-
[show abstract]
[hide abstract]
ABSTRACT: 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. © 2013 Wiley Periodicals, Inc.
Hippocampus 02/2013; · 5.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Journal of Cognitive Neuroscience 11/2012; · 5.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Imaging in medicine 06/2012; 4(3):343-357.
-
[show abstract]
[hide abstract]
ABSTRACT: To elucidate the relationship between the 2 hallmark proteins of Alzheimer disease (AD), amyloid-(Aβ) and tau, and clinical decline over time among cognitively normal older individuals.
A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments.
Research centers across the United States and Canada.
We examined 107 participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination.
Using linear mixed effects models, we investigated the relationship between cerebrospinal fluid (CSF) phospho-tau 181 (p-tau(181p)),CSF Aβ(1-42), and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes, and the Alzheimer Disease Assessment Scale-cognitive subscale.
We found a significant relationship between decreased CSF Aβ(1-42) and longitudinal change in global CDR,CDR-Sum of Boxes, and Alzheimer Disease Assessment Scale-cognitive subscale in individuals with elevated CSFp-tau(181p). In the absence of CSF p-tau(181p), the effect of CSF Aβ(1-42) on longitudinal clinical decline was not significantly different from 0.
In cognitively normal older individuals,A-associated clinical decline during a mean of 3 years may occur only in the presence of ongoing downstream neurodegeneration.
Archives of neurology 04/2012; 69(6):709-13. · 6.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Given the diversity of stimuli encountered in daily life, a variety of strategies must be used for learning new information. Relating and encoding visual and verbal stimuli into memory has been probed using various tasks and stimulus types. Engagement of specific subsequent memory and cortical processing regions depends on the stimulus modality of studied material; however, it remains unclear whether different encoding strategies similarly influence regional activity when stimulus type is held constant. In this study, participants encoded object pairs using a visual or verbal associative strategy during fMRI, and subsequent memory was assessed for pairs encoded under each strategy. Each strategy elicited distinct regional processing and subsequent memory effects: middle/superior frontal, lateral parietal, and lateral occipital for visually associated pairs and inferior frontal, medial frontal, and medial occipital for verbally associated pairs. This regional selectivity mimics the effects of stimulus modality, suggesting that cortical involvement in associative encoding is driven by strategy and not simply by stimulus type. The clinical relevance of these findings, probed in a patient with a recent aphasic stroke, suggest that training with strategies utilizing unaffected cortical regions might improve memory ability in patients with brain damage.
Journal of Cognitive Neuroscience 03/2012; 24(6):1398-410. · 5.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To apply a recently developed native-space (or native-surface) method to compare resting functional magnetic resonance (MR) imaging correlations (functional connectivity) measured in patients with Parkinson-related dementia (PRD) to those measured in cognitively unimpaired, age-matched control subjects with or without Parkinson disease (PD).
The study was approved by the institutional review board and complied with HIPAA regulations. Participants included cognitively unimpaired elderly individuals (n = 19), cognitively unimpaired patients with PD (n = 19), and patients with PRD (n = 18). Resting functional MR data were assessed by calculating correlation coefficients between blood oxygen level-dependent time series of a seed region and of other regions of interest selected a priori. Two seeds were used: a medial parietal region that contributes to the default network affected in Alzheimer disease and the caudate, which is affected by loss of dopaminergic inputs in PD. Correlation analyses were performed in the native space of individual subjects to avoid confounds from transformation to an average brain. Two-sample t tests were applied to data from each native-surface region of interest, and vertex-wise comparisons were made by using two-sample t tests at each vertex on the group surface; statistical results were corrected for multiple comparisons. Cortical thickness and striatal volumes were also compared across groups for the regions of interest.
Corticostriatal functional correlations were decreased in PRD patients relative to elderly control subjects in bilateral prefrontal regions; largest difference was observed in the right caudal middle frontal region (r = 0.48 in PRD patients and 0.81 in elderly control subjects, uncorrected P = .001). Conversely, there was no significant difference across groups in the strength of default-network correlations. There was also no significant difference across groups in cortical thickness or striatal volume.
PRD was associated with selective disruption of corticostriatal resting functional MR imaging correlations, which suggests that resting functional MR imaging analyzed in subject-native space may be a useful biomarker in this disease. Additionally, at least in the present cohort, this technique was more sensitive to PRD changes than was quantitative structural MR imaging.
Radiology 02/2012; 263(1):226-34. · 5.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The relationship between neurodegeneration and the 2 hallmark proteins of Alzheimer's disease, amyloid-β (Aβ) and tau, is still unclear. Here, we examined 286 nondemented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal magnetic resonance (MR) imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy rate, cerebrospinal fluid (CSF) p-tau(181p) and CSF Aβ(1-42) . We found a significant relationship between elevated entorhinal cortex atrophy rate and decreased CSF Aβ(1-42) only with elevated CSF p-tau(181p) . Our findings indicate that Aβ-associated volume loss occurs only in the presence of phospho-tau in humans at risk for dementia.
Annals of Neurology 10/2011; 70(4):657-61. · 11.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
NeuroImage 09/2011; 59(3):2452-63. · 5.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Brain Imaging and Behavior 09/2011; 6(1):16-26. · 1.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Journal of neuroscience methods 06/2011; 198(2):301-11. · 2.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To assess whether single-time-point and longitudinal volumetric magnetic resonance (MR) imaging measures provide predictive prognostic information in patients with amnestic mild cognitive impairment (MCI).
