Alzheimer’s Disease CSF Biomarker Profiles in Idiopathic Normal Pressure Hydrocephalus

Abstract

Patients with idiopathic normal pressure hydrocephalus (iNPH) frequently show pathologic CSF Aβ42 levels, comparable with Alzheimer’s Disease (AD). Nevertheless, the clinical meaning of these findings has not been fully explained. We aimed to assess the role of AD CSF biomarkers (Aβ42, Aβ42/Aβ40, p-tau, t-tau) in iNPH. To this purpose, we enrolled 44 patients diagnosed with iNPH and 101 with AD. All the patients underwent CSF sampling. We compared CSF biomarker levels in iNPH and AD: Aβ42 levels were not different between iNPH and AD, while Aβ42/Aβ40, p-tau, and t-tau were significantly different and showed excellent accuracy in distinguishing iNPH and AD. A multiple logistic regression analysis showed that Aβ42/Aβ40 was the variable that most contributed to differentiating the two groups. Furthermore, iNPH patients with positive Aβ42/Aβ40 had higher p-tau and t-tau than iNPH patients with negative Aβ42/Aβ40. Those iNPH patients who showed cognitive impairment had lower Aβ42/Aβ40 and higher p-tau than patients without cognitive impairment. We concluded that positive CSF Aβ42 with negative Aβ42/Aβ40, p-tau, and t-tau is a typical CSF profile of iNPH. On the contrary, positive Aβ42/Aβ40 in iNPH patients, especially when associated with positive p-tau, may lead to suspicion of a coexistent AD pathology.

Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders

“…The iNPH disease is a neurodegenerative disease and subtype of dementia with close histopathological overlap towards AD 58 ; for example, accumulation in the brain of Aβ and/or tau is seen in a significant proportion of iNPH subjects 59 . Moreover, previous studies showed a comparable reduction of CSF production and turnover in AD and iNPH patients 60 , though CSF Aβ40, Aβ42, and T-/P-tau also were able to differentiate iNPH from AD subjects 61 . iNPH involves impaired glymphatic function 12 , 62 , which was proposed as a common mechanism behind dementias and AD 63 .…”

“…In line with this observation, iNPH patients not responding to shunt surgery had increased CSF T-tau concentration 64 , 65 , and also increased CSF NfL concentration 65 . Cognitively impaired iNPH patients also had higher P-tau concentration than cognitively intact iNPH subjects 61 . They also presented a lower Aβ42/Aβ40 ratio 61 .…”

“…Cognitively impaired iNPH patients also had higher P-tau concentration than cognitively intact iNPH subjects 61 . They also presented a lower Aβ42/Aβ40 ratio 61 . Here, we found that impaired clearance of tracer from CSF was associated with a significantly lower plasma Aβ42/Aβ40 ratio in iNPH patients at 24 h and within the total cohort at 48 h after tracer injection.…”

Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review

“…In an attempt to use CSF biomarkers to differentiate iNPH from subcortical ischemic vascular disease (SSVD), Manniche et al (2020) suggested that lower concentrations of Aβ42 and t-tau were found in patients with iNPH compared to patients with subcortical vascular dementia, while concentration of p-tau in the CSF was similar in both diseases [ 47 ]. Said et al (2022) suggested that in iNPH patients CSF concentration of Aβ42 was higher and those of t-tau and p-tau were lower than in AD patients [ 48 ], while Mazzeo et al (2022) found that Aβ42/Aβ40, p-tau, and t-tau were significantly lower in iNPH than in AD and that Aβ42 concentration was similar in these two diseases [ 49 ]. Finally, all amyloid fragments’ CSF concentrations were found to be decreased in iNPH and SSVD compared to healthy individuals, with iNPH patients having lower concentrations than those with SSVD [ 50 ].…”

Molecular Signatures of Normal Pressure Hydrocephalus: A Large-scale Proteomic Analysis of Cerebrospinal Fluid

“…Previous studies have mainly focused on the potential of classical AD cerebrospinal fluid (CSF) biomarkers in differential diagnosis of iNPH from similar clinical entities and long-term response after shunt surgery 11,12 . Lower levels of neurofilament light (NfL), amyloidβ 1-42 (Aβ 1-42 ), amyloidβ 1-40 (Aβ 1-40 ), total tau (t-tau), and phosphorylated tau 181 (p-Tau181) have been associated with long-term improvement in gait outcomes after shunt surgery [11][12][13] .…”