Current Challenges for the Early Detection of Alzheimer's Disease: Brain Imaging and CSF Studies

Abstract

The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to the subtle brain changes that occur in the preclinical stage of the disease. Reductions in the cerebral metabolic rate of glucose (CMRglc), a measure of neuronal function, have proven to be a promising tool in the early diagnosis of AD. In vivo brain 2-[18F]fluoro-2-Deoxy-D-glucose-positron emission tomography (FDG-PET) imaging demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. There is increasing evidence that hypometabolism appears during the preclinical stages of AD and can predict decline years before the onset of symptoms. This review will give an overview of FDG-PET results in individuals at risk for developing dementia, including: presymptomatic individuals carrying mutations responsible for early-onset familial AD; patients with Mild Cognitive Impairment (MCI), often a prodrome to late-onset sporadic AD; non-demented carriers of the Apolipoprotein E (ApoE) ε4 allele, a strong genetic risk factor for late-onset AD; cognitively normal subjects with a family history of AD; subjects with subjective memory complaints; and normal elderly followed longitudinally until they expressed the clinical symptoms and received post-mortem confirmation of AD. Finally, we will discuss the potential to combine different PET tracers and CSF markers of pathology to improve the early detection of AD.

Insulin/IGF Signaling-Related Gene Expression in the Brain of a Sporadic Alzheimer's Disease Monkey Model Induced by Intracerebroventricular Injection of Streptozotocin

“…In addition, cerebral glucose utilization and energy metabolism declined prior to the onset of symptoms [6,7]. Moreover, in brains of sAD patients, insulin resistance and strikingly reduced expression of insulin/insulin-like growth factor (IGF) signalingrelated genes were reported [8,9].…”

Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer’s Disease (sAD)-Like Pathology

“…Administration of STZ in a rodent's brain has been shown to produce neuroinflammation, oxidative stress, and biochemical alterations considered to be a valid experimental model of the early pathophysiological changes in neurodegenerative disease [6,7]. STZ-ICV also causes chronic loss and production of glucose in the brain and more importantly impaired glucose metabolism considered as a major feature of the early stages of sAD [8]. STZ-ICV leads to altered expression of both mRNA transcripts and proteins of insulin signaling pathway-related genes and AD-related genes such as APP, tau, and β-site APP cleaving enzyme 1 (BACE) in rodents and monkey brains [9,10].…”

Deficits in face perception in the amnestic form of mild cognitive impairment

“…As a result, approximately 80% of subjects with aMCI will have a diagnosis of AD after a period of 6 years [3]. Neuroimaging studies show structural [4][5][6][7] and functional features [8] in patients with aMCI that are intermediate between those of healthy subjects and AD patients, consistent with neuropathologic evidence of transitional pathologic findings [9,10]. Furthermore, magnetic resonance imaging studies have shown atrophy in not only medial temporal structures but also the inferior and lateral temporal lobes, the cingulate gyrus, and the parietal and frontal lobes, depending on the stage of disease [11][12][13][14].…”