Alzheimer’s disease (AD) is a chronic progressive disease of aging with memory impairment at its core. In 2011, the National Institute on Aging (NIA) and the AD Association (AA) recommended new diagnostic criteria for AD, which clearly suggest that AD is a continuous process, including the pre-dementia stage and the dementia stage. The pre-dementia stage is divided into the mild cognitive impairment (MCI) stage and the pre-mild cognitive impairment (pre-MCI) stage. The study of biomarkers in MCI and pre-MCI stages will help in the pre-dementia diagnosis of AD and provide an important basis for further prevention and treatment.
The main pathophysiological changes in AD are amyloid deposition and neurodegeneration. Markers reflecting amyloid deposition are mainly positron emission tomography (PET) amyloid imaging and body fluid [beta amyloid (Aβ)42/Aβ40 concentrations in cerebrospinal fluid and blood; markers reflecting neurodegeneration include reduced brain function [manifested by reduced 18 fluoro-fluorodeoxyglucose (18F- FDG) uptake and functional MRI showing resting network connectivity], brain atrophy on T1 structural MRI, and increased total and phosphorylated tau (p-tau) concentrations in CSF.
Recently, Professor Jack proposed the hypothesis of a dynamic biomarker waterfall in AD, suggesting that both amyloid pathology and neurodegeneration occur before the onset of clinical symptoms in AD, and that amyloid pathology is the earliest event causing neurodegeneration in AD leading to dementia, and that the order of neurodegenerative pathology is reduced brain function, tau hyperphosphorylation and synaptic and cellular deficits. This hypothesis postulates that there are specific markers that reflect the pathophysiological features of each clinical stage of AD, including the pre-MCI, MCI and dementia stages.
The cerebrospinal fluid (CSF) is considered an ideal source of biomarkers because of its direct contact with brain tissue, its ability to directly reflect pathological changes in brain tissue (Aβ reflects brain amyloid deposition and tau reflects neurodegeneration), and the low cost of the test. CSF can be used not only as a diagnostic marker in AD dementia, but the characteristic CSF changes in AD (decreased Aβ42 and increased tau protein) can also be used to predict the transition to MCI. Studies have shown that MCI patients who will convert to dementia in the future have CSF Aβ42 and tau changes at baseline similar to those in AD dementia, whereas MCI patients who do not convert to dementia have CSF similar to healthy controls. Several studies have also explored whether these markers could be used to detect patients in the pre-MCI phase of AD. Results from two population-based studies showed a decrease in CSF Aβ42 in cognitively normal older adults who converted to AD, but no significant changes in total tau and p-tau, suggesting that amyloid pathological changes precede pathological changes in tau. A study of familial AD showed that familial AD gene carriers showed significant decreases in CSF Aβ42 and increases in total tau and p-tau 15-20 years before the onset of clinical symptoms (i.e., pre-MCI phase), suggesting that the same CSF changes as in AD dementia exist in the pre-clinical phase of AD and that CSF could potentially be used as a biomarker for the pre-MCI phase.
Peripheral blood Blood is an ideal specimen for the clinical search for early AD diagnostic markers because it is easy to obtain and detect. Studies have shown that blood-derived markers can be used to improve the diagnostic accuracy of MCI and dementia and to predict and monitor the regression of MCI. As Aβ is believed to play a key role in the pathogenesis of AD, blood Aβ has become a more intensively studied biomarker in recent years. Several studies have shown that plasma Aβ42 is significantly elevated in AD patients and that plasma Aβ42 levels are increased in MCI patients compared to age-matched normal controls, but plasma Aβ42 has not been widely accepted as a stable biomarker.
Advances in Impact Marker Research Amyloid PET Several studies have confirmed that amyloid deposition is the earliest pathologic change in AD, but the relationship between the extent of amyloid deposition and changes in AD progression is unclear.PET amyloid imaging is the most direct method to measure amyloid deposition in the living brain, and Pittsburgh complex B (PIB) was the first amyloid PET reagent. Compared to the amyloid marker 11C-PIB, which has a half-life of only half an hour, 18F-AV-45 has the advantage of a long half-life (up to 2.5 hours) and is suitable for multicenter studies, and this marker has been used in neuroimaging risk factor (ADNI) studies in the United States and Canada. The extent of amyloid deposition in the brain.
