Person:

Dickerson, Bradford

Objective: New diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) have been developed using biomarkers aiming to establish whether the clinical syndrome is likely due to underlying AD. We investigated the utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers in predicting progression from amnesic MCI to dementia, testing the hypotheses that (1) markers of amyloid and neurodegeneration provide distinct and complementary prognostic information over different time intervals, and that (2) evidence of neurodegeneration in amyloid-negative MCI individuals would be useful prognostically. Methods: Data were obtained from the ADNI-1 (Alzheimer's Disease Neuroimaging Initiative Phase 1) database on all individuals with a baseline diagnosis of MCI, baseline MRI and CSF data, and at least one follow-up visit. MRI data were processed using a published set of a priori regions of interest to derive a measure known as the ``AD signature,'' as well as hippocampal volume. The CSF biomarkers amyloid-β, total tau, and phospho tau were also examined. We performed logistic regression analyses to identify the best baseline biomarker predictors of progression to dementia over 1 or 3 years, and Cox regression models to test the utility of these markers for predicting time-to-dementia. Results: For prediction of dementia in MCI, the AD signature cortical thickness biomarker performed better than hippocampal volume. Although CSF tau measures were better than CSF amyloid-β at predicting dementia within 1 year, the AD signature was better than all CSF measures at prediction over this relatively short-term interval. CSF amyloid-β was superior to tau and AD signature at predicting dementia over 3 years. When CSF amyloid-β was dichotomized using previously published cutoff values and treated as a categorical variable, a multivariate stepwise Cox regression model indicated that both the AD signature MRI marker and the categorical CSF amyloid-β marker were useful in predicting time-to-event diagnosis of AD dementia. Conclusion: In amnesic MCI, short-term (1 year) prognosis of progression to dementia relates strongly to baseline markers of neurodegeneration, with the AD signature MRI biomarker of cortical thickness performing the best among MRI and CSF markers studied here. Longer-term (3 year) prognosis in these individuals was better predicted by a marker indicative of brain amyloid. Prediction of time-to-event in a survival model was predicted by the combination of these biomarkers. These results provide further support for emerging models of the temporal relationship of pathophysiologic events in AD and demonstrate the utility of these biomarkers at the prodromal stage of the illness.

The objective of our study was to evaluate whether cognitively normal (CN) elderly participants showing elevated cortical beta-amyloid (Aβ) deposition have a consistent neuroanatomical signature of brain atrophy that may characterize preclinical Alzheimer's disease (AD). 115 CN participants who were Aβ-positive (CN +) by amyloid PET imaging; 115 CN participants who were Aβ-negative (CN −); and 88 Aβ-positive mild cognitive impairment or AD participants (MCI/AD +) were identified. Cortical thickness (FreeSurfer) and gray matter volume (SPM5) were measured for 28 regions-of-interest (ROIs) across the brain and compared across groups. ROIs that best discriminated CN − from CN + differed for FreeSurfer cortical thickness and SPM5 gray matter volume. Group-wise discrimination was poor with a high degree of uncertainty in terms of the rank ordering of ROIs. In contrast, both techniques showed strong and consistent findings comparing MCI/AD + to both CN − and CN + groups, with entorhinal cortex, middle and inferior temporal lobe, inferior parietal lobe, and hippocampus providing the best discrimination for both techniques. Concordance across techniques was higher for the CN − and CN + versus MCI/AD + comparisons, compared to the CN − versus CN + comparison. The weak and inconsistent nature of the findings across technique in this study cast doubt on the existence of a reliable neuroanatomical signature of preclinical AD in elderly PiB-positive CN participants.

