Cerebrospinal Fluid β-Amyloid and Tau Proteins for the Diagnosis of Alzheimer Disease

Abstract Background: Accumulation of β-amyloid protein (Aβ) and tau protein is the main feature of Alzheimer disease neuropathogenesis. Anesthetic isoflurane, but not desflurane, may increase Aβ levels in vitro and in animals. Therefore, we set out to determine the effects of isoflurane and desflurane on cerebrospinal fluid (CSF) levels of Aβ and tau in humans. Methods: The participants were assigned into spinal anesthesia (N = 35), spinal plus desflurane anesthesia (N = 33), or spinal plus isoflurane anesthesia (N = 38) group by randomization using computer-generated lists. Pre- and postoperative human CSF samples were obtained through an inserted spinal catheter. The levels of Aβ (Aβ40 and Aβ42) and total tau in the CSF were determined. Results: Here, we show that isoflurane, but not desflurane, was associated with an increase in human CSF Aβ40 levels (from 10.90 to 12.41 ng/ml) 24 h after the surgery under anesthesia compared to spinal anesthesia (from 11.59 to 11.08 ng/ml), P = 0.022. Desflurane, but not isoflurane, was associated with a decrease in Aβ42 levels 2 h after the surgery under anesthesia (from 0.39 to 0.35 ng/ml) compared to spinal anesthesia (from 0.43 to 0.44 ng/ml), P = 0.006. Isoflurane and desflurane did not significantly affect the tau levels in human CSF. Conclusions: These studies have established a system to study the effects of anesthetics on human biomarkers associated with Alzheimer disease and cognitive dysfunction. These findings have suggested that isoflurane and desflurane may have different effects on human CSF Aβ levels.

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Pathophysiology of Alzheimer Disease

10.2310/neuro.1335 ◽

2017 ◽

Author(s):

David Knopman

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Cortical Thickness ◽

Hippocampal Volume ◽

Csf Biomarkers ◽

Amyloid Pet ◽

Symptomatic Disease ◽

18F Fluorodeoxyglucose ◽

Β Amyloid ◽

Cortical Association Areas

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations. Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein

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Pathophysiology of Alzheimer Disease

10.2310/im.1335 ◽

2017 ◽

Author(s):

David Knopman

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Cortical Thickness ◽

Hippocampal Volume ◽

Csf Biomarkers ◽

Amyloid Pet ◽

Symptomatic Disease ◽

18F Fluorodeoxyglucose ◽

Β Amyloid ◽

Cortical Association Areas

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations. Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein

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Reduced coupling between cerebrospinal fluid flow and global brain activity is linked to Alzheimer disease–related pathology

PLoS Biology ◽

10.1371/journal.pbio.3001233 ◽

2021 ◽

Vol 19 (6) ◽

pp. e3001233

Author(s):

Feng Han ◽

Jing Chen ◽

Aaron Belkin-Rosen ◽

Yameng Gu ◽

Liying Luo ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Driving Forces ◽

Brain Activity ◽

Amyloid Β ◽

High Amplitude ◽

Tau Proteins ◽

Cerebrospinal Fluid Flow ◽

Metabolite Clearance ◽

Global Brain

The glymphatic system plays an important role in clearing the amyloid-β (Aβ) and tau proteins that are closely linked to Alzheimer disease (AD) pathology. Glymphatic clearance, as well as Aβ accumulation, is highly dependent on sleep, but the sleep-dependent driving forces behind cerebrospinal fluid (CSF) movements essential to the glymphatic flux remain largely unclear. Recent studies have reported that widespread, high-amplitude spontaneous brain activations in the drowsy state and during sleep, which are shown as large global signal peaks in resting-state functional magnetic resonance imaging (rsfMRI), are coupled with CSF movements, suggesting their potential link to glymphatic flux and metabolite clearance. By analyzing multimodal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) project, here we showed that the coupling between the global fMRI signal and CSF influx is correlated with AD-related pathology, including various risk factors for AD, the severity of AD-related diseases, the cortical Aβ level, and cognitive decline over a 2-year follow-up. These results provide critical initial evidence for involvement of sleep-dependent global brain activity, as well as the associated physiological modulations, in the clearance of AD-related brain waste.

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