Putative ante-mortem indicators of Alzheimer’s dementia: Analysis of fluid biomarker and neuroimaging studies

  • Author / Creator
    Malik, Manoj K
  • Dementia is a clinical state, characterized by symptoms indicative of deterioration of memoryand cognitive functions that interferes with social or occupational functioning. According to2018 statistics, around 50 million people are living with dementia, and this number will increaseto 131.5 million by the year 2050. Furthermore, the financial burden of dementia in the globaleconomy was around 1 trillion US$ in the year 2018. Among different forms ofneurodegenerative dementia, Alzheimer’s disease (AD) is the most common, accounting for upto 60-80% among all dementias. AD proceeds through a precursor stage, known as MildCognitive Impairment (MCI), between healthy ageing and full dementia. Subjects with MCI,however, may or may not progress to AD or related dementia. Contemporary diagnosis of AD isbased on clinical examinations and cognitive grading, but definitive diagnosis is currentlypossible only following autopsy or, rarely, biopsy. Despite massive investment in the search fortherapies of AD, all clinical trials of AD indicate a current lack of effective drug therapies for ADdementia. This may be due to excessive damage to brain prior to clinical symptom onset, or toinsufficient understanding with respect to diagnosis and disease progression. In addition,evidence in the literature has been inconsistent with the classification of AD patients fromnormal ageing, and the relationship between body fluid metabolite concentrations and severity ofAD dementia.This PhD investigation sought to synthesize evidence from the existing literature by usingsystematic review and meta-analysis procedures for additional knowledge contributing toimproved diagnosis, prognosis, and prediction of AD dementia. The investigation addressedthree questions (i) Is differential diagnosis of Alzheimer’s disease versus healthy ageing possiblebased on body fluid metabolites? (ii) Do concentrations of ante-mortem body fluid metabolites correlate with severity of Alzheimer’s disease dementia? (iii) Can we predict age at onset ofAlzheimer’s disease dementia from concentrations of body fluid metabolites? In addition, asystematic investigation of neuroimaging studies was carried out to assess the evidence forpossible neuroimaging-based differential diagnosis and prediction of AD dementia from healthyageing and other related dementia.In conclusion, this doctoral investigation found that the cerebrospinal fluid CSF amyloid beta(Aβ) (1-42), hyperphosphorylated tau (P-tau) and total tau (T-tau) protein concentrations weresignificantly different in AD patients’ than healthy controls. In addition, there are some otherbiofluid metabolites that are being extensively investigated as potential biomarkers for ADresearch. Furthermore, none of these biofluid metabolites have been found to be predictive forboth the severity of dementia and age at onset for AD. Some of the CSF biomarkers such as Aβoligomers, norepinephrine, and pyruvate concentrations demonstrate a significant predictiveinformation about AD dementia severity, but based on the small number of studies withrelatively small patient sample size, these findings may not be generalizable to the broader ADpatient population and further research is needed. In addition, this systematic investigation alsoindicates a large variation of methodology across studies, which needs to be considered in futureclinical research.

  • Subjects / Keywords
  • Graduation date
    Spring 2019
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
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