Glucose metabolism in normal aging and Alzheimer’s disease: methodological and physiological considerations for PET studies
0
L. Mosconi (&) Department of Psychiatry, Center for Brain Health, NYU School of Medicine
, 145 East 32nd Street, 2nd floor,
New York, NY 10016, USA
Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder associated with progressive loss of cognitive function. 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) has long been used to measure resting-state cerebral metabolic rates of glucose, a proxy for neuronal activity. Several FDG PET studies have shown that metabolic reductions occur decades before onset of AD symptoms, suggesting that metabolic deficits may be an upstream event in at least some late-onset AD cases. This review explores this possibility, initially discussing the link between AD pathology, neurodegeneration, oxidative stress, and AD, and then discussing findings of FDG PET hypometabolism in AD patients as well as in at-risk individuals, especially those with a first-degree family history of late-onset AD. While the rare early-onset form of AD is due to autosomal dominant genetic mutations, the etiology and pathophysiology of age-dependent, late-onset AD is more complex. Recent FDG PET studies have shown that adult children of AD-affected mothers are more likely than those with AD-fathers to show AD-like brain changes. Given the connection between glucose metabolism and mitochondria, and the fact that mitochondrial DNA is maternally inherited in humans, it is here argued that altered bioenergetics may be an upstream event in those with a maternal history of late-onset AD. Biomarkers of AD have great potential for identifying AD endophenotypes in at-risk individuals, which may help direct investigation of potential susceptibility genes.
-
Alzheimers disease (AD), the leading cause of dementia in
the elderly, is a neurodegenerative disorder characterized
by an insidious onset and progressive declines in memory,
attention, and language. At present, AD affects
approximately 10 % of individuals 65 years of age, with the
prevalence doubling every 5 years up to age 80, above
which the prevalence exceeds 40 % [1].
Longitudinal studies of normal individuals who go on to
develop AD show that there is a somewhat abrupt
transition in cognitive symptom decline between the preclinical
stage and the early stage of AD. Gradual cognitive decline
in the preclinical stage reaches an inflection point that
gives way to a comparatively steep loss of cognitive
abilities, which is the hallmark of clinical AD. Typically, the
relatively rapid loss of cognitive abilities is what leads
family members or caregivers to bring patients in for
evaluation. By the time patients come in for diagnosis, too
much irreversible brain damage may already have occurred
for any treatments to be effective. Interventions, once
developed, ideally would be implemented long before
symptoms occur. While risk factors such as apolipoprotein
E (ApoE) e4 genotype and family history have been
identified, their predictive value remains to be established,
and their presence may not be enough to justify the
potential risks of medical interventions (as they become
available) in non-symptomatic individuals. Therefore,
another major goal in AD research is the identification of
diagnostic markers, especially for the preclinical stages of
disease when symptoms are not yet clinically relevant, such
as in at-risk individuals.
Currently, a definite diagnosis of AD can only be made
by neuropathology, which is regarded as the gold standard,
and is based on post-mortem detection of specific
pathological lesions: amyloid-beta (A) plaques in the
extracellular space and blood vessels, intracellular
neurofibrillary tangles (NFT), and neuronal and synaptic
loss in specific brain regions [24]. Changes in brain
histopathology, and consequently in brain structure and
function, are known to precede the signs and symptoms of
the disease by many years. AD pathology and associated
neurodegeneration are estimated to begin 2030 years
before any clinical manifestations of the disease become
evident [24]. Neurodegeneration is the umbrella term for
the progressive loss of structure or function of neurons,
including death of neurons. Many neurodegenerative
diseases, including AD, occur as a result of neurodegenerative
processes. Plaques and tangles have long been considered
upstream events in AD, leading to subsequent
neurodegeneration and neuronal apoptosis. According to a popular
theoretical model in AD, the amyloid cascade
hypothesis, Ab plaques increase during the preclinical phase of
AD, causing synapse loss and neuronal death [5]. However,
other mechanisms such as oxidative stress are known to
boost neurodegeneration, and may precede and promote A
plaque deposition [6], thus having as strong an impact as
pathological lesions. The central role for A in AD is
strongly supported by studies of the rare early-onset
(\60 years) forms of familial AD, which are caused by
mutations in the amyloid precursor protein (APP),
presenilin 1 an (...truncated)