Cerebrospinal Fluid Levels of β-Amyloid 40 and β-Amyloid 42 are Proportionately Decreased in Amyloid Positron-Emission Tomography Negative Idiopathic Normal-Pressure Hydrocephalus Patients

Abstract

Background and Purpose Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) could be misleading in idiopathic normal-pressure hydrocephalus (iNPH). We therefore investigated the CSF biomarkers in 18F-florbetaben amyloid-negative positron-emission tomography (PET) [amyloid PET(−)] iNPH, amyloid-positive PET [amyloid PET(+)] AD, and cognitively normal (CN) subjects. Methods Ten amyloid PET(+) AD patients (56.7±5.6 years old, mean±standard deviation), 10 amyloid PET(−) iNPH patients (72.8±4.5 years old), and 8 CN subjects (61.2±6.5 years old) were included. We measured the levels of β-amyloid (Aβ)40, Aβ42, total tau (t-tau) protein, and phosphorylated tau (p-tau) protein in the CSF using enzyme-linked immunosorbent assays. Results The level of Aβ42 and the Aβ42/Aβ40 ratio in the CSF were significantly lower in AD than in iNPH or CN subjects. The Aβ40 level did not differ significantly between AD and iNPH ( p =1.000), but it did between AD and CN subjects ( p =0.032). The levels of both t-tau and p-tau were higher in AD than in iNPH or CN subjects. The levels of Aβ42, Aβ40, t-tau, and p-tau were lower in iNPH than in CN subjects, but there was no significant difference after controlling for age. Conclusions Our results suggest that the mechanism underlying low CSF Aβ levels differs between amyloid PET(−) iNPH and amyloid PET(+) AD subjects. The lower levels of all CSF biomarkers in iNPH patients might be due to reduced clearances from extracellular fluid and decreased brain metabolism of the periventricular zone in iNPH resulting from glymphatic dysfunction.

Cerebrospinal Fluid Biomarkers for the Diagnosis and Classification of Alzheimer's Disease Spectrum

“…In fact, recent studies showed that CSF Aβ42 levels can be decreased in pure NPH. 23 24 25 We compared our cutoffs with previously established cutoffs obtained from other memory clinics in Korea. As a result, our Aβ42 cutoff was comparable with Jung et al's (Aβ42 < 631.8, p-tau > 56.4, and t-tau > 271.6) and our t-tau cutoff was comparable with Park et al's (Aβ42 < 481.8, p-tau > 57.0, and t-tau > 326.0).…”

“…It is also noteworthy that there are other conditions causing false positive CSF Aβ42 and t-tau results: CSF Aβ42 is reported to be decreased, albeit inconsistently, in frontotemporal dementia, vascular dementia, dementia of Lewy body, 30 or in normal pressure hydrocephalus. 31 CSF t-tau, which is a neuronal injury marker, can increase in various brain disorders such as stroke, trauma, and non-AD dementias, especially in rapidly progressing dementias such as Creutzfeldt-Jakob Disease.…”

Cerebrospinal Fluid Alzheimer’s Biomarkers and Neurofilament Light Profile of Idiopathic Normal Pressure Hydrocephalus in China: A PUMCH Cohort Study

“…Also, in the study by Wilsson et al [14], CSF t -tau, p -tau 181 , and Aβ 42 levels were all significantly lower than controls. In the study using amyloid PET, Kim et al [15] revealed Aβ 42 levels were decreased in iNPH and AD patients and more in AD. In our cohort, t -tau and p -tau 181 level of iNPH was not distinguishable from control and significantly lower than AD.…”

“…Also, the abnormal CSF dynamic and turnover as well as reduced glymphatic system clearance of Aβ in iNPH patients also contributed to the amyloid mismetabolism [18]. The proportionate decrease of Aβ 42 and Aβ 40 in CSF of iNPH but not in AD also suggested there were discrete amyloid clearance and pathology in these 2 diseases [15, 19]. p -tau 181 was related to the formation of neurofibrillary tangles in AD, which was not detected in iNPH.…”

History in Perspective: The prime pathological players and role of phytochemicals in Alzheimer’s disease

“…These changes have been known to play a part in decreasing the pattern of learning and memory processes and impairing cognitive properties ( Hartman and Ross, 2018 ). In cerebrospinal fluid (CSF), a disproportion of Aβ to Aβ42 protein is a key criterion to confirm the pathology of AD clinically ( Kim et al, 2019 ). Even though the symptoms of diverse neurodegenerative dementias are often similar, each is usually distinguished by the deposition of its characteristic protein isoform in specific brain areas.…”