Spatially distinct atrophy is linked to β-amyloid and tau in preclinical Alzheimer disease

Abstract

Objectives: To determine whether an MRI-based Alzheimer disease (AD) signature biomarker can detect tau-related neurodegeneration in preclinical AD, and to assess whether AD signature cortical thinning is associated with cognitive changes in cognitively normal (CN) older individuals. Methods:In a large cohort of CN individuals (n 5 188), we measured the hippocampal volume and cortical thickness within independently defined AD signature regions. We cross-sectionally assessed the associations between AD signature cortical thinning or hippocampal atrophy with CSF biomarkers of tau (increased tau) and b-amyloid (Ab) (decreased Ab42). We also examined the impact of AD signature cortical thinning or other biomarker changes (i.e., hippocampal atrophy, reduced CSF Ab42, or increased CSF tau) on cognitive performance in CN individuals.Results: Elevated CSF tau was associated with AD signature cortical thinning but not hippocampal atrophy. In contrast, decreased CSF Ab42 was associated with hippocampal loss but not AD signature cortical thinning. In addition, AD signature cortical thinning was associated with lower visuospatial performance. Reduced CSF Ab42 was related to poorer performance on episodic memory. Isolated amyloidosis is the earliest stage of preclinical Alzheimer disease (AD), followed by neurodegeneration and then subtle cognitive decline. Conclusions:1 However, recent work has observed that some cognitively normal (CN) individuals have neurodegeneration (e.g., AD-like brain atrophy on structural MRI) independent of amyloidosis.2-4 These observations motivate the investigation of tau-related neurodegenerative process in preclinical AD. In addition, discrepant data exist regarding the relationships between amyloidosis or neurodegeneration and cognitive decline in preclinical AD. 3,5 Neurodegeneration can be measured using the hippocampal volume or cortical thickness within the topography affected by AD (i.e., "AD signature").6,7 The AD signature has been shown to predict prognosis in individuals without dementia, 8 although an important gap remains. Specifically, the AD topography has been derived primarily as a function of clinical assessment and not biomarkers. Many supposed CN older persons may have biomarker evidence of AD pathology.9 Some individuals with clinically defined AD do not have biomarker evidence of AD pathology. 10 Here, we refined the AD signature using a cohort of clinical and biomarker-confirmed CN and symptomatic AD individuals. In a separate group of CN individuals (n 5 188), we investigated whether abnormal CSF biomarker of tau pathology was associated with

Cognitive reserve and cortical thickness in preclinical Alzheimer’s disease

“…We hypothesize that this interaction may be due to individual differences in the ability to cope with underlying pathology. Biomarkers of neuronal injury and atrophy are hypothesized to become increasingly abnormal as individuals get closer in time to clinical symptom onset (Jack et al 2013) and they tend to correlate with cognitive performance and clinical impairment (e.g., Dickerson et al 2009; Fox et al 1999; Wang et al 2015; Wirth et al 2013). In line with this, there was no direct association between mean cortical thickness and risk of clinical symptom onset more than 7 years from baseline.…”

“…The present study examined cortical thickness measures in eight FreeSurfer-labeled regions of interest (ROI) selected to reflect regions classified as ‘AD vulnerable’ cortical regions by at least two previous studies’ (i.e., cross-study overlap includes Dickerson et al 2009; Sabuncu et al 2011; Wang et al 2015), suggesting these regions are sensitive to AD-related atrophy across multiple cohorts. The ROIs included: the entorhinal cortex, temporal pole, inferior temporal gyrus, middle temporal gyrus, inferior parietal cortex, superior parietal cortex, precuneus, and posterior cingulate cortex (averaged over the left and right hemispheres) (see Fig.…”

“…These were selected as control regions because previous studies have indicated that these regions demonstrate minimal differences between controls and patients with dementia due to AD (e.g., Dickerson et al 2009; Sabuncu et al 2011; Wang et al 2015). Thickness measures were not adjusted for intracranial cavity size, as is standard in the field (e.g., Westman et al 2013).…”

Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between β-Amyloid and Tauopathy

“…The topography of AD-related cortical neurodegeneration has been delineated by MRI as the AD cortical signature, 20 in which volumetric loss is correlated with tau burden measured at autopsy 21 or CSF assay. 22 Thus, [ 18 F]-AV-1451 binding in AD cortical signature regions may be useful for staging of AD.…”

Effects of Detraining on Ach, AchE, β-amyloid, Apolipoprotein Expression and Cognitive Function in Brain Tissue of Memory Impairment Rats

“…Amyloid plaques are visible protein aggregates derived from the dimers and oligomers of brain amyloid-β protein, while neurofibrillary tangles are composed of a compact filamentous network of helical filaments of hyperphosphorylated tau protein. Together these neuropathological changes are thought to result in the loss of synapses and neuronal cell death, leading in cognitive dysfunction 3,4 . The aetiology of late-onset AD remains largely unknown but is believed to be multifaceted, resulting from both genetic and environmental factors 5 .…”