Neuroimaging PET and Functional MRI Poised to Catch Early Alzheimer’s Disease

Neuroimaging has come a long way over the last twenty years with exciting and innovative implications for patients living with Alzheimer’s dementia and the clinicians tasked with their diagnosis and treatment.  In the past neuroimaging was utilized to rule out organic or structural causes of dementia rather than to specifically diagnose Alzheimer’s disease or track its progression and prognosis.1 More recently imaging modalities such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are being used to find structural changes and protein signatures in the brain that allow researchers and clinicians to diagnose dementia in the preclinical phase and even make predictions about disease progression and prognosis.2  

Alzheimer’s disease and subcortical vascular dementia are leading causes of cognitive decline in the later years of life.2 Key features of Alzheimer’s disease include variable term memory loss and the presence of Beta-amyloid plaques and neurofibrillary tau tangles while subcortical vascular dementia is characterized by frontal executive cognitive dysfunction and extensive cerebrovascular disease.3 It is not uncommon for Beta-amyloid plaque deposition to coexist with cerebrovascular disease with both independently contributing to brain structural degradation and cognitive decline.2

Modern imaging techniques such as functional MRI (fMRI) have emerged as a promising tool for understanding disease-related changes in brain functional networks demonstrating differential effects of Alzheimer’s disease and cerebrovascular disease pathologies on intrinsic functional connectivity in affected brains.2 For instance, studies have shown that increased beta-amyloid burden is associated with reduced whole-brain functional connectivity.4 fMRI has been instrumental in the discovery of functional connectivity within the brain. Functional connectivity describes the idea that different parts of the brain communicate with each other during periods of activity and inactivity.5 Researches have described resting and active modes associated with functional areas of the brain such as the default mode network associated with resting and the executive control network which deals with making decisions and taking action.5

While Alzheimer’s disease primarily affects memory, cerebrovascular disease is associated with disruptions in the frontoparietal executive control network leading to difficulty planning, paying attention, and initiating tasks. To date little research has focused on functional connectivity changes in patients with coexisting Alzheimer’s disease and cerebrovascular disease. Chong et al. designed and conducted a study aimed at determining if patients with and without beta-amyloid burden and cerebrovascular disease would display divergent functional connectivity changes over time.2 In their study fMRI and Pittsburg Compound B PET (PiB-PET) scanning modalities were used to detect vascular lesions and beta-amyloid respectively with patients being followed for four years after baseline examination.2

As expected, Chong et al. found that patients with both cerebrovascular disease and high beta-amyloid burden showed a steeper longitudinal decline compared to patients with cerebrovascular disease alone.2 Further, the results showed that Alzheimer’s was specifically associated with declines in default mode network functional connectivity compared to disruptions in the executive control network found in patients with primarily cerebrovascular disease.2 Cutting edge MRI combined with PET imaging technologies were instrumental in facilitating this head to head comparison.

These findings by Chong et al. support the use of advanced imaging for determining the potential course of disease in patients with mild cognitive decline later in life. We are getting closer to being able to screen for preclinical signs predicting Alzheimer’s disease offering the opportunity to intervene earlier with the goal of postponement or even prevention as treatment strategies evolve. In a recent study by Mattsson et al. it was found that optimized tau PET classifiers may diagnose Alzheimer’s disease with high accuracy and both tau PET and structural brain MRI can capture partly unique information relevant for the clinical deterioration in Alzheimer’s disease.6

The ultimate goal of advanced imaging technologies in dementia and Alzheimer’s disease is to search for and discover imaging markers that can be used as outcomes in clinical trials leading to an ability to slow, delay or prevent cognitive decline.1 Other advances are on the horizon with diffusion tensor imaging (DTI) and associated tractography MRI technologies allowing for arterial spin measures of cerebral blood flow along with PET tracers and ligands targeting the elusive neurofibrillary tangles found as biomarkers in Alzheimer’s disease.1

When considering a disease that only becomes apparent late in life it may be necessary to intervene at very early stages even when no symptoms exist. If successful, imaging as a biomarker could provide the key to developing disease-modifying or even disease preventing strategies.

There is still more work to be done. While advanced imaging is emerging as an early diagnostic tool in Alzheimer’s disease and vascular dementia, its primary focus at this time is to direct ongoing research in the hopes of improving the quality of life for patients and families living with progressive cognitive decline.