Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia

Abstract

Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E 4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether 4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20 -39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 4 heterozygotes, all with the 3͞ 4 genotype, and 15 noncarriers of the 4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult 4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middleaged 4 carriers, the young 4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.apolipoprotein E ͉ positron emission tomography ͉ glucose metabolism ͉ brain mapping ͉ surrogate markers A lzheimer's dementia (AD) afflicts Ϸ10% of those over the age of 65 and almost half of those over the age of 85 (1). To develop and test effective primary prevention therapies, it would be helpful to characterize brain changes associated with the susceptibility to AD as early as possible before the onset of cognitive impairment (2).Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with AD have abnormally low cerebral metabolic rates for glucose (CMRgl) in posterior cingulate, parietal, temporal, and prefrontal cortex and a progressive decline in these rates over time (3-8). We (2, 9, 10) and others (11, 12) have been using PET to detect and track these functional brain abnormalities before the onset of dementia in carriers of the apolipoprotein E (APOE) 4 allele, a common Alzheimer's susceptibility gene associated with up to half of cases of late-onset AD (13-15). Previously, we found that cognitively normal 50-to 65-year-old 4 carriers have abnormally low CMRgl in each of the same regions as patients with probable AD and abnormal rates of regional CMRgl decline over time (2, 9, 10). We now consider whether 4 carriers have these regional brain abnormalities as relatively young adults, several decades before the possible onset of dementia. Our a...

Image-Derived Input Function for Brain PET Studies: Many Challenges and Few Opportunities

“…Nevertheless, these investigations did not prompt widespread adoption of IDIF and, indeed, the number of clinical research protocols using IDIF as a tool to reduce invasiveness in patients is very limited. Chen et al used their IDIF method for [ 18 F]-FDG (Chen et al, 1998) to measure cerebral metabolic rate for glucose in young adults at genetic risk for late-onset Alzheimer's dementia (Reiman et al, 2004), to differentiate healthy subjects from Alzheimer's patients (Chen et al, 2006), and to evaluate healthy adults reporting dream-enactment behaviors (Caselli et al, 2006). Schiepers et al used an IDIF method based on factor analysis to study patients with brain tumors using [ 18 F]-fluorothymidine (Schiepers et al, 2007b) and [ 18 F]-FDOPA (Fueger et al, 2010;Schiepers et al, 2007a).…”

Ketone Bodies as a Therapeutic for Alzheimer's Disease

“…14 The regional reductions in CMRglc in AD may be due to reduction in the density or activity of terminal neuronal fields or glial cells, a metabolic defect within neurons or glia, or a combination of these factors. In a series of experiments, Reiman et al 15 examined the onset of hypometabolism in nondemented subjects at risk for AD. In an early study, Reiman et al 12 screened subjects between the ages of 50 and 65 years of age with a family history of AD for those who were homozygous for the E4 allele, and therefore at high risk of developing AD.…”

“…The homozygotes and controls did not differ in any cognitive test, yet the E4/E4 homozygotes showed declines in glucose metabolism in the same regions identified in AD subjects. 12 In a follow-up study examining young adults, 15 12 E4 carriers (E4/E3) were compared with 15 E4 noncarriers. Similar to the previous study, E4 carriers (E4(ϩ)) were found to have low CMRglc bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex, despite showing no signs of cognitive impairment.…”

“…The authors conclude that "Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before possible onset of dementia." 15 Therefore, low regional CMRglc appears to be a very early event in the disease process, well before any clinical signs of dementia are evident, and well before cell loss or plaque deposition is predicted to have occurred (FIG. 1).…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…In vitro and in vivo preclinical AD models indicate that deficits in mitochondrial function, metabolic enzyme expression and activity, cerebral glucose metabolism, and free radical scavenging are coupled with mitochondrial Aβ load and Aβ-binding alcohol dehydrogenase (ABAD) expression [12,13,24,25]. Importantly, clinical studies indicate that mitochondrial deficits observed in preclinical models are evident in human-derived platelets [14,15,[26][27][28][29]. The antecedent decline in mitochondrial function and brain metabolism indicates an early and potentially causal role in AD pathogenesis.…”