Numerous studies have documented the normal age-related decline of neural structure, function, and cognitive performance. Preliminary evidence suggests that meditation may reduce decline in specific cognitive domains and in brain structure. Here we extended this research by investigating the relation between age and fluid intelligence and resting state brain functional network architecture using graph theory, in middle-aged yoga and meditation practitioners, and matched controls. Fluid intelligence declined slower in yoga practitioners and meditators combined than in controls. Resting state functional networks of yoga practitioners and meditators combined were more integrated and more resilient to damage than those of controls. Furthermore, mindfulness was positively correlated with fluid intelligence, resilience, and global network efficiency. These findings reveal the possibility to increase resilience and to slow the decline of fluid intelligence and brain functional architecture and suggest that mindfulness plays a mechanistic role in this preservation.

Introduction: One major factor that influences the heterogeneity of Alzheimer's disease (AD) is age: younger AD patients more frequently exhibit atypical forms of AD. We propose that this age-related heterogeneity can be understood better by considering age-related differences in atrophy in the context of large-scale brain networks subserving cognitive functions that contribute to memory. Methods: We examined data from 75 patients with mild AD dementia from Alzheimer's Disease Neuroimaging Initiative. These individuals were chosen because they have cerebrospinal fluid amyloid and p-tau levels in the range suggesting the presence of AD neuropathology, and because they were either younger than age 65 years early-onset AD (EOAD) or age 80 years or older late-onset AD (LOAD). Results: In the EOAD group, the most prominent atrophy was present in the posterior cingulate cortex, whereas in the LOAD group, atrophy was most prominent in the medial temporal lobe. Structural covariance analysis showed that the magnitude of atrophy in these epicenters is strongly correlated with a distributed atrophy pattern similar to distinct intrinsic connectivity networks in the healthy brain. An examination of memory performance in EOAD dementia versus LOAD dementia demonstrated relatively more prominent impairment in encoding in the EOAD group than in the LOAD group, with similar performance in memory storage in LOAD and EOAD but greater impairment in semantic memory in LOAD than in EOAD. Discussion The observations provide novel insights about age as a major factor contributing to the heterogeneity in the topography of AD-related cortical atrophy.

There has been a growing interest in understanding how contemplative practices affect brain functional organization. However, most studies have restricted their exploration to predefined networks. Furthermore, scientific comparisons of different contemplative traditions are largely lacking. Here we explored differences in whole brain resting state functional connectivity between experienced yoga practitioners, experienced meditators, and matched controls. Analyses were repeated in an independent sample of experienced meditators and matched controls. Analyses utilizing Network-Based Statistics (Zalesky et al., 2010) revealed difference components for yoga practitioners > controls and meditators > controls in which the right caudate was a central node. Follow up analyses revealed that yoga practitioners and meditators had significantly greater degree centrality in the caudate than controls. This greater degree centrality was not driven by single connections but by greater connectivity between the caudate and numerous brain regions. Findings of greater caudate connectivity in meditators than in controls was replicated in an independent dataset. These findings suggest that yoga and meditation practitioners have stronger functional connectivity within basal ganglia cortico-thalamic feedback loops than non-practitioners. Although we could not provide evidence for its mechanistic role, this greater connectivity might be related to the often reported effects of meditation and yoga on behavioral flexibility, mental health, and well-being.

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases.

The volume of parcellated conical regions is a composite measure related to both thickness and surface area. It is not clear whether volumetric decreases in medial temporal lobe (MTL) cortical regions in aging and Alzheimer's disease (AD) are due to thinning, loss of surface area, or both, nor is it clear whether aging and AD differ in their effects on these properties. Participants included 28 Younger Normals, 47 Older Normals, and 29 patients with mild AD. T1-weighted MRI data were analyzed using a novel semi-automated protocol (presented in a companion article) to delineate the boundaries of entorhinal (ERC), perirhinal (PRC), and posterior parahippocampal (PPHC) cortical regions and calculate their mean thickness, surface area, and volume. Compared to Younger Normals, Older Normals demonstrated moderately reduced ERC and PPHC volumes, which were due primarily to reduced surface area. In contrast. the expected AD-related reduction in ERC volume was produced by a large reduction in thickness with minimal additional effect (beyond that of aging) on surface area. PRC and PPHC also showed large AD-related reductions in thickness. Of all these MTL morphometric measures, ERC and PRC thinning were the best predictors of poorer episodic memory performance in AD. Although the volumes of MTL cortical regions may decrease with both aging and AD, thickness is relatively preserved in normal aging, while even in its mild clinical stage, AD is associated with a large degree of thinning of MTL cortex. These differential morphometric effects of aging and AD may reflect distinct biologic processes and ultimately may provide insights into the anatomic substrates of change in memory-related functions of MTL cortex.

