Abstract of online articleStructural brain changes in normal individuals with a maternal history of Alzheimer's
Introduction
Alzheimer's disease (AD) is the most common cause of dementia in the elderly population, affecting millions of people worldwide (Hebert et al., 2004). Once disease-modifying drugs become available, reliable diagnosis of AD at its earliest stages is increasingly important, because treatment effects may be most beneficial before the pathological progress is well advanced. To accomplish this goal, it is necessary to identify at-risk individuals, and to develop biological markers that predict and correlate with clinical change, in order to track disease progression and monitor treatment effects.
While genetic mutations have been identified in the early-onset familial forms of AD, the genetic mechanisms involved in the more common late-onset AD (LOAD) remain largely unknown. Several studies have shown that having a family history of LOAD is a major risk factor for developing the disease among cognitively normal (NL) individuals (Farrer et al., 1997). The risk for developing LOAD is 4- to 10-fold higher in first degree relatives of LOAD patients, and is highest in children of parents affected by LOAD (Cupples et al., 2004, Green et al., 2002, Silverman et al., 2005). Epidemiological studies have shown both maternal (Edland et al., 1996) and paternal transmission of LOAD (Ehrenkrantz et al., 1999). However, having an AD-affected mother appears to confer greater risk to the offspring than having an AD-affected father, was associated with poorer cognitive performance in late life and with a more predictable age at onset of dementia (Debette et al., 2009, Duara et al., 1993; Edland et al., 1996, Gomez-Tortosa et al., 2007, Locke et al., 1995).
We and others have been using brain imaging to provide biological endophenotypes related to maternally and paternally transmitted risk of LOAD in NL individuals. Using [18F] fluorodeoxyglucose positron emission tomography (FDG-PET), we demonstrated that NL with a maternal family history of LOAD (FHm) show progressive reductions in cerebral metabolic rates of glucose (CMRglc) in AD-vulnerable regions compared with NL with a paternal history (FHp) and to NL with negative family history (FH−) (Mosconi et al., 2007, Mosconi et al., 2009). In contrast, NL FHp showed no metabolic abnormalities (Mosconi et al., 2007, Mosconi et al., 2009). Additionally, a recent cross-sectional magnetic resonance imaging (MRI) study showed reduced gray matter volumes, an indicator of brain atrophy, in NL with a family history of LOAD compared with controls, with the reductions being more severe in FHm than in FHp (Honea et al., 2010). However, this study was based on retrospective examination of existing MRI scans, which resulted in relatively small and uneven groups, and subjects were fairly old, with a mean age of 74 years (Honea et al., 2010). Additionally, the ApoE-4 genotype was found in over 60% FHm while a minority of FHp and FH− were ApoE-4 carriers. Because ApoE-4 genotype is a major risk factor for LOAD, and is associated with increased atrophy (Chen et al., 2007), it remains unclear whether gray matter volume (GMV) reductions in FHm were due to the relatively high proportion of ApoE-4 carriers or more specifically to maternal history of LOAD.
The present MRI study used voxel-based morphometry to map regional gray matter volume reductions in a cohort of 60 NL individuals (mean age 63 years, 30% ApoE-4 carriers), divided into 3 size-matched, demographically balanced groups based on their family history of LOAD. We examined whether late-middle-aged NL with LOAD parents, particularly FHm, showed reduced gray matter volumes several years before the possible onset of dementia.
Section snippets
Subjects
We examined 60 clinically and cognitively normal (NL) subjects, divided into 3 size-matched, demographically balanced groups of 20 subjects each, based on their parental family history of LOAD (see below). All subjects were prospectively recruited at New York University School of Medicine to participate in ongoing longitudinal brain MRI studies. These included individuals interested in research participation and risk consultation, spouses, family members, and caregivers of patients
Subjects' characteristics
Demographic and neuropsychological measures of the subjects are shown in Table 1. There were no differences across FH groups for age, gender, education, ApoE status, MMSE scores and neuropsychological test performance (Table 1).
Voxel-based morphometry
After correcting for TIV, as compared with FH− subjects, FH+ subjects showed significantly decreased GMV in middle and inferior frontal gyri of the right hemisphere, and in inferior parietal lobule of the left hemisphere (p < 0.05, FWE-corrected) (Table 2). No regions
Discussion
The present VBM MRI study shows GMV reductions in AD-vulnerable regions of adult children of parents affected with LOAD, which were related to the affected parent's gender. Specifically, NL FHm showed reduced GMV in AD-vulnerable brain regions as compared with FH− and FHp subjects of similar demographic characteristics. Specifically, NL FHm showed reduced GMV in the precuneus compared with both FH− and FHp groups, and additional regional GMV reductions in frontal and parieto-temporal cortices
Disclosure statement
Drs. Berti, Murray, Pupi, and Tsui have no actual or potential conflicts of interest. Drs. Mosconi, Li, and de Leon have received compensation for consulting services from Abiant Imaging Inc. Dr. Glodzik is PI on an investigator-initiated clinical trial supported by Forrest Labs. Dr. de Leon has received honoraria from the French Alzheimer's Foundation, and is PI on an investigator-initiated clinical trial supported by Neuroptix. Dr. De Santi is an employee at Bayer Health Care Pharmaceuticals.
Acknowledgements
This study was supported by NIH-NIA AG035137, AG032554, AG13616, AG12101, AG08051, AG022374, NIH-NCRR MO1RR0096, the Alzheimer's Association, and an anonymous Foundation.
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