The molecular basis for degenerative dementia

Biomarkers for AD can be categorized into two broad categories:

• 1. Markers of amyloid-beta accumulation

     • CSF assays of amyloid beta1-42

       • AD is associated with a decrease in CSF amyloid-beta1-42 that is generally thought to represent evidence of that amyloid-beta is polymerizing and depositing as fibrillar plaques

     • PET amyloid

       • PET imaging of amyloid-beta utilizes derivatives of histopathological stains such as thioflavins, that bind to fibrillar forms of amyloid-beta

       • Amyloid-PET is = demonstration of amyloid plaque pathology at autopsy

       • A negative amyloid PET equates to no amyloid deposits and that the likelihood of cognitive impairment due to AD is low.

  2. Markers of neuronal injury or neurodegeneration

     • Molecular markers

       • Elevated CSF phosphorylated (P) tau and total tau

     • Imaging markers of synaptic dysfunction

       • FDG-PET measures glucose metabolism in brain. The characteristic pattern of FDG-PET abnormalities associated in AD is bilateral temporoparietal hypo-metabolism. Frontal hypometabolism is also reported in later stages of AD.

       • fMRI can assess brain function during cognitive tasks, does not need contrast or radioactive substance. fMRI during the resting state, sometimes referred to as "task-free" fMRI using blood oxygen level-dependent (BOLD) imaging. Correlation between activity within neural networks is assessed.

       • Fc-MRI (functional connectivity MRI)

       • ASL-MRI (Arterial spin labeling MRI)

     • Imaging markers of neuronal loss and atrophy

       • Volumetric MRI measures AD characteristics atrophy in the medial temporal lobe structures (including the hippocampus and entorhinal cortex), and by cortical thinning of the heteromodal cortices including posterior cingulate, precuneus, lateral parietal, temporal, and frontal regions. Visual variants in AD demonstrate posterior cortical atrophy and those with prominent language deficits demonstrate left temporal atrophy.

The most important concept to recognize in considering the high image-to-pathology correlation is that amyloid positivity does not reliable distinguish clinical diagnosis, so that neurological normal people as well as those with MCI, AD dementia, and other neurodegenerative diseases including DLB can all be "amyloid positive."

It is important to note that both CSF and PET amyloid imaging markers are thought to reflect amyloid accumulation in fibrillar forms and may not reveal other forms of A-beta, such as smaller soluble species of so-called oligomeric species of A-beta that some believe represent the toxic forms of A-beta.

Default network implicated in memory and other complex cognitive processes include precuneus, posterior cingulate, inferior parietal, lateral temporal, and superior frontal cortices, which are particularly vulnerable to amyloid deposition. The earliest and most heavily affected brain regions are the middle frontal gyri (part of the cognitive control network) and parietal precuneus/posterior cingulate regions which are considered the key node regions of the default-mode network.