Michael Brickhouse

Hippocampal Hyperactivation Associated with Cortical Thinning in Alzheimer's Disease Signature Regions in Non-Demented Elderly Adults

Alzheimers disease (AD) is associated with functional and structural alterations in a distributed network of brain regions supporting memory and other cognitive domains. Functional abnormalities are present in mild cognitive impairment (MCI) with evidence of early hyperactivity in medial temporal lobe regions, followed by failure of hippocampal activation as dementia develops. Atrophy in a consistent set of cortical regions, the “cortical signature of AD,” has been reported at the stage of dementia, MCI, and even in clinically normal (CN) older individuals predicted to develop AD. Despite multiple lines of evidence for each of these findings, the relationship between this structural marker of AD-related neurodegeneration and this functional marker of the integrity of the episodic memory system has not yet been elucidated. We investigated this relationship in 34 nondemented older humans (CN, N = 18; MCI, N = 16). Consistent with previous studies, we found evidence of hippocampal hyperactivation in MCI compared with CN. Additionally, within this MCI group, increased hippocampal activation correlated with cortical thinning in AD-signature regions. Even within the CN group, increased hippocampal activity was negatively correlated with cortical thinning in a subset of regions, including the superior parietal lobule (r = −0.66; p < 0.01). These findings, across a continuum of nondemented and mildly impaired older adults, support the hypothesis that paradoxically increased hippocampal activity may be an early indicator of AD-related neurodegeneration in a distributed network.

Naming impairment in Alzheimer's disease is associated with left anterior temporal lobe atrophy

There is considerable debate about the neuroanatomic localization of semantic memory, the knowledge of culturally shared elements such as objects, concepts, and people. Two recent meta-analyses of functional imaging studies (fMRI and PET) sought to identify cortical regions involved in semantic processing. Binder and colleagues (Binder et al., 2009) identified several regions of interest, widely distributed throughout the frontal, parietal, and temporal cortices. In contrast, Lambon Ralph and colleagues (2010) focused on the anterior temporal lobe, and found that when the potential for signal loss is accounted for (due, for example, to distortion artifact or field of view restriction), significant regional activation is detected. We set out to determine whether the anterior temporal lobe plays a significant role in picture naming, a task which relies on semantic memory. We examined a relatively large sample of patients with early Alzheimers disease (N=145), a multifocal disease process typically characterized in the early stages by problems with episodic memory and executive function. Hypothesis-driven analyses based on regions of interest derived from the meta-analyses as well as exploratory analyses across the entire cerebral cortex demonstrated a highly specific correlation between cortical thinning of the left anterior temporal lobe and impaired naming performance. These findings lend further support to theories that include a prominent role for the anterior temporal lobe in tasks that rely on semantic memory.

Cortical atrophy in presymptomatic Alzheimer's disease presenilin 1 mutation carriers

Background Sporadic late-onset Alzheimers disease (AD) dementia has been associated with a ‘signature’ of cortical atrophy in paralimbic and heteromodal association regions measured with MRI. Objective To investigate whether a similar pattern of cortical atrophy is present in presymptomatic presenilin 1 E280A mutation carriers an average of 6 years before clinical symptom onset. Methods 40 cognitively normal volunteers from a Colombian population with familial AD were included; 18 were positive for the AD-associated presenilin 1 mutation (carriers, mean age=38) whereas 22 were non-carriers. T1-weighted volumetric MRI images were acquired and cortical thickness was measured. A priori regions of interest from our previous work were used to obtain thickness from AD-signature regions. Results Compared to non-carriers, presymptomatic presenilin 1 mutation carriers exhibited thinner cortex within the AD-signature summary measure (p<0.008). Analyses of individual regions demonstrated thinner angular gyrus, precuneus and superior parietal lobule in carriers compared to non-carriers, with trend-level effects in the medial temporal lobe. Conclusion Results demonstrate that cognitively normal individuals genetically determined to develop AD have a thinner cerebral cortex than non-carriers in regions known to be affected by typical late-onset sporadic AD. These findings provide further support for the hypothesis that cortical atrophy is present in preclinical AD more than 5 years prior to symptom onset. Further research is needed to determine whether this method could be used to characterise the age-dependent trajectory of cortical atrophy in presymptomatic stages of AD.

Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study

IMPORTANCE Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellín, Colombia, between August 2011 and June 2012. MAIN OUTCOMES AND MEASURES All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding-dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. RESULTS Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were -0.590 [0.50] for noncarriers and -0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons). CONCLUSIONS AND RELEVANCE Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.

Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale

Patients with frontotemporal dementia (FTD) often exhibit prominent, early and progressive impairments in social behaviour. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview, which grades the types and severity of social behavioural symptoms in seven domains. In 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others’ social and emotional behaviour. Our findings underscore observations that FTD is associated with heterogeneous social symptoms that can be understood in a refined manner by measuring impairments in component processes subserved by dissociable neural networks. Furthermore, these findings support the validity of the SIRS as an instrument to measure the social symptoms of patients with FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in natural history studies and in clinical trials of putative interventions to improve social functioning.

Alzheimer's disease: The influence of age on clinical heterogeneity through the human brain connectome

One major factor that influences the heterogeneity of Alzheimers 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.

