Recent research suggests that multiple factors contribute to the NPH phenotype. However, we do not know how frequently these factors occur and overlap.

Assess the frequency of congenital, genetic, vascular, impaired CSF absorption and degenerative contributors in patients with clinical diagnoses of normal pressure hydrocephalus (NPH).

Clinical data, genetic variants, neuroimaging, and blood/CSF-biomarkers of Alzheimer disease (AD) were systematically measured in patients with NPH diagnosed at our tertiary care center (03-2020 to 07-2024). Brain MRIs were independently reviewed by two neurologists for presence/absence of disproportionately enlarged subarachnoid space hydrocephalus (DESH) and white matter hyperintensities (Fazekas score).

Sixty-five patients were diagnosed with NPH (mean age 71.3±8.7 years; 45% females). Average head circumference was 57.3±2.1 cm. Head circumference was >98th percentile of expected in 20/58 (35%) patients, suggesting a congenital contribution. Loss of function mutations in the CWH43 gene were detected in 5/43 (12%) patients. Neuroimaging revealed DESH in 45/65 (69%) patients, indicating impaired CSF absorption above the Sylvian fissures; moderate-to-severe white matter disease (Fazekas score of 2-3) in 30/65 (45%) patients; and both in 27/65 (41%) patients (p<0.001). Plasma pTau217 levels were increased (>0.185 pg/mL) in 19/61 (31%) patients, suggesting concurrent AD neuropathologic change. Plasma pTau217 levels were inversely associated with performance on bedside tests of cognition (Spearman Rho = -0.56; p=<0.001), supporting a contribution of concurrent AD to cognitive impairment in NPH.  Multiple factors (i.e., large head circumference, CWH43 mutations, DESH, white matter disease, AD pathology) were present in 62% of participants, with a median of 2 (range 0-4) factors per patient.

Clinical, genetic, neuroimaging, and biomarker data suggest multiple factors contribute to NPH. The myriad potential contributors suggest that NPH is a syndrome. These findings emphasize the value of comprehensive assessments across multiple domains when evaluating suspected NPH patients and suggest potential benefits of multifaceted management approaches.