The brain cognitive reserve hypothesis: A review with emphasis on the contribution of nuclear medicine neuroimaging techniques

Abstract

Neuropathological and clinical evidence indicates that the clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain reserve capacity. The brain or cognitive reserve (BCR) hypothesis states that high premorbid intelligence, education, and an active and stimulating lifestyle provide reserve capacity, which acts as a buffer against the cognitive deficits due to accumulating neuropathology. Neuroimaging studies that assessed the BCR hypothesis are critically reviewed with emphasis on study design and statistical analysis. Many studies were performed in the last two decades owing to the increasing availability of positron emission tomography (PET) and PET/computed tomography scanners and to the synthesis of new radiopharmaceuticals, including tracers for amyloid and tau proteins. Studies with different tracers provided complementary consistent results supporting the BCR hypothesis. Many studies were appropriately designed with a measure of reserve, a measure of brain anatomy/function/neuropathology, and a measure of cognitive functions that are necessary. Most of the early studies were performed with PET and [ 18F]fluorodeoxyglucose, and occasionally with [ 15O]water, reporting a significant association between higher occupation/education and lower glucose metabolism (blood flow) in associative temporo‐parietal cortex in patients with AD and also in patients with MCI, after correcting for the degree in the cognitive impairment. On the contrary, performances on several neuropsychological tests increased with increasing education for participants with elevated [ 11C]PiB uptake. Studies with the tracers specific for tau protein showed that patients with AD with elevated tau deposits had higher cognitive performances compared with patients with similar levels of tau deposits. BCR in AD is also associated with a preserved cholinergic function. The BCR hypothesis has been validated with methodologically sound study designs and sophisticated neuroimaging techniques using different radiotracers and providing an explanation for neuropathological and clinical observations on patients with AD.

Newly Generated and Non-Newly Generated “Immature” Neurons in the Mammalian Brain: A Possible Reservoir of Young Cells to Prevent Brain Aging and Disease?

“…All these data strongly indicate that protective/compensatory mechanisms could be responsible for resistance to neurological diseases/dementia or significant delay of the clinical symptoms. Despite fragmentary information due to obvious difficulties encountered in studying humans, it is clearly emerging that some individuals with Alzheimer disease-like neuropathology do not become symptomatic during their lifetime, and that it may require more pathology for the individuals with greater brain reserve to manifest clinical dementia [136,137,138,139]. Individuals that remain cognitively intact in spite of having accumulation of amyloid plaques and neurofibrillary tangles to an extent comparable to that normally observed in fully symptomatic Alzheimer’s disease (AD) are referred to as “non-demented with Alzheimer’s neuropathology” [138,140].…”

Hippocampal resting-state functional connectivity with the mPFC and DLPFC moderates and mediates the association between education level and memory function in subjective cognitive decline

“…A broad consensus to explain this is that individuals with HE level tend to have greater brain reserve or compensational ability. A highly educated person might be able to compensate for the neurodegeneration, therefore maintaining a normal memory or cognitive functional level for a longer time than less educated people [42].…”

Pathobiological Subtypes of Alzheimer Disease

“…HcSp-AD cases have been found to have the highest level of education, while MA-AD patients had the lowest, suggesting that high education may be one of the factors protecting the hippocampus and thus contributing to the fact that LP-AD may be unmasked and may contribute more to the clinical manifestation of the disease. The theory of cognitive reserve suggests that education is beneficial for the brain by forming more efficient and pathology-resistant networks; it may act as surrogate for or act in synergy with cognitive or social engagement [77, 78]. This suggests that people with higher reserve can cope with brain pathology better [79].…”