Amyloid and anatomical correlates of executive functioning in middle-aged offspring of patients with late-onset Alzheimer's disease.

A traditional hallmark of cognitive impairment associated with late-onset Alzheimer´s disease (LOAD) is episodic memory impairment. However, early alterations have been identified in brain regions associated with executive function in asymptomatic, middle-age offspring of patients with LOAD (O-LOAD) compared to those with no family history. We hypothesized that executive function among O-LOAD would correlate with structural and amyloid brain imaging differently from those without a family history of LOAD (control subjects, CS). Executive function, cortical thickness, and in-vivo Aß deposits were quantified in 30 O-LOAD and 25 CS. Associations were observed among O-LOAD only. Cortical thickness in the left lateral orbitofrontal cortex was positively associated with Design Fluency. The Stroop Color and Word Test, correlated positively with right rostral mid-frontal cortex thickness. Trails Making Test-B was inversely related to left medial orbitofrontal thickness. Tower of London total time was positively associated with ß-amyloid deposition in the right precuneus. These results support previous evidence that early executive dysfunction might reflect subtle, early changes in persons at risk of LOAD and suggests that executive function alterations deserve further exploration in the LOAD literature.

Disrupted functional connectivity of the locus coeruleus in healthy adults with parental history of Alzheimer's disease.

Prevention and early treatment strategies for Alzheimer's disease (AD) are hampered by the lack of research biomarkers. Neuropathological changes in the Locus Coeruleus (LC) are detected early in AD, and noradrenaline plays a neuroprotective role in LC projecting areas. We assessed functional connectivity (FC) of the brainstem in asymptomatic individuals at familial risk for AD hypothesizing that FC of the LC will be decreased in relation to not-at-risk individuals. Thirty-one offspring of patients with late-onset AD (O-LOAD) (22 females; mean age ± SD = 50.36 ± 8.32) and 28 healthy controls (HC) (20 females; mean age ± SD = 53.90 ± 8.44) underwent a neurocognitive evaluation and a resting-state functional magnetic resonance imaging acquisition. In FC analyses we evaluated whole-brain global connectivity of the brainstem area, and subsequently assessed seed-to-voxel FC patterns from regions showing between-group differences. O-LOAD individuals scored worse in neurocognitive measures of memory and overall functioning (pFDR<0.05). In imaging analyses, we observed that O-LOAD individuals showed decreased global connectivity in a cluster encompassing the left LC (peak = -4, -34, -32, pTFCE<0.05). Seed-to-voxel analyses revealed that this finding was largely explained by decreased connectivity between the LC and the cerebellar cortex. Moreover, FC between the LC and the left cerebellum correlated positively with delayed recall scores. FC between the LC and the cerebellar cortex is decreased in the healthy offspring of patients with LOAD, such connectivity measurements being associated with delayed memory scores. The assessment of FC between the LC and the cerebellum may serve as a biomarker of AD vulnerability.

White matter fiber density abnormalities in cognitively normal adults at risk for late-onset Alzheimer's disease.

Tau accumulation affecting white matter tracts is an early neuropathological feature of late-onset Alzheimer's disease (LOAD). There is a need to ascertain methods for the detection of early LOAD features to help with disease prevention efforts. The microstructure of these tracts and anatomical brain connectivity can be assessed by analyzing diffusion MRI (dMRI) data. Considering that family history increases the risk of developing LOAD, we explored the microstructure of white matter through dMRI in 23 cognitively normal adults who are offspring of patients with Late-Onset Alzheimer's Disease (O-LOAD) and 22 control subjects (CS) without family history of AD. We also evaluated the relation of white matter microstructure metrics with cortical thickness, volumetry, in vivo amyloid deposition (with the help of PiB positron emission tomography -PiB-PET) and regional brain metabolism (as FDG-PET) measures. Finally we studied the association between cognitive performance and white matter microstructure metrics. O-LOAD exhibited lower fiber density and fractional anisotropy in the posterior portion of the corpus callosum and right fornix when compared to CS. Among O-LOAD, reduced fiber density was associated with lower amyloid deposition in the right hippocampus, and greater cortical thickness in the left precuneus, while higher mean diffusivity was related with greater cortical thickness of the right superior temporal gyrus. Additionally, compromised white matter microstructure was associated with poorer semantic fluency. In conclusion, white matter microstructure metrics may reveal early differences in O-LOAD by virtue of parental history of the disorder, when compared to CS without a family history of LOAD. We demonstrate that these differences are associated with lower fiber density in the posterior portion of the corpus callosum and the right fornix.

