Tharick A Pascoal's research while affiliated with McGill University and other places

... Surprisingly, we did not observe this pattern; instead, tau-PET tended to be more strongly related to both upstream and downstream measures, compared to plasma p-tau217. A recent study showed that while p-tau217 related to amyloid-PET only in cognitively unimpaired participants, p-tau217 mostly correlated with tau-PET in symptomatic patients, potentially due to amyloid pathology reaching a plateau [33]. Yet, this explanation might not be sufficient to explain our findings as our sample included patients with a variability in amyloid levels (see next paragraph). ...

... 5,6 To measure p-tau217, a novel commercially available assay from ALZpath (ALZpathDX) was used. 43 All samples from the same participant were analyzed in the same analytical run, and each sample was quantified in duplicate. Internal quality controls (iQC) at three different concentrations, for each measurand, were analyzed in duplicate in the beginning and end of each run. ...

... Alzheimer's disease is characterized by a pathological cascade involving accumulation of aggregated proteins 24 , neurophysiological disruptions 25,26 , and neurodegeneration 27 , which together express as memory and cognitive impairment 28 (for a review, see Knopman et al., 2021 29 ). It is well known that aging and Alzheimer's disease is associated with neurophysiological changes such as neuronal hyperexcitability 25 , impaired excitatory-inhibitory balance 30 , and abnormal static functional connectivity between regions 31 and large-scale cortical networks 32,33 . ...

... Alzheimer's Disease (AD) is characterized by the progressive accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), with tau protein aggregates forming paired helical filaments (PHFs) and straight filaments (SFs) central to AD pathogenesis (1)(2)(3)(4)(5)(6). Positron emission tomography (PET) imaging with Aβ and tau ligands has enhanced diagnostic accuracy and understanding of AD progression (7). First-generation tau-PET ligands have enabled in vivo detection of tau tangles and have predictive capabilities for brain atrophy and cognitive decline in pre-symptomatic individuals (8)(9)(10)(11)(12)(13)(14). ...

... One of the key advantages of using RNA-Seq for comprehensive AD profiling is its ability to interrogate the entire transcriptome and assess the diagnostic potential of previously reported ADassociated genes. Reactive astrocytes have been associated with AD diagnosis and prognosis (47,48). ...

... Plasma NTA-tau was measured using an in-house assay, described in detail elsewhere (31,39). Brie y, the NTA assay targets soluble N-terminal tau fragments (phosphorylated and non-phosphorylated), and utilizes mouse monoclonal antibodies targeting amino acids (aa) 159-163 (HT7, #MN1000, ThermoScienti c, used as a capture antibody) and aa 6-18 (Tau12, BioLegend, used as detector ). ...

... p-tau217, have demonstrated the greatest potential to identify ADspecific processes, showing high accuracy for identifying neuropathological or biomarker-confirmed AD and predicting cognitive decline. [4][5][6][7][8] While p-tau231 may be more sensitive to incipient amyloid beta (Aβ) pathology, plasma p-tau217 seems the most well suited for clinical implementation, presenting the highest fold increases in cognitively impaired patients with AD-type pathology, and it can dynamically track longitudinal AD clinical progression. 4,6,7,[9][10][11] Plasma Aβ, in the form of the Aβ42/Aβ40 ratio, has also shown good performance in detecting Aβ pathology, but its modest fold change (reduced by 8% to 14% in AD compared to Aβ-negative controls, when in the CSF it is reduced by > 50%) 12,13 makes it more vulnerable to analytical fluctuations normally observed in a day-to-day clinical chemistry routine. ...

... These include the use of the ratio of the beta-amyloid peptides Aβ1-42/1-40, P-tau a marker of tau pathology, and neurofilament light (NfL), a biomarker of neuroaxonal damage [5,6]. There are also promising biomarkers of amyloid, tau and neurodegeneration in plasma [7] and they are in the process of being validated in real life populations, with plasma P-tau 217 looking particularly promising [8][9][10][11]. However, all these tests are expensive to perform, require invasive procedures, have to be pre-handled and centrifuged at source, and analyses performed in specialist laboratories. ...

... Unfortunately, the molecular causes of neuropathy are not fully understood. For example, Alzheimer disease (AD) is characterized by the presence of amyloid beta-containing plaques and tau-containing neurofibrillary tangles [2][3][4]. AD is an often hereditary, sporadic neuropathy responsible for amnestic cognitive deficits in the prototypical variant as well as nonamnestic cognitive deficits in other less-common forms. It causes acquired cognitive impairments in mid-to-late life, but its clinical impact on patients is modified by other cerebrovascular and neurodegenerative conditions [5,6]. ...

... Multiple recent studies propose that the presence of comorbidities may significantly influence the diagnostic performance of plasma Aβ42/40 [33][34][35]. These findings are of great importance, considering the high complexity of blood plasma as well as peripheral Aβ expression. ...