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1.  Imbalance of incidental encoding across tasks: An explanation for non-memory-related hippocampal activations? 
Journal of experimental psychology. General  2013;142(4):10.1037/a0033461.
Functional neuroimaging studies have increasingly noted hippocampal activation associated with a variety of cognitive functions such as decision-making, attention, perception, incidental learning, prediction and working memory, which have little apparent relation to declarative memory. Such findings might be difficult to reconcile with classical hippocampal lesion studies that show remarkable sparing of cognitive functions outside the realm of declarative memory. Even the oft-reported hippocampal activations during confident episodic retrieval are not entirely congruent with evidence that hippocampal lesions reliably impair encoding but inconsistently affect retrieval. Here we explore the conditions under which the hippocampus responds during episodic recall and recognition. Our findings suggest that anterior hippocampal activity may be related to the imbalance of incidental encoding across tasks and conditions, rather than due to retrieval, per se. Incidental encoding and hippocampal activity may be reduced during conditions where retrieval requires greater attentional engagement. During retrieval, anterior hippocampal activity decreases with increasing search duration and retrieval effort, and this deactivation corresponds with a coincident impaired encoding of the external environment (Israel, Seibert, Black, & Brewer, 2010; Reas & Brewer, 2013; Reas, Gimbel, Hales, & Brewer, 2011). In light of this emerging evidence, we discuss the proposal that some hippocampal activity observed during memory retrieval, or other non-memory conditions, may in fact be attributable to concomitant encoding activity which is regulated by the attentional demands of the principal task.
doi:10.1037/a0033461
PMCID: PMC3834009  PMID: 23773160
memory; hippocampus; encoding; retrieval; fMRI
2.  Mean signal and response time influences on multivoxel signals of contextual retrieval in the medial temporal lobe 
Brain and Behavior  2014;e00302.
Abstract
Introduction
The medial temporal lobe supports integrating the “what,” “where,” and “when” of an experience into a unified memory. However, it remains unclear how representations of these contextual features are neurally encoded and distributed across medial temporal lobe subregions.
Methods
This study conducted functional magnetic resonance imaging of the medial temporal lobe, while participants retrieved pair, spatial, and temporal source memories. Multivoxel classifiers were trained to distinguish between retrieval conditions before and after correction for mean signal and response times, to more thoroughly characterize the multivoxel signal associated with memory context.
Results
Activity in perirhinal and parahippocampal cortex dissociated between memory for associated items and memory for their spatiotemporal context, and hippocampal activity was linked to memory for spatial context. However, perirhinal and hippocampal classifiers were, respectively, driven by effects of mean signal amplitude and task difficulty, whereas the parahippocampal classifier survived correction for these effects.
Conclusion
These findings demonstrate dissociable coding mechanisms for episodic memory context across the medial temporal lobe, and further highlight a critical distinction between multivoxel representations driven by spatially distributed activity patterns, and those driven by the regional signal.
doi:10.1002/brb3.302
PMCID: PMC4312925  PMID: 25646149
Episodic memory; fMRI; medial temporal lobe; multivoxel pattern analysis; retrieval
3.  CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner 
Brain imaging and behavior  2012;6(1):16-26.
Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer’s disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318 AD or mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.
doi:10.1007/s11682-011-9137-0
PMCID: PMC4305449  PMID: 21892657
Imaging genetics; Quantitative neuroimaging; CETP; Alzheimer’s disease; Dementia; APOE
4.  Retrieval Search and Strength Evoke Dissociable Brain Activity during Episodic Memory Recall 
Journal of cognitive neuroscience  2012;25(2):219-233.
Neuroimaging studies of episodic memory retrieval have revealed activations in the human frontal, parietal, and medial-temporal lobes that are associated with memory strength. However, it remains unclear whether these brain responses are veritable signals of memory strength or are instead regulated by concomitant subcomponents of retrieval such as retrieval effort or mental search. This study used event-related fMRI during cued recall of previously memorized word-pair associates to dissociate brain responses modulated by memory search from those modulated by the strength of a recalled memory.