Brain Structural and Amyloid Correlates of Recovery From Semantic Interference in Cognitively Normal Individuals With or Without Family History of Late-Onset Alzheimer's Disease.

Failure to recover from proactive semantic interference (frPSI) has been shown to be more sensitive than traditional cognitive measures in different populations with preclinical Alzheimer's disease. The authors sought to characterize the structural and amyloid in vivo correlates of frPSI in cognitively normal offspring of patients with late-onset Alzheimer's disease (O-LOAD), compared with individuals without a family history of neurodegenerative disorders (CS). The authors evaluated the LASSI-L, a test tapping frPSI and other types of semantic interference and delayed recall on the RAVLT, along with 3-T MRI volumetry and positron emission tomography Pittsburgh compound B, in 27 O-LOAD and 18 CS with equivalent age, sex, years of education, ethnicity, premorbid intelligence, and mood symptoms. Recovery from proactive semantic interference (frPSI) and RAVLT delayed recall were lower in O-LOAD cases. Structural correlates of both cognitive dimensions were different in CS and O-LOAD, involving brain regions concerned with autonomic, motor, and motivational control in the former, and regions traditionally implicated in Alzheimer's disease in the latter. Better recovery from retroactive semantic interference was associated with less amyloid load in the left temporal lobe in O-LOAD but not CS. In middle-aged cognitively normal individuals with one parent affected with LOAD, frPSI was impaired compared with persons without a family history of LOAD. The neuroimaging correlates of such cognitive measure in those with one parent with LOAD involve Alzheimer's-relevant brain regions even at a relatively young age.

Cortical thickness, brain metabolic activity, and in vivo amyloid deposition in asymptomatic, middle-aged offspring of patients with late-onset Alzheimer's disease.

The natural history of preclinical late-onset Alzheimer's disease (LOAD) remains obscure and has received less attention than that of early-onset AD (EOAD), in spite of accounting for more than 99% of cases of AD. With the purpose of detecting early structural and functional traits associated with the disorder, we sought to characterize cortical thickness and subcortical grey matter volume, cerebral metabolism, and amyloid deposition in persons at risk for LOAD in comparison with a similar group without family history of AD. We obtained 3T T1 images for gray matter volume, FDG-PET to evaluate regional cerebral metabolism, and PET-PiB to detect fibrillar amyloid deposition in 30 middle-aged, asymptomatic, cognitively normal individuals with one parent diagnosed with LOAD (O-LOAD), and 25 comparable controls (CS) without family history of neurodegenerative disorders (CS). We observed isocortical thinning in AD-relevant areas including posterior cingulate, precuneus, and areas of the prefrontal and temporoparietal cortex in O-LOAD. Unexpectedly, this group displayed increased cerebral metabolism, in some cases overlapping with the areas of cortical thinning, and no differences in bilateral hippocampal volume and hippocampal metabolism. Given the importance of age in this sample of individuals potentially developing early AD-related changes, we controlled results for age and observed that most differences in cortical thickness and metabolism became nonsignificant; however, greater deposition of ß-amyloid was observed in the right hemisphere including temporoparietal cortex, postcentral gyrus, fusiform inferior and middle temporal and lingual gyri. If replicated, the present observations of morphological, metabolic, and amyloid changes in cognitively normal persons with family history of LOAD may bear important implications for the definition of very early phenotypes of this disorder.

Failure to Recover from Proactive Semantic Interference and Abnormal Limbic Connectivity in Asymptomatic, Middle-Aged Offspring of Patients with Late-Onset Alzheimer's Disease.

BACKGROUND: We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer's disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. OBJECTIVE: To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. METHODS: We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. RESULTS: Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. CONCLUSION: The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations.

Relationship between Cognitive and Sleep-wake Variables in Asymptomatic Offspring of Patients with Late-onset Alzheimer's Disease.

Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep-wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 ± 0.4 vs. 8.6 ± 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler's vocabulary 51.4 ± 1.3 vs. 44.3 ± 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 ± 0.47 h vs. 3.8 ± 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep-wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.