Effects of cognitive reserve depend on executive and semantic demands of the task

Background Cognitive reserve (CR) is one factor that helps to maintain cognitive function in patients with Alzheimer’s disease (AD). Whether the effects of CR depend on the semantic/executive components of the task remains unknown. Methods 470 patients (138 with AD, 332 with mild cognitive impairment (MCI)) were selected from the Alzheimer’s Disease Neuroimaging Initiative database. Linear regression models were used to determine the effects of CR (years of education) on cognitive performance after controlling for demographic factors and regional cortical atrophy. First, we assessed memory tasks with low (Auditory Verbal Learning Test (AVLT) discriminability), moderate (AVLT delayed recall) and high (Logical Memory Test (LMT) delayed recall) executive/semantic components. Next, we assessed tasks with lower (digit span forward, Trails A) or higher (digit span backwards, Trails B) executive demands, and lower (figure copying) or higher (naming, semantic fluency) semantic demands. Results High CR was significantly associated with performance on the LMT delayed recall, approached significance in the AVLT delayed recall and was not significantly associated with performance on AVLT discriminability. High CR was significantly associated with performance on the Trails B and digit span backwards, mildly associated with Trails A performance and was not associated with performance on digit span forwards. High CR was associated with performance on semantic but not visuospatial tasks. High CR was associated with semantic tasks in patients with both MCI and AD, but was only associated with executive functions in patients with MCI. Conclusion CR may relate to executive functioning and semantic knowledge, leading to preserved cognitive performance in patients with AD pathology.

VERBAL FLUENCY IN ATYPICAL PHENOTYPES OF ALZHEIMER’S DISEASE

lineal model with age as covariate) for the three groups in MMSE1⁄4 MiniMental State Examination; CAMCOG-R1⁄4 Cambridge Cognitive AssessmentRevised; TMT-A1⁄4 Trail Making TestForm A seconds; TMT-B1⁄4 Trail Making TestFormB seconds; BNT1⁄4Boston Naming Test total score; CVLT-SDFR1⁄4 Short Delay Free Recall from California Verbal Learning Test; CVLT-SDCR1⁄4 Short Delay Cued Recall from California Verbal Learning Test; CVLT-LDFR1⁄4 Long Delay Free Recall from California Verbal Learning Test; CVLTLDCR1⁄4LongDelay Cued Recall fromCalifornia Verbal Learning Test; CVLT-Recognition. Poster Presentations: Sunday, July 22, 2018 P537

The personalized Alzheimer's disease cortical thickness index predicts likely pathology and clinical progression in mild cognitive impairment

An Alzheimers disease (AD) biomarker adjusted for age‐related brain changes should improve specificity for AD‐related pathological burden.

Atrophy in distinct corticolimbic networks subserving social-affective behavior in semantic-variant primary progressive aphasia

OBJECTIVE : Semantic-variant Primary Progressive Aphasia(svPPA) is a neurodegenerative disorder with core impairments in semantic memory. Although many svPPA patients also exhibit symptoms involving social-emotional behavior, these have received relatively little study. We investigated atrophy in large-scale brain networks subserving social-emotional behaviors in svPPA compared to controls. BACKGROUND : We previously defined three social-emotional brain networks in healthy subjects. The perception network guiding detection/interpretation of social sensory cues includes the fusiform gyrus, ventral temporal pole, superior temporal sulcus and lateral orbitofrontal cortex. The affiliation network facilitating prosocial behaviors includes the ventromedial prefrontal, subgenual and rostral anterior cingulate cortices, dorsal temporal pole, hippocampus, parahippocampus, entorhinal cortex and nucleus accumbens. The aversion network mediating avoidant behaviors includes the insula, caudal anterior cingulate cortex and putamen. These networks are linked to amygdalar subregions. We hypothesized that these three networks would exhibit atrophy in svPPA and relate to socioemotional impairment. DESIGN/METHODS : Seventeen svPPA subjects and thirty age-and-gender matched controls were studied. T1-weighted MPRAGE MRI scans were acquired, and FreeSurfer software was used to process data and extract cortical thickness or volumetric data across a priori regions-of-interest. Findings were statistically significant at p≤0.005 to correct for multiple comparisons. The types and severity of social symptoms were rated using the Social Impairment Rating Scale (SIRS). RESULTS : svPPA subjects showed left-lateralized perception(z-score=-4.729; p<0.0001) and affiliation(z-score=-3.483; p=0.0005) network atrophy. Trends toward bilateral amygdala and right perception network atrophy were also observed. Left affiliation network atrophy correlated with SIRS socioemotional detachment sub-scores(r=0.56; p=0.037). The aversion network and control networks (mentalizing and mirror networks) did not show statistically significant atrophy. CONCLUSIONS : svPPA patients demonstrated left-lateralized perception and affiliation network atrophy which may provide the biological basis for social-emotional deficits in these patients. Future symptom-specific analyses may further clarify these brain-behavior relationships. Study Supported by: R21 NS077059, R21 MH097094, and R25 NS065743-05S1. Disclosure: Dr. Perez has nothing to disclose. Dr. Makaretz has nothing to disclose. Dr. Caso has nothing to disclose. Dr. Stepanovic has nothing to disclose. Dr. Brickhouse has nothing to disclose. Dr. Quimby has nothing to disclose. Dr. Hochberg has nothing to disclose. Dr. Xia has nothing to disclose. Dr. Dickerson has received personal compensation for activities with Pfizer, Inc., En Vivo, and Merck.