Abstract The resting connectivity of the brain’s salience network, particularly the ventral subsystem of the salience network, has been previously associated with various measures of affective reactivity. Numerous studies have demonstrated that increased affective arousal leads to enhanced consolidation of memory. This suggests that individuals with greater ventral salience network connectivity will exhibit greater responses to affective experience, leading to a greater enhancement of memory by affect. To test this hypothesis, resting ventral salience connectivity was measured in 41 young adults, who were then exposed to neutral and negative affect inductions during a paired associate memory test. Memory performance for material learned under both negative and neutral induction was tested for correlation with resting connectivity between major ventral salience nodes. The results showed a significant interaction between mood induction (negative vs neutral) and connectivity between ventral anterior insula and pregenual anterior cingulate cortex, indicating that salience node connectivity predicted memory for material encoded under negative, but not neutral induction. These findings suggest that the network state of the perceiver, measured prior to affective experience, meaningfully influences the extent to which affect modulates memory. Implications of these findings for individuals with affective disorder, who show alterations in both connectivity and memory, are considered.

The middle longitudinal fascicle (MdLF) is a major fiber connection running principally between the superior temporal gyrus and the parietal lobe, neocortical regions of great biological and clinical interest. Although one of the most prominent cerebral association fiber tracts it has only recently been discovered in humans. In this high angular resolution diffusion imaging (HARDI) MRI study, we delineated the two major fiber connections of the human MdLF, by examining morphology, topography, cortical connections, biophysical measures, volume and length in seventy-four brains. These two fiber connections course together through the dorsal temporal pole and the superior temporal gyrus maintaining a characteristic topographic relationship in the mediolateral and ventrodorsal dimensions. As these pathways course towards the parietal lobe, they split to form separate fiber pathways, one following a ventrolateral trajectory and connecting with the angular gyrus and the other following a dorsomedial route and connecting with the superior parietal lobule. Based on the functions of their cortical affiliations, we suggest that the superior temporal-angular connection of the MdLF, i.e., STG(MdLF)AG plays a role in language and attention, whereas the superior temporal-superior parietal connection of the MdLF, i.e., STG(MdLF)SPL is involved in visuospatial and integrative audiovisual functions. Furthermore, the MdLF may have clinical implications in neurodegenerative disorders such as primary progressive aphasia, frontotemporal dementia, posterior cortical atrophy, corticobulbar degeneration and Alzheimer’s disease as well as attention-deficit/hyperactivity disorder and schizophrenia.

Patients with dementia due to Alzheimer’s disease (AD) have increased risk of developing delirium. This study investigated the relationship between a magnetic resonance imaging (MRI)-derived biomarker associated with preclinical AD and postoperative delirium. Participants were older adults (≥70 years) without dementia who underwent preoperative MRI and elective surgery. Delirium incidence and severity were evaluated daily during hospitalization. Cortical thickness was averaged across a published set of a priori brain regions to derive a measure known as the “AD signature.” Logistic and linear regression was used, respectively, to test whether the AD signature was associated with delirium incidence in the entire sample (N=145) or with the severity of delirium among those who developed delirium (N=32). Thinner cortex in the AD signature did not predict incidence of delirium (odds ratio=1.15, p=.38), but was associated with greater delirium severity among those who developed delirium (b=−1.2, p=.014). These results suggest that thinner cortices, perhaps reflecting underlying neurodegeneration due to preclinical AD, may serve as a vulnerability factor that increases severity once delirium occurs.