Search-related deactivations, dissociated from activity due to memory strength, were observed in regions of the default network, whereas distinctly strength-dependent activations were present in superior and inferior parietal and dorsolateral PFC. Both search and strength regulated activity in dorsal anterior cingulate and anterior insula. These findings suggest that, although highly correlated and partially subserved by overlapping cognitive control mechanisms, search and memory strength engage dissociable regions of frontoparietal attention and default networks.
doi:10.1162/jocn_a_00335
PMCID: PMC4091972  PMID: 23190328
5.  Effortful Retrieval Reduces Hippocampal Activity and Impairs Incidental Encoding 
Hippocampus  2013;23(5):367-379.
Functional imaging studies frequently report that the hippocampus is engaged by successful episodic memory retrieval. However, considering that concurrent encoding of the background environment occurs during retrieval and influences medial temporal lobe activity, it is plausible that hippocampal encoding functions are reduced with increased attentional engagement during effortful retrieval. Expanding upon evidence that retrieval efforts suppress activity in hippocampal regions implicated in encoding, this study examines the influence of retrieval effort on encoding performance and the interactive effects of encoding and retrieval on hippocampal and neocortical activity. Functional magnetic resonance imaging was conducted while subjects performed a word recognition task with incidental picture encoding. Both lower memory strength and increased search duration were associated with encoding failure and reduced hippocampal and default network activity. Activity in the anterior hippocampus tracked encoding, which was more strongly deactivated when incidental encoding was unsuccessful. These findings highlight potential contributions from background encoding processes to hippocampal activations during neuroimaging studies of episodic memory retrieval.
doi:10.1002/hipo.22096
PMCID: PMC4049294  PMID: 23378272
fMRI; hippocampus; episodic memory; encoding; retrieval
6.  The role of clusterin in amyloid-β associated neurodegeneration 
JAMA neurology  2014;71(2):180-187.
Importance
Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer's disease (AD) neurodegeneration. However, the precise role of clusterin in AD pathogenesis is still not well understood.
Objective
To elucidate the relationship between clusterin, amyloid-β (Aβ), p-tau, and rate of brain atrophy over time among non-demented older individuals.
Design
A longitudinal cohort of cognitively normal older participants (HC) and individuals with mild cognitive impairment (MCI) assessed with baseline lumbar puncture and longitudinal structural MRI.
Setting
Research centers across the United States and Canada.
Participants
We examined 241 non-demented older individuals (91 participants with a Clinical Dementia Rating (CDR) of 0 and 150 individuals with a CDR of 0.5).
Main Outcome Measures
Using linear mixed effects models, we investigated interactions between CSF clusterin, CSF Aβ1-42 and CSF p-tau181p on atrophy rate of the entorhinal cortex and hippocampus.
Results
Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on entorhinal cortex atrophy rate, but not on hippocampal atrophy rate. CSF clusterin was associated with entorhinal cortex atrophy rate among CSF Aβ1-42 positive individuals, but not among CSF Aβ1-42 negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin and CSF Aβ1-42 and CSF p-tau181p on entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the MCI and HC cohorts.
Conclusions and Relevance
In non-demented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the AD neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss.
doi:10.1001/jamaneurol.2013.4560
PMCID: PMC4118752  PMID: 24378367
7.  An expanded role for neuroimaging in the evaluation of memory impairment 
Alzheimer’s disease (AD) affects millions of people worldwide. The neuropathologic process underlying AD begins years, if not decades, before the onset of memory decline. Recent advances in neuroimaging suggest that it is now possible to detect AD-associated neuropathological changes well before dementia onset. Here, we evaluate the role of recently developed in vivo biomarkers in the clinical evaluation of AD. We discuss how assessment strategies might incorporate neuroimaging markers to better inform patients, families and clinicians when memory impairment prompts a search for diagnosis and management options.
doi:10.3174/ajnr.A3644
PMCID: PMC4077712  PMID: 23764728
8.  APOE ε4 does not modulate amyloid-β associated neurodegeneration in preclinical Alzheimer’s disease 
Background and Purpose
Among cognitively normal older individuals, the relationship between the two hallmark proteins of Alzheimer’s disease (AD), amyloid-β (Aβ) and tau, the ε4 allele of apolipoprotein E (APOE ε4), and neurodegeneration is not well understood.
