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Course
Dementia is the most common type of neurodegenerative disease, with Alzheimer Disease (AD) constituting about two-thirds of these cases. It is an intricate condition with definite pathological findings and various clinical presentations. Its neuropathologic features are defined by amyloid-beta (Aβ) plaques and neurofibrillary tangles with aggregated tau proteins, causing neuroinflammation, reactive astrogliosis, and gradual synapse and neuronal loss with transmitter deficiencies, leading to slow and progressive cognitive impairment. Although an amnestic syndrome with insidious onset and gradual progression is the typical clinical phenotype of AD, an important proportion of cases with AD pathology present with non-amnestic cognitive disorders. Logopenic variant of primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), corticobasal syndrome (CBS), and behavioral or dysexecutive variants of frontal AD are atypical clinical presentations of AD pathology. Additionally, AD neuropathological cascades start years before the apparent beginning of the clinical symptoms of the disease and spread in a consistent pattern with subsequent neuroanatomical and neurophysiological changes. Therefore, clinical findings of AD are in a continuum but remain heterogeneous from cognitively unimpaired through mild cognitive impairment (MCI) to severe dementia. MCI is often considered a prodromal stage of AD, and patients with amnestic MCI progress to probable AD at a rate of ∼10–15% per year, while 11%–33% of them develop it within the first 2 years. However, over 50% of patients with MCI remain stable when some may improve in follow-up evaluations. Thus, accurate diagnosis and the prediction of the development of AD in its prodromal phase, particularly within 1 to 2 years of MCI onset, can help treat early and minimize the progression of the disease. This is particularly important with recent clinical trials demonstrating potential disease modifying effect of anti-amyloid therapies. Moreover, AD pathology can frequently co-occur with other neurodegenerative and vascular diseases; therefore, accurate timely differential diagnosis is critical for appropriate care and precise treatment strategies.
Understanding the role of biomarkers in the early diagnosis of AD appears imperative. Pathophysiologic and topographical biomarkers have significantly improved the diagnosis of typical and atypical phenotypes of AD, helping clinicians recognize and differentiate AD phenotypes from other types of dementia and neurodegenerative diseases. Pathophysiologic biomarkers, including amyloid PET, and fluid biomarkers such as CSF concentrations of Aβ, tau proteins, and NfL, along with plasma concentrations of Aβ, tau, and NfL, play a crucial role in this diagnostic enhancement. Topographic biomarkers, such as fluorodeoxyglucose (FDG)-PET, amyloid and tau PET, and MRI, assess the regional involvement of AD pathology. The CSF Aβ42/Aβ40 ratio measurement is a robust biomarker in detecting cerebral Aβ pathology and AD diagnosis. A noticeable feature of the Aβ42/Aβ40 ratio is that their levels are altered in the preclinical stages of AD. They can identify Aβ pathology with high accuracy in both individuals with unimpaired cognition and patients with MCI.
Recent studies have shown that plasma pTau217 and pTau181 can differentiate AD from other forms of dementia and tauopathies; and another recent study demonstrated that the diagnostic performance of pTau217 is similar to that of both CSF biomarkers and tau-PET imaging. In several clinical and analytical validations, we showed that plasma pTau217 (AUC 0.92 to 0.93) exhibited enhanced clinical performance compared to pTau181 (AUC 0.81) for diagnosing AD. Notably, plasma pTau217 begins to change earlier than other pTau variants, serving as a useful predictive tool for diagnosing AD in its preclinical stages. Regarding T-tau concentrations, which reflect the extension and intensity of neuronal degeneration and brain damage in AD, CSF T-tau concentrations increase, correlating with lower MMSE scores and rapid cognitive decline. The ratio of plasma T-tau to plasma Aβ42 improves diagnostic utility, associated with longitudinal changes in cerebral Aβ deposition and predicting tau deposition in the brain. This ratio proves to be a strong predictive biomarker of longitudinal neurodegeneration in AD. Elevated Nfl levels in AD patients' CSF, plasma, and serum have also been documented. Interestingly, in individuals carrying a familial AD mutation, changes in Nfl concentrations in the blood precede clinical symptoms, suggesting its potential for indicating the initiation of neurodegeneration and correlating with disease progression, especially rapid clinical deterioration.
In summary, fluid biomarkers help differentiate AD from other neurodegenerative dementias, and identify AD in the earliest stages when disease modifying therapies have the biggest potential benefit. In this course, we will discuss the phenotypic presentation and diagnosis of the AD spectrum, along with its differential diagnosis, using clinical examples and biomarkers for the early and precise diagnosis of both typical and atypical AD. We describe how this approach can support clinical decision-making and improve patient care and management, especially when disease modifying therapy for AD is on the horizon.
Speaker: Ging-Yuek Robin Hsiung, MD, MHSc, FRCPC, FACP, FAAN – Division of Neurology, University of British Columbia
Speaker: Hans Frykman, MD PhD FRCPC – Division of Neurology, University of British Columbia
Speaker: Hans Frykman, MD PhD FRCPC – Division of Neurology, University of British Columbia
Speaker: Ging-Yuek Robin Hsiung, MD, MHSc, FRCPC, FACP, FAAN – Division of Neurology, University of British Columbia
Speaker: Hans Frykman, MD PhD FRCPC – Division of Neurology, University of British Columbia
Speaker: Ging-Yuek Robin Hsiung, MD, MHSc, FRCPC, FACP, FAAN – Division of Neurology, University of British Columbia
