, the mechanisms of NME8 in iNPH and other neurodegenerative processes are worth further study.

Associations of intracranial pressure with brain biopsy, radiological findings, and shunt surgery outcome in patients with suspected idiopathic normal pressure hydrocephalus.

BACKGROUND: It remains unclear how intracranial pressure (ICP) measures are associated with brain biopsies and radiological markers. Here, we aim to investigate associations between ICP and radiological findings, brain biopsies, and shunt surgery outcome in patients with suspected idiopathic normal pressure hydrocephalus (iNPH). METHOD: In this study, we retrospectively analyzed data from 73 patients admitted with suspected iNPH to Kuopio University Hospital. Of these patients, 71% underwent shunt surgery. The NPH registry included data on clinical and radiological examinations, 24-h intraventricular pressure monitoring, and frontal cortical biopsy. RESULTS: The mean ICP and mean ICP pulse wave amplitude were not associated with the shunt response. Aggregations of Alzheimer's disease (AD)-related proteins (amyloid-ß, hyperphosphorylated tau) in frontal cortical biopsies were associated with a poor shunt response (P = 0.014). High mean ICP was associated with Evans' index (EI; P = 0.025), disproportional sylvian and suprasylvian subarachnoid spaces (P = 0.014), and focally dilated sulci (P = 0.047). Interestingly, a high pulse wave amplitude was associated with AD-related biopsy findings (P = 0.032), but the mean ICP was not associated with the brain biopsy. The ICP was not associated with medial temporal lobe atrophy, temporal horn widths, or white matter changes. ICP B waves were associated with less atrophy of the medial temporal lobe (P = 0.018) and more severe disproportionality between the sylvian and suprasylvian subarachnoid spaces (P = 0.001). CONCLUSIONS: The EI and disproportional sylvian and suprasylvian subarachnoid spaces were associated with mean ICP. Disproportionality was also associated with ICP B waves. These associations, although rather weak, with elevated ICP in 24-h measurements, support their value in iNPH diagnostics and suggest that these radiological markers are potentially related to the pathogenesis of iNPH. Interestingly, our results suggested that elevated pulse wave amplitude might be associated with brain amyloid accumulation.

Multimodal analysis to predict shunt surgery outcome of 284 patients with suspected idiopathic normal pressure hydrocephalus.

OBJECTIVES: Optimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer's disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH. METHODS: In this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients' memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure. RESULTS: Our analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC = 0.58). CONCLUSIONS: Prediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.

Feasibility of radiological markers in idiopathic normal pressure hydrocephalus.

BACKGROUND: Various radiological markers have been proposed for diagnostics in idiopathic normal pressure hydrocephalus (iNPH). We examined the usefulness of radiological markers in the diagnostics and prediction of shunt response in iNPH. METHOD: In this retrospective cohort study, we evaluated brain CT or MRI scans of 390 patients with suspected iNPH. Based on a 24-h intraventricular pressure monitoring session, patients were classified into a non-NPH (n = 161) or probable iNPH (n = 229) group. Volumes of cerebrospinal fluid compartments (lateral ventricles, sylvian and suprasylvian subarachnoid spaces and basal cisterns) were visually assessed. Disproportionally enlarged subarachnoid spaces, flow void, white matter changes, medial temporal lobe atrophy and focally dilated sulci were evaluated. Moreover, we measured quantitative markers: Evans' index (EI), the modified cella media index, mean width of the temporal horns and callosal angle. RESULTS: iNPH was more likely in patients with severe volumetric disproportion between the suprasylvian and sylvian subarachnoid spaces than in those without disproportion (OR 7.5, CI 95 % 4.0-14.1, P < 0.0001). Mild disproportion (OR 2.6, CI 95 % 1.4-4.6, P = 0.001) and narrow temporal horns (OR per 1 mm 0.91, CI 95 % 0.84-0.98, P = 0.014) were also associated with an iNPH diagnosis. Other radiological markers had little association with the iNPH diagnosis in the final combined multivariate model. Interestingly, EI was higher in non-NPH than iNPH patients (0.40 vs. 0.38, P = 0.039). Preoperative radiological markers were not associated with shunt response. CONCLUSIONS: Visually evaluated disproportion was the most useful radiological marker in iNPH diagnostics. Narrower temporal horns also supported an iNPH diagnosis, possibly since atrophy was more pronounced in the non-NPH than iNPH group.