Materials and Methods
We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed effects model, we concurrently investigated main and interactive effects between APOE ε4 genotype and CSF Aβ1-42, CSF phospo-tau (p-tau181p) and CSF Aβ1-42, and APOE ε4 genotype and CSF p-tau181p on entorhinal cortex atrophy rate. We also examined the relationship between APOE ε4, CSF p-tau181p, and CSF Aβ1-42 on atrophy rate of other AD-vulnerable neuroanatomic regions.
Results
The full model with main and interactive effects demonstrated a significant interaction only between CSF p-tau181p and CSF Aβ1-42 on entorhinal cortex atrophy rate indicating elevated atrophy over time in individuals with increased CSF p-tau181p and decreased CSF Aβ1-42. APOE ε4 genotype was significantly and specifically associated with CSF Aβ1-42. However, the interaction between APOE ε4 genotype and either CSF Aβ1-42 or CSF p-tau181p on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.
Conclusions
Based upon our findings and building upon prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD where APOE ε4 primarily influences Alzheimer’s pathology via Aβ-related mechanisms and in turn, Aβ-associated neurodegeneration occurs only in the presence of phospho-tau.
doi:10.3174/ajnr.A3267
PMCID: PMC4041629  PMID: 22976236
preclinical AD; neurodegeneration; p-tau; amyloid-β; APOE
9.  Prospective longitudinal MRI study of brain volumes and diffusion changes during the first year after moderate to severe traumatic brain injury 
NeuroImage : Clinical  2014;5:128-140.
The objectives of this prospective study in 62 moderate–severe TBI patients were to investigate volume change in cortical gray matter (GM), hippocampus, lenticular nucleus, lobar white matter (WM), brainstem and ventricles using a within subject design and repeated MRI in the early phase (1–26 days) and 3 and 12 months postinjury and to assess changes in GM apparent diffusion coefficient (ADC) in normal appearing tissue in the cortex, hippocampus and brainstem. The impact of Glasgow Coma Scale (GCS) score at admission, duration of post-traumatic amnesia (PTA), and diffusion axonal injury (DAI) grade on brain volumes and ADC values over time was assessed. Lastly, we determined if MRI-derived brain volumes from the 3-month scans provided additional, significant predictive value to 12-month outcome classified with the Glasgow Outcome Scale—Extended after adjusting for GCS, PTA and age.
Cortical GM loss was rapid, largely finished by 3 months, but the volume reduction was unrelated to GCS score, PTA, or presence of DAI. However, cortical GM volume at 3 months was a significant independent predictor of 12-month outcome. Volume loss in the hippocampus and lenticular nucleus was protracted and statistically significant first at 12 months. Slopes of volume reduction over time for the cortical and subcortical GGM were significantly different. Hippocampal volume loss was most pronounced and rapid in individuals with PTA > 2 weeks. The 3-month volumes of the hippocampus and lentiform nucleus were the best independent predictors of 12-month outcome after adjusting for GCS, PTA and age. In the brainstem, volume loss was significant at both 3 and 12 months. Brainstem volume reduction was associated with lower GCS score and the presence of DAI. Lobar WM volume was significantly decreased first after 12 months. Surprisingly DAI grade had no impact on lobar WM volume. Ventricular dilation developed predominantly during the first 3 months, and was strongly associated with volume changes in the brainstem and cortical GM, but not lobar WM volume.
Higher ADC values were detected in the cortex in individuals with severe TBI, DAI and PTA > 2 weeks, from 3 months. There were no associations between ADC values and brain volumes, and ADC values did not predict outcome.
