Brain imaging of cognitively normal individuals with 2 parents affected by late-onset AD

Abstract

Objectives: This brain imaging study examines whether cognitively normal (NL) individuals with 2 parents affected by late-onset Alzheimer disease (LOAD) show evidence of more extensive Alzheimer disease pathology compared with those who have a single parent affected by LOAD.Methods: Fifty-two NL individuals received MRI, 11 C-Pittsburgh compound B (PiB)-PET, and 18 F-fluoro-2-deoxyglucose (FDG)-PET. These included 4 demographically balanced groups (n 5 13/group, aged 32-72 years, 60% female, 30% APOE e4 carriers) of NL individuals with maternal (FHm), paternal (FHp), and maternal and paternal (FHmp) family history of LOAD, and with negative family history (FH2). Statistical parametric mapping, voxel-based morphometry, and z-score mapping were used to compare MRI gray matter volumes (GMVs), partial volumecorrected PiB retention, and FDG metabolism across FH groups and vs FH2. Alzheimer disease (AD) is an age-related neurodegenerative disease and the most common form of dementia. Clinical studies indicate that by the time patients seek diagnosis, the amount of irreversible brain damage that may have already occurred hinders treatment potential. Effective interventions, as they become available, ideally would be implemented in at-risk individuals before symptoms occur.Having a family history (FH) of AD is a major risk factor for developing the disease. 1,2 While the rare early-onset forms of AD (EOAD) have autosomal dominant genetic inheritance, the risk of developing late-onset AD (LOAD) (i.e., .99% of the AD population older than 60 years) is influenced by genetic and nongenetic factors.1 Although LOAD does not show recognizable mendelian inheritance, risk is to some extent genetically determined, as shown by the familial aggregation of many cases.2 Among probands, those with a parent affected by LOAD are at particularly high risk, 3,4 and the risk is higher still when both parents are affected. [5][6][7] However, because only ,5% of individuals have both parents affected by LOAD, 2,5-7 the clinical profile associated with this rare circumstance has been poorly studied and epidemiologic findings have not been characterized by the use of biomarkers.

Early detection of Alzheimer's disease using PiB and FDG PET

“…Similar changes have been reported in cognitively normal individuals at high risk for AD due to expression of the ApoE4 alelle (Reiman et al, 1996; Small et al, 2000). Further, hypometabolism has been reported in cognitively normal individuals with a parent with AD (Mosconi et al, 2009; Mosconi et al, 2014; Mosconi et al, 2008a; Mosconi et al, 2013). Changes in cerebral metabolism also have been detected in MCI in many studies (Arnaiz et al, 2001; Chetelat and Baron, 2003; Chetelat et al, 2003; Del Sole et al, 2008; Garibotto et al, 2008; Li et al, 2008a; Li et al, 2008b; Mevel et al, 2007; Mosconi et al, 2006; Mosconi et al, 2008b; Perneczky et al, 2007).…”

Perimenopause as a neurological transition state

“…114 Glucose metabolism in the brain is established as being critical to neurological function and that evidence of hypometabolism is apparent several decades before diagnosis of neurodegenerative diseases such as Alzheimer disease. [115][116][117] Depression Increased risk of depression in perimenopausal women is supported by evidence from several longitudinal studies that have documented odds ratios ranging from 1.8 to 2.9 of increased risk compared with women in premeno pause. 33,35,36 During perimenopause, both hot flushes and depression can occur early in the transition in women with no previous history of these symptoms although depression was more likely to precede hot flushes.…”

Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner

“…In the hypothesis of the amyloid cascade and in a recently formulated hypothetical biomarker model, they were put downstream to amyloid and tau deposition . However, studies in subjects at risk of AD, for example, young ApoE4 carriers (Reiman et al, 2004;Scarmeas et al, 2003;Wierenga et al, 2013) or subjects with a family history of AD (Mosconi et al, 2014), have revealed alterations in glucose metabolism and CBF. Thus, a very early and causative effect might be possible.…”