This study was conducted with institutional review board approval and in compliance with HIPAA regulations. Written informed consent was obtained from all participants or the participants' legal guardians. Cross-validated discriminant analyses of MR imaging measures were performed to differentiate 164 Alzheimer disease (AD) cases from 203 healthy control cases. Separate analyses were performed by using data from MR images obtained at one time point or by combining single-time-point measures with 1-year change measures. Resulting discriminant functions were applied to 317 MCI cases to derive individual patient risk scores. Risk of conversion to AD was estimated as a continuous function of risk score percentile. Kaplan-Meier survival curves were computed for risk score quartiles. Odds ratios (ORs) for the conversion to AD were computed between the highest and lowest quartile scores.
Individualized risk estimates from baseline MR examinations indicated that the 1-year risk of conversion to AD ranged from 3% to 40% (average group risk, 17%; OR, 7.2 for highest vs lowest score quartiles). Including measures of 1-year change in global and regional volumes significantly improved risk estimates (P = 001), with the risk of conversion to AD in the subsequent year ranging from 3% to 69% (average group risk, 27%; OR, 12.0 for highest vs lowest score quartiles).
Relative to the risk of conversion to AD conferred by the clinical diagnosis of MCI alone, MR imaging measures yield substantially more informative patient-specific risk estimates. Such predictive prognostic information will be critical if disease-modifying therapies become available.
http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101975/-/DC1.
Radiology 04/2011; 259(3):834-43. · 5.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 (ms) of the retrieval cue and lasted less than 400 ms. 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 ms 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.
NeuroImage 03/2011; 55(2):788-93. · 5.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Cognitive neuroscience 03/2011; 2(1):19-23. · 0.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Human Brain Mapping 02/2011; 32(2):171-81. · 5.88 Impact Factor
-
J. Cognitive Neuroscience. 01/2011; 23:880-895.
-
[show abstract]
[hide abstract]
ABSTRACT: The process of associating items encountered over time and across variable time delays is fundamental for creating memories in daily life, such as for stories and episodes. Forming associative memory for temporally discontiguous items involves medial temporal lobe structures and additional neocortical processing regions, including prefrontal cortex, parietal lobe, and lateral occipital regions. However, most prior memory studies, using concurrently presented stimuli, have failed to examine the temporal aspect of successful associative memory formation to identify when activity in these brain regions is predictive of associative memory formation. In the current study, functional MRI data were acquired while subjects were shown pairs of sequentially presented visual images with a fixed interitem delay within pairs. This design allowed the entire time course of the trial to be analyzed, starting from onset of the first item, across the 5.5-s delay period, and through offset of the second item. Subjects then completed a postscan recognition test for the items and associations they encoded during the scan and their confidence for each. After controlling for item-memory strength, we isolated brain regions selectively involved in associative encoding. Consistent with prior findings, increased regional activity predicting subsequent associative memory success was found in anterior medial temporal lobe regions of left perirhinal and entorhinal cortices and in left prefrontal cortex and lateral occipital regions. The temporal separation within each pair, however, allowed extension of these findings by isolating the timing of regional involvement, showing that increased response in these regions occurs during binding but not during maintenance.
Journal of Neurophysiology 01/2011; 105(4):1454-63. · 3.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Frontiers in Human Neuroscience 01/2011; 5:112. · 2.34 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Expert Review of Neurotherapeutics 11/2010; 10(11):1675-88.
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Expert Review of Neurotherapeutics 10/2010; 10(11):1675-1688.
-
[show abstract]
[hide abstract]
ABSTRACT: To quantify the effect sizes of regional metabolic and morphometric measures in patients with preclinical and mild Alzheimer disease (AD) to aid in the identification of noninvasive biomarkers for the early detection of AD.
The study was conducted with institutional review board approval and in compliance with HIPAA regulations. Written informed consent was obtained from each participant or participant's legal guardian. Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging data were analyzed from 80 healthy control (HC) subjects, 68 individuals with AD, and 156 with amnestic mild cognitive impairment (MCI), 69 of whom had single-domain amnestic MCI. Regions of interest (ROIs) were derived after coregistering FDG PET and MR images by using high-throughput, subject-specific procedures. The Cohen d effect sizes were calculated for 42 predefined ROIs across the brain. Statistical comparison of the largest overall effect sizes for MR imaging and PET was performed. Metabolic effect sizes were determined with and without accounting for regional atrophy. Discriminative accuracy of ROIs showing the largest effect sizes were compared by calculating receiver operating characteristic curves.
For all disease groups, the hippocampus showed the largest morphometric effect size and the entorhinal cortex showed the largest metabolic effect size. In mild AD, the Cohen d effect size for hippocampal volume (1.92) was significantly larger (P < .05) than that for entorhinal metabolism (1.43). Regression of regional atrophy substantially reduced most metabolic effects. For all group comparisons, the areas under the receiver operating characteristic curves were significantly larger for hippocampal volume than for entorhinal metabolism.
The current results show no evidence that FDG PET is more sensitive than MR imaging to the degeneration occurring in preclinical and mild AD, suggesting that an MR imaging finding may be a more practical clinical biomarker for early detection of AD.
Radiology 09/2010; 256(3):932-42. · 5.73 Impact Factor