Highlights
•Longitudinal study of brain volume changes following TBI•3 month MRI derived volumes are independent predictors of outcome at 12 months.•PTA, GCS and DAI have different impacts on different brain volumes.•Subcortical and cortical GM volume losses follow significantly different trajectories.•Significant changes in cortical ADC values develop slowly while volume changes are rapid.
doi:10.1016/j.nicl.2014.03.012
PMCID: PMC4110353  PMID: 25068105
Post-traumatic amnesia; Diffuse axonal injury; Glasgow Coma Scale; ADC; Outcome
10.  Elaboration versus Suppression of Cued Memories: Influence of Memory Recall Instruction and Success on Parietal Lobe, Default Network, and Hippocampal Activity 
PLoS ONE  2014;9(2):e89037.
Functional imaging studies of episodic memory retrieval consistently report task-evoked and memory-related activity in the medial temporal lobe, default network and parietal lobe subregions. Associated components of memory retrieval, such as attention-shifts, search, retrieval success, and post-retrieval processing also influence regional activity, but these influences remain ill-defined. To better understand how top-down control affects the neural bases of memory retrieval, we examined how regional activity responses were modulated by task goals during recall success or failure. Specifically, activity was examined during memory suppression, recall, and elaborative recall of paired-associates. Parietal lobe was subdivided into dorsal (BA 7), posterior ventral (BA 39), and anterior ventral (BA 40) regions, which were investigated separately to examine hypothesized distinctions in sub-regional functional responses related to differential attention-to-memory and memory strength. Top-down suppression of recall abolished memory strength effects in BA 39, which showed a task-negative response, and BA 40, which showed a task-positive response. The task-negative response in default network showed greater negatively-deflected signal for forgotten pairs when task goals required recall. Hippocampal activity was task-positive and was influenced by memory strength only when task goals required recall. As in previous studies, we show a memory strength effect in parietal lobe and hippocampus, but we show that this effect is top-down controlled and sensitive to whether the subject is trying to suppress or retrieve a memory. These regions are all implicated in memory recall, but their individual activity patterns show distinct memory-strength-related responses when task goals are varied. In parietal lobe, default network, and hippocampus, top-down control can override the commonly identified effects of memory strength.
doi:10.1371/journal.pone.0089037
PMCID: PMC3929625  PMID: 24586492
11.  Stability of resting fMRI interregional correlations analyzed in subject-native space: a one-year longitudinal study in healthy adults and premanifest Huntington’s disease 
Neuroimage  2011;59(3):2452-2463.
The pattern of interregional functional MRI correlations at rest is being actively considered as a potential noninvasive biomarker in multiple diseases. Before such methods can be used in clinical studies it is important to establish their usefulness in three ways. First, the long-term stability of resting correlation patterns should be characterized, but there have been very few such studies. Second, analysis of resting correlations should account for the unique neuroanatomy of each subject by taking measurements in native space and avoiding transformation of functional data to a standard volume space (e.g., Talairach-Tournox or Montreal Neurological Institute atlases). Transformation to a standard volume space has been shown to variably influence the measurement of functional correlations, and this is a particular concern in diseases which may cause structural changes in the brain. Third, comparisons within the patient population of interest and comparisons between patients and age-matched controls, should demonstrate sensitivity to any disease-related disruption of resting functional correlations. Here we examine the test-retest stability of resting fMRI correlations over a period of one year in a group of healthy adults and in a group of cognitively intact individuals who are gene-positive for Huntington’s disease. A recently-developed method is used to measure functional correlations in the native space of individual subjects. The utility of resting functional correlations as a biomarker in premanifest Huntington’s disease is also investigated. Results in control and premanifest Huntington’s populations were both highly consistent at the group level over one year. We thus show that when resting fMRI analysis is performed in native space (to reduce confounds in registration between subjects and groups) it has good long-term stability at the group level. Individual-subject level results were less consistent between visit 1 and visit 2, suggesting further work is required before resting fMRI correlations can be useful diagnostically for individual patients. No significant effect of premanifest Huntington’s disease on prespecified interregional fMRI correlations was observed relative to the control group using either baseline or longitudinal measures. Within the premanifest Huntington’s group, though, there was evidence that decreased striatal functional correlations might be associated with disease severity, as gauged by estimated years to symptom onset or by striatal volume.
doi:10.1016/j.neuroimage.2011.08.105
PMCID: PMC3254727  PMID: 21945695
test-retest; reliability; default network; fMRI; functional connectivity
12.  Reaction time, memory strength, and fMRI activity during memory retrieval: Hippocampus and default network are differentially responsive during recollection and familiarity judgments 
Cognitive neuroscience  2011;2(1):19-23.