A study of 18F-AV-45PET in patients with MCI showed that amyloid deposition was already evident in patients with early MCI and that brain amyloid deposition peaked in late MCI (i.e., plateau phase). Small sample case studies have shown that intracerebral amyloid deposition is already present in familial AD during the asymptomatic phase (i.e., pre-MCI phase) even before brain atrophy and cerebral hypometabolism, suggesting that PET amyloid imaging may have some diagnostic value for pre- MCI and may be the earliest biomarker to appear. Long-term amyloid imaging PET follow-up studies in non-demented older adults have shown that amyloid deposition can occur in cognitively normal older adults and increases progressively with age. Based on the amyloid cascade waterfall theory, amyloid deposition labeled with 18F-AV-45 is expected to be an early biomarker for the diagnosis of pre-MCI.
Glucose metabolism PET Changes in synaptic function in AD patients can be examined and evaluated by 18F-FDG PET. 18F-FDG PET has been used clinically in the diagnosis and differential diagnosis of the dementia stage of AD, where patients with dementia may have reduced glucose metabolism in the temporoparietal and superior/posterior temporal regions, posterior cingulate cortex and precuneus; preliminary studies have shown that patients in the pre-MCI stage may have brain glucose metabolism decreases, but some studies have also shown that brain glucose metabolism rates do not decrease significantly until the MCI stage.
Structural MRI Structural MRI can detect regional or whole brain atrophy due to axonal degeneration, synapses, and cell death. Hippocampal and medial temporal lobe volumes are classic measures, and it is generally accepted that atrophy of medial temporal lobe structures, such as the hippocampus and internal olfactory cortex, occurs prior to the onset of dementia symptoms, i.e., the MCI phase. Recent studies have shown that cortical thickness thinning and whole brain volume reduction can occur in MCI patients and that these two indicators are also used to predict whether MCI will progress to dementia. Although most researchers believe that structural brain abnormalities tend to follow brain amyloid deposits and functional brain abnormalities, a similar study in 2012 showed that cortical atrophy characteristic of AD can occur in patients with familial AD up to 5 years before the onset of clinical symptoms. In addition to cortical atrophy, two different studies from Lee (USA) and Ryan (UK) in 2013 yielded consistent results that asymptomatic carriers of familial AD mutations showed atrophy of the subcortical nuclei, with volume loss in the hypothalamus, nucleus accumbens and caudate nucleus.
Functional magnetic resonance Resting-state functional magnetic resonance (fMRI) is a new technique that has emerged in recent years to study brain function. Several resting-state fMRI studies have confirmed the presence of reduced functional connectivity in the resting-state default network, attention network, and executive function network in patients with AD dementia stage. A study of the executive control network in amnestic MCI showed that patients with amnestic MCI can show not only a decline in functional brain connectivity, but also an enhancement of functional connectivity in some brain regions, suggesting the coexistence of impairment (decline) and compensation (enhancement) of functional connectivity during the MCI phase. Recently, several different studies have shown that older adults with amyloid deposits but normal cognitive function already have memory-related decreases in resting-state network connectivity, and even cognitively normal older adults carrying the apolipoprotein (APOE) ε4 gene may show altered resting-state functional network connectivity even in the absence of amyloid deposits. These findings suggest that brain dysfunction may occur in the pre-MCI stage and that resting-state fMRI may be an early biomarker for the diagnosis of pre-MCI.
In summary, biomarkers of AD are currently a hot topic in AD research, and biomarkers have clinical significance in the diagnosis of AD (especially in MCI and pre-MCI). imaging; the second is biomarkers of neuronal damage, including elevated cerebrospinal fluid tau protein, FDGPET showing decreased temporoparietal cortical glucose metabolism and structural MRI showing basal, medial or lateral temporal lobe atrophy and medial parietal cortical atrophy.