Alzheimer: Phosphorylation of Tau proteins leads to disintegration of microtubuli in a neuron axon
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Different brain diseases feature different blood levels of certain biomarkers, according to a new study in Journal of Neurology, Neurosurgery, and Psychiatry. This could be a major step forward for diagnosis, treatment, and trials, which all current depend on clinical diagnosis, positron emission tomography, and cerebrospinal fluid analysis. The lead author of the study was Leonidas Chouliaras, of the University of Cambridge in England.

Many neurologic plasma biomarkers are being studied, particularly in Alzheimer’s, which is the most common of these conditions. But, “Head-to-head comparisons, across multiple dementias and over time, are required to assess their potential for differential diagnosis and trials monitoring,” the authors write.

The team measured plasma biomarkers in 63 people with amyloid-positive mild cognitive impairment (MCI)and Alzheimer’s disease(AD), 117 people with Lewy body dementia (LBD), 28 people with frontotemporal dementia (FTD), 19 people with progressive supranuclear palsy (PSP), and 73 dementia-free controls.

The patients all had clinical exams with cognitive and neuropsychiatric assessments at baseline, which were repeated annually for up to three years. Plasma biomarkers were measured using single molecule immunoassays.

Among these 300 adults, neurofilament light (NfL) was elevated in all people with dementias compared with controls. In addition: P-tau181 was elevated in MCI and AD compared with all other groups. Aβ42/40 was lower in MCI and AD compared with controls and FTD. GFAP was elevated in MCI and AD and LBD.  These plasma biomarkers could be used to classify between MCI and AD and controls, FTD ,and PSP with high accuracy but showed limited ability in differentiating MCI and AD from LBD.

No differences were detected in the levels of plasma biomarkers when comparing PET-Aβ positive and negative LBD. P-tau181, NfL and GFAP were associated with baseline and longitudinal cognitive decline in a disease specific pattern.

The best diagnostic accuracy was achieved in distinguishing Alzheimer’s from frontotemporal dementia. None of the biomarkers could discriminate Alzheimer’s from Lewy body dementia.

“After the first discovery of cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease and its long analytical validation process, a new matrix (blood) for old and novel candidate markers is changing the way we approach biomarkers in neurological diseases,” wrote Lucilla Parnetti, of the University of Perugia in Italy, and co-authors in an accompanying editorial.

Blood Aβ42/Aβ40 and p-tau181 reflect amyloidosis and tauopathy in Alzheimer’s disease with reliability similar to that of cerebrospinal fluid (CSF), Parnetti and colleagues noted.  “Also, ongoing neurodegeneration and neuroinflammation can be efficiently quantified by blood NfL and GFAP, respectively.”

In this study, age was associated with p-tau181, NfL, and GFAP levels, but not Αβ42/40. Sex was not associated with significant differences in biomarker levels. Baseline mean ages ranged from 64.5 in the frontotemporal dementia group to 75.6 in people with Lewy body dementia.

When PET amyloid-positive and amyloid-negative cases of Lewy body dementia were compared, no differences in p-tau181, Αβ42/40, NfL, or GFAP plasma levels were seen. This contrasts to another study that found p-tau181 could identify AD co-pathology in LBD. But that study used CSF Aβ42/40 and PET tau instead of PET amyloid, Chouliaras and co-authors note.

The researchers acknowledged several limitations to the study. For example it did not include CSF, PET, or postmortem confirmation of diagnosis for all participants. There may have also been mixed or alternative pathologies among the participants.

Nonetheless, this represents more promise for better diagnosis and management of neurological diseases.

“The non-invasiveness of blood sampling is the main benefit of plasma over CSF, which makes blood-based biomarkers easily repeatable along time as outcome measure for disease-modifying treatments,” Parnetti and colleagues wrote..

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