Retrieval is often subdivided into recollection and familiarity. Memory-strength and reaction time (RT) differ for each, complicating fMRI studies of these processes. Recollection leads to greater activity in the hippocampus and default network (DN). Increased DN activity with recollection is thought to reflect self-referential processes, but prior studies have not accounted for varying RT, which modulates DN activity and is consistently faster for recollection than familiarity. This study examined the influence of RT and memory-strength on recollection and familiarity activity. The results show the hippocampus functionally dissociated from DN during retrieval. DN was generally influenced by RT and signal was suppressed when subjects were task-engaged in recollection or familiarity; suppression was greater for slower trials of either type. The hippocampus showed a positive deflection of fMRI activity only for recollection trials; activation was greater for slower recollection trials, but RT did not influence hippocampal activity during familiarity trials.
doi:10.1080/17588928.2010.513770
PMCID: PMC3026441  PMID: 21278912
memory recall; medial temporal lobe; precuneus; parietal; fMRI
13.  Heart fatty acid binding protein and Aβ-associated Alzheimer’s neurodegeneration 
Background
Epidemiological and molecular findings suggest a relationship between Alzheimer’s disease (AD) and dyslipidemia, although the nature of this association is not well understood.
Results
Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-β (Aβ), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF Aβ1–42 and occurred irrespective of phospho-tau181p status.
Conclusions
Our findings indicate that Aβ-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer’s disease neurodegeneration.
doi:10.1186/1750-1326-8-39
PMCID: PMC3850652  PMID: 24088526
Alzheimer’s disease; Fatty acids; Lipids; Amyloid; Tau; Brain atrophy
14.  Default network correlations analyzed on native surfaces 
Journal of neuroscience methods  2011;198(2):301-311.
Disruptions of interregional correlations in the blood oxygenation level dependent fMRI signal have been reported in multiple diseases, including Alzheimer’s disease and mild cognitive impairment. “Default network” regions that overlap with areas of earliest amyloid deposition have been highlighted by these reports, and abnormal default network activity is also observed in unimpaired elderly subjects with high amyloid burden. However, one limitation of current methods for analysis of interregional correlations is that they rely on transformation of functional data to an atlas volume (e.g., Talairach-Tournoux or Montreal Neurological Institute atlases) and may not adequately account for anatomic variation between subjects, particularly in the presence of atrophy. We assessed the utility of the FreeSurfer cortical parcellation to analyze default network functional correlations on the native surfaces of individual subjects. Group-level quantitative analysis was accomplished by comparing correlations between equivalent structures in different subjects. The method was applied to resting-state fMRI data from young, healthy subjects; preliminary results were also obtained from cognitively unimpaired elderly subjects and patients with Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies.
