Association Between Cerebrospinal Fluid Biomarkers and Age-related Brain Changes in Patients with Normal Pressure Hydrocephalus

Abstract

Our study aimed to: 1)investigate the diagnostic utility of CSF Aβ42, t-tau, and p-tau to differentiate normal-pressure-hydrocephalus(NPH) from Alzheimer's-disease(AD) and normal-controls; and 2) investigate if age and ventricular size affect the levels of CSF biomarkers in NPH patients. We recruited 131 participants: (a)Suspected-NPH: 72 with ventriculomegaly and clinical symptoms of NPH. These participants were then divided into two groups of 1)Probable-NPH (N = 38) and 2)Unlikely-NPH (n = 34) based on whether participants experienced gait improvement after removal of a large amount of CSF; (b)AD group: 30 participants with CSF biomarkers and cognitive symptoms consistent with AD; (c)Control-group: 29 participants who were cognitively and functionally normal. Lower levels of CSF Aβ42 and p-tau were observed in the probable-NPH compared to the normal controls(444.22 ± 163.3 vs. 1213.75 ± 556.5; and 26.05 ± 9.2 vs. 46.16 ± 13.3 pg/mL; respectively). Lower levels of CSF p-tau and t-tau were found in the probable-NPH compared to the AD(26.05 ± 9.2 vs. 114.95 ± 28.2; and 193.29 ± 92.3 vs. 822.65 ± 311.5 pg/mL; respectively) but the CSF-Aβ42 was low in both the probable-NPH and AD. CSF-Aβ42 correlated with age and Evans-index only in the probable-NPH(r = 0.460, p = 0.004; and r = −0.530, p = 0.001; respectively). Our study supports the hypothesis that agerelated atrophy results in better Aβ42 clearance in the CSF because of the increase in the interstitial space. Normal pressure hydrocephalus (NPH) is a syndrome associated with enlarged ventricles without marked elevation in cerebrospinal fluid (CSF) pressure 1. Clinical symptoms include gait and balance impairment, cognitive deficits, and urinary urgency/incontinence 1. In both NPH and Alzheimer's disease (AD) decreased CSF levels of the amyloid β−42 (Aβ42) have been found; however, in contrast to AD, total tau (t-tau) and phospho-tau (p-tau) levels are not increased in NPH cases 2,3. It has been hypothesized that the low Aβ42 in the presence of low t-tau and p-tau is due to the decrease in interstitial space that precludes amyloid precursor protein (APP) fragments and tau proteins from being effectively cleared by CSF and consequently the levels of these proteins decrease in the CSF 4. This hypothesis was based on two major observations: 1) low levels of all APP fragments (i.e., Aβ38, Aβ40, Aβ42, sAPPα, and sAPPβ) in CSF obtained both by lumbar and ventricular methods of patients with NPH compared to health controls, which all increased back to normal after shunting 1 and 2) Aβ clearance from the interstitial fluid is increased during sleep when the size of interstitial space increases by 60% 5. The aims of our study were to: 1) investigate the diagnostic utility of CSF Aβ42, t-tau, and p-tau to differentiate NPH from AD and normal controls; and 2) investigate if age and ventricular size affect the levels of these CSF biomarkers in NPH patients. Answers to these questions would improve understanding of CSF Aβ42, t-tau, and p-tau production/clearance and facilitate ...

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

“…Our first result confirmed that patients with iNPH have CSF Aβ 42 concentrations comparable to AD and lower concentrations of p-tau and t-tau than AD, as widely described in previous studies [ 21 , 40 , 41 , 42 ]. In more detail, about 70% of patients in our series had positive CSF Aβ 42 , while p-tau and t-tau were positive in 7% and 11% of patients, respectively, which is consistent with a previous report by Santangelo et al [ 21 ].…”

CSF Biomarkers Predict Gait Outcomes in Idiopathic Normal Pressure Hydrocephalus

“…A recent study was also not able to validate the usefulness of Aβ 1-42 to differentiate iNPH from AD. 21 Using conservative improvement criteria, our study extends these findings in a large cohort by showing that elevated baseline levels of pTau181 were associated with poor long-term improvement after shunt surgery. Conversely, pTau181 only modestly predicted immediate improvement after TT.…”

Cerebrospinal fluid amyloid beta and glial fibrillary acidic protein concentrations in Huntington’s disease

“…There was no association between age and CSF Aβ42 concentration (r = − 0.322 p = 0.179) or CSF GFAP concentration (r = − 0.167, p = 0.693). Previous studies have not found a correlation between age and Aβ42 concentration in healthy individuals [49–51], but regarding GFAP a significant positive correlation between age and protein concentration has been noted in healthy individuals [48].…”