Alzheimer's disease core biomarkers are associated with worse baseline and postoperative cognitive profiles in idiopathic normal pressure hydrocephalus: findings from the Bologna PRO-Hydro study.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome affecting the elderly. Recent studies have reported a high prevalence of neurodegenerative copathologies in iNPH, particularly Alzheimer's disease (AD). Neuropsychological studies in iNPH sample revealed variable and heterogeneous cognitive profile. Few studies have examined cognitive differences according to neurodegenerative copathology, and none has systematically applied a comprehensive neuropsychological battery while stratifying patients by AD biomarkers both before and after surgery. The main objective of this study was to assess baseline differences in the neuropsychological profile of iNPH patients with and without AD core biomarkers, using a comprehensive neuropsychological battery. The secondary aim was to investigate changes in neuropsychological functions from baseline to short-term postoperative outcomes in the overall sample and in subgroups with and without AD biomarkers.

METHODS: Patients underwent a standardized inpatient work-up including clinical evaluation, comprehensive neuropsychological assessment, and cerebrospinal fluid (CSF) biomarkers analysis. A multidisciplinary team selected candidates for surgery. An extensive clinical and neuropsychological reassessment was performed six months after surgery.

RESULTS: From 2015 to 2025, 226 (97 females) consecutive iNPH patients completed the baseline evaluation. Among these, 102 shunted iNPH patients (46 females) underwent six-month postoperative neuropsychological assessment. The cognitive profile in all individuals revealed deficits in attentive-executive functions with a significant improvement after surgery. Overall, 24.3% of iNPH participants showed a pathological phosphorylated tau/beta-amyloid 1-42 ratio (pTau/Aβ42+). At baseline, pTau/Aβ42+ (n = 53) patients revealed worse neuropsychological performances than those (n = 165) with normal pTau/Aβ ratio (pTau/Aβ42-), with more pronounced memory impairment. At six-month follow-up, the pTau/Aβ42 + group exhibited poorer cognitive outcomes compared to pTau/Aβ42- one, particularly in general cognition, short- and long-term verbal and visuo-spatial memory, and executive functions.

CONCLUSIONS: Nearly one-quarter of patients exhibited AD core biomarkers positivity. iNPH patients with AD core biomarkers copathology showed an earlier cognitive onset and worse neuropsychological performances at baseline. At follow-up, the pTau/Aβ42 + group demonstrated poorer cognitive outcomes in specific cognitive domains compared to the pTau/Aβ42 - group. These differences in cognitive profiles at baseline and six months after surgery in iNPH patients with AD core biomarker positivity may have clinical relevance.