doi:10.1016/j.jneumeth.2011.04.010
PMCID: PMC3111080  PMID: 21514321
resting state; default network; fMRI; functional connectivity; dementia; FreeSurfer; atlas; registration
15.  Search-Related Suppression of Hippocampus and Default Network Activity during Associative Memory Retrieval 
Episodic memory retrieval involves the coordinated interaction of several cognitive processing stages such as mental search, access to a memory store, associative re-encoding, and post-retrieval monitoring. The neural response during memory retrieval is an integration of signals from multiple regions that may subserve supportive cognitive control, attention, sensory association, encoding, or working memory functions. It is particularly challenging to dissociate contributions of these distinct components to brain responses in regions such as the hippocampus, which lies at the interface between overlapping memory encoding and retrieval, and “default” networks. In the present study, event-related functional magnetic resonance imaging (fMRI) and measures of memory performance were used to differentiate brain responses to memory search from subcomponents of episodic memory retrieval associated with successful recall. During the attempted retrieval of both poorly and strongly remembered word pair associates, the hemodynamic response was negatively deflected below baseline in anterior hippocampus and regions of the default network. Activations in anterior hippocampus were functionally distinct from those in posterior hippocampus and negatively correlated with response times. Thus, relative to the pre-stimulus period, the hippocampus shows reduced activity during intensive engagement in episodic memory search. Such deactivation was most salient during trials that engaged only pre-retrieval search processes in the absence of successful recollection or post-retrieval processing. Implications for interpretation of hippocampal fMRI responses during retrieval are discussed. A model is presented to interpret such activations as representing modulation of encoding-related activity, rather than retrieval-related activity. Engagement in intensive mental search may reduce neural and attentional resources that are otherwise tonically devoted to encoding an individual’s stream of experience into episodic memory.
doi:10.3389/fnhum.2011.00112
PMCID: PMC3202230  PMID: 22046159
fMRI; hippocampus; default network; memory; retrieval
16.  Parietal activity in episodic retrieval measured by fMRI and MEG 
NeuroImage  2010;55(2):788-793.
Understanding the functional role of the left lateral parietal cortex in episodic retrieval requires characterization of both spatial and temporal features of activity during memory tasks. In a recent study using magnetoencephalography (MEG), we described an early parietal response in a cued-recall task. This response began within 100 milliseconds of the retrieval cue and lasted less than 400 milliseconds. Spatially, the effect reached significance in all three anatomically defined left lateral parietal subregions included in the study. Here we present a multimodal analysis of both hemodynamic and electrophysiologic responses in the same cued-recall paradigm. Functional MRI (fMRI) was used to more precisely reveal the portion of the parietal cortex with the greatest response. The MEG data set was then reanalyzed to show the early MEG time course of the region identified by fMRI. We found that the hemodynamic response is greatest within the intraparietal sulcus. Further, the MEG pattern in this region shows a strong response during the first 300 milliseconds following the cue to retrieve. Finally, when individual-dipole MEG activity is analyzed for the left cortical surface over the early 300-millisecond time window, significant recall-related activity is limited to a relatively small portion of the left hemisphere that overlaps the region identified by fMRI in the intraparietal sulcus.
doi:10.1016/j.neuroimage.2010.11.078
PMCID: PMC3035726  PMID: 21134473
parietal; memory; retrieval; recall; fMRI; MEG
17.  Biomarkers for the clinical evaluation of the cognitively impaired elderly: amyloid is not enough 
Imaging in medicine  2012;4(3):343-357.
The number of elderly patients seeking clinical treatment for memory problems will rise sharply in coming years as our population ages. These patients present a challenge for diagnosis and prognosis since cognitive problems in older patients can arise from many etiologies, some of which are curable. With the development of clinically available biomarkers for detecting Alzheimer’s disease pathology in living patients, evaluation of cognitively impaired elderly patients is about to undergo a major paradigm shift. This article describes the two classes of biomarkers available for assessing Alzheimer’s disease risk: those that indicate presence of amyloid pathology and those that provide evidence of neuronal injury and neurodegeneration. We argue that, currently, incorporation of biomarkers of neurodegeneration can help in patient prognosis whereas tests for amyloid, if used in isolation, have potential for harm. Amyloid tests are clinically useful only when evidence suggests progressive cognitive decline or neurodegeneration.
doi:10.2217/iim.12.27
PMCID: PMC3573528  PMID: 23420460
Alzheimer’s disease; amyloid imaging; biomarker; florbetapir; MCI; mild cognitive impairment; MRI; PET
18.  Dissociation of Frontal and Medial Temporal Lobe Activity in Maintenance and Binding ofSequentially Presented Paired Associates 
Journal of cognitive neuroscience  2009;21(7):1244-1254.
Substructures of the prefrontal cortex (PFC) and the medial-temporal lobe are critical for associating objects presented over time. Previous studies showing frontal and medial-temporal involvement in associative encoding have not addressed the response specificity of these regions to different aspects of the task, which include instructions to associate and binding of stimuli. This study used a novel paradigm to temporally separate these two components of the task by sequential presentation of individual images with or without associative instruction; fMRI was used to investigate the temporal involvement of the PFC and the parahippocampal cortex in encoding each component. Although both regions showed an enhanced response to the second stimulus of a pair, only the PFC had increased activation during the delay preceding a stimulus when associative instruction was given. These findings present new evidence that prefrontal and medial-temporal regions provide distinct temporal contributions during associative memory formation.
doi:10.1162/jocn.2009.21096
PMCID: PMC2674124  PMID: 18752401
20.  Amyloid-β associated volume loss occurs only in the presence of phospho-tau 
Annals of Neurology  2011;70(4):657-661.
The relationship between neurodegeneration and the two hallmark proteins of Alzheimer's disease, amyloid-β (Aβ) and tau, is still unclear. Here, we examined 286 non-demented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal MR imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy, CSF p-tau181p and CSF Aβ1-42. We found a significant relationship between elevated entorhinal cortex atrophy and decreased CSF Aβ1-42 only with elevated CSF p-tau181p. Our findings indicate that Aβ-associated volume loss occurs only in the presence of phospho-tauin humans at risk for dementia.
doi:10.1002/ana.22509
PMCID: PMC3368003  PMID: 22002658
21.  Amyloid-β associated clinical decline occurs only in the presence of elevated p-tau 
Archives of neurology  2012;69(6):709-713.
Objective
To elucidate the relationship between the two hallmark proteins of Alzheimer's disease (AD), amyloid-β (Aβ) and tau, and clinical decline over time among cognitively normal older individuals.
Design
A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments.
Setting
Research centers across the United States and Canada.
Patients
We examined one hundred seven participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination.
Main Outcome Measures
Using linear mixed effects models, we investigated the relationship between CSF p-tau181p, CSF Aβ1-42 and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog).
Results
We found a significant relationship between decreased CSF Aβ1-42 and longitudinal change in global CDR, CDR-SB, and ADAS-cog in individuals with elevated CSF p-tau181p. In the absence of CSF p-tau181p, the effect of CSF Aβ1-42 on longitudinal clinical decline was not significantly different from zero.
Conclusions
In cognitively normal older individuals, Aβ-associated clinical decline over a mean of three years may occur only in the presence of ongoing, “downstream” neurodegeneration.
doi:10.1001/archneurol.2011.3354
PMCID: PMC3423526  PMID: 22529247
22.  Early Parietal Response in Episodic Retrieval Revealed With MEG 
Human brain mapping  2011;32(2):171-181.
Recent neuroimaging and lesion studies have led to competing hypotheses for potential roles of the left lateral parietal lobe in episodic memory retrieval. These hypotheses may be dissociated by whether they imply a role in preretrieval or postretrieval processes. For example, one hypothesis is the left parietal cortex (particularly in more ventral subregions) forms part of an “episodic buffer” that supports the online representation of the retrieved target, a role that is, by definition, postretrieval. An alternate view maintains parietal activity (particularly in more dorsal subregions) contributes to top-down orientation of attention to retrieval search, a preretrieval role. The present investigation seeks to reveal the earliest onset of lateral parietal activity in three anatomically-defined subregions of the left lateral parietal cortex to identify any preretrieval activation. Subjects performed a pair-cued recall task while neural activity was recorded with magnetoencephalography (MEG) at millisecond temporal resolution. MEG data were then mapped to each subject’s cortical surface using dynamic statistical parametric mapping (dSPM). Both dorsal and ventral regions showed retrieval-related activations beginning within ~100 ms of the cue to retrieve and lasting up to 400 ms. We conclude that this early and transient pattern of activity in lateral parietal cortex is most consistent with a preretrieval role, possibly in directing attention to episodic memory retrieval.
doi:10.1002/hbm.21014
PMCID: PMC3107600  PMID: 20623759
long-term memory; cued recall; attention; magnetoencephalography; dSPM; human
23.  Quantitative structural MRI for early detection of Alzheimer’s disease 
Expert review of neurotherapeutics  2010;10(11):1675-1688.
Alzheimer’s disease (AD) is a common progressive neurodegenerative disorder that is not currently diagnosed until a patient reaches the stage of dementia. There is a pressing need to identify AD at an earlier stage, so that treatment, when available, can begin early. Quantitative structural MRI is sensitive to the neurodegeneration that occurs in mild and preclinical AD, and is predictive of decline to dementia in individuals with mild cognitive impairment. Objective evidence of ongoing brain atrophy will be critical for risk/benefit decisions once potentially aggressive, disease-modifying treatments become available. Recent advances have paved the way for the use of quantitative structural MRI in clinical practice, and initial clinical use has been promising. However, further experience with these measures in the relatively unselected patient populations seen in clinical practice is needed to complete translation of the recent enormous advances in scientific knowledge of AD into the clinical realm.
doi:10.1586/ern.10.162
PMCID: PMC3182103  PMID: 20977326
amyloid; biomarker; CSF; mild cognitive impairment; prodromal Alzheimer’s disease; quantitative neuroimaging; volumetric imaging
24.  Brain Atrophy in Healthy Aging Is Related to CSF Levels of Aβ1-42 
Cerebral Cortex (New York, NY)  2010;20(9):2069-2079.
Reduced levels of β-amyloid1-42 (Aβ1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer’s disease (AD), likely reflecting Aβ deposition in plaques and neuronal and axonal damage. It is not known whether these biomarkers are associated with brain atrophy also in healthy aging. We tested the relationship between CSF levels of Aβ1-42 and tau (total tau and tau phosphorylated at threonine 181) proteins and 1-year brain atrophy in 71 cognitively normal elderly individuals. Results showed that under a certain threshold value, levels of Aβ1-42 correlated highly with 1-year change in a wide range of brain areas. The strongest relationships were not found in the regions most vulnerable early in AD. Above the threshold level, Aβ1-42 was not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded that Aβ1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals but that reductions independent of CSF levels of Aβ1-42 is common. Further research and follow-up examinations over several years are needed to test whether degenerative pathology will eventually develop in the group of cognitively normal elderly individuals with low levels of Aβ1-42.
doi:10.1093/cercor/bhp279
PMCID: PMC3025722  PMID: 20051356
aging; amyloid; cerebral cortex; CSF biomarkers; MRI
25.  Early Stages of Figure–Ground Segregation during Perception of the Face–Vase 
Journal of cognitive neuroscience  2010;23(4):880-895.
The temporal sequence of neural processes supporting figure–ground perception was investigated by recording ERPs associated with subjects’ perceptions of the face–vase figure. In Experiment 1, subjects continuously reported whether they perceived the face or the vase as the foreground figure by pressing one of two buttons. Each button press triggered a probe flash to the face region, the vase region, or the borders between the two. The N170/vertex positive potential (VPP) component of the ERP elicited by probes to the face region was larger when subjects perceived the faces as figure. Preceding the N170/VPP, two additional components were identified. First, when the borders were probed, ERPs differed in amplitude as early as 110 msec after probe onset depending on subjects’ figure–ground perceptions. Second, when the face or vase regions were probed, ERPs were more positive (at ~150–200 msec) when that region was perceived as figure versus background. These components likely reflect an early “border ownership” stage, and a subsequent “figure–ground segregation” stage of processing. To explore the influence of attention on these stages of processing, two additional experiments were conducted. In Experiment 2, subjects selectively attended to the face or vase region, and the same early ERP components were again produced. In Experiment 3, subjects performed an identical selective attention task, but on a display lacking distinctive figure–ground borders, and neither of the early components were produced. Results from these experiments suggest sequential stages of processing underlying figure–ground perception, each which are subject to modifications by selective attention.
doi:10.1162/jocn.2010.21438
PMCID: PMC3071650  PMID: 20146604

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