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.
test-retest; reliability; default network; fMRI; functional connectivity
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.
memory recall; medial temporal lobe; precuneus; parietal; fMRI
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.
Alzheimer’s disease; amyloid imaging; biomarker; florbetapir; MCI; mild cognitive impairment; MRI; PET
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.
resting state; default network; fMRI; functional connectivity; dementia; FreeSurfer; atlas; registration
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.
parietal; memory; retrieval; recall; fMRI; MEG
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.
fMRI; hippocampus; default network; memory; retrieval
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.
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.
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 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).
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.
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.
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.
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.
long-term memory; cued recall; attention; magnetoencephalography; dSPM; human
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.
amyloid; biomarker; CSF; mild cognitive impairment; prodromal Alzheimer’s disease; quantitative neuroimaging; volumetric imaging
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.
aging; amyloid; cerebral cortex; CSF biomarkers; MRI
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.
Recent findings suggest that functional brain imaging might be used to identify consciousness in patients diagnosed with persistent vegetative state and minimally conscious state. Michael Rafii and James Brewer discuss the potential for fMRI's wider implementation in clinical practice, and associated caveats.
Brain atrophy and altered CSF-levels of amyloid beta (Aβ42) and the microtubule-associated protein tau are potent biomarkers of Alzheimer's Disease (AD) related pathology. However, the relationship between CSF biomarkers and brain morphometry is poorly understood. Thus, we addressed the following questions: (1) Can CSF biomarker levels explain the morphometric differences between normal controls (NC) and patients with mild cognitive impairment (MCI) or AD? (2) How are CSF biomarkers related to atrophy across the brain? (3) How closely are CSF biomarkers and morphometry related to clinical change (CDR sum of boxes [CDR-sb])? 370 participants (105 NC/ 175 MCI/ 90 AD) from the Alzheimer's Disease Neuroimaging Initiative were studied, of whom 309 were followed for one and 176 for two years. Analyses were performed across the entire cortical surface, as well as for 30 cortical and subcortical regions of interest (ROIs). Results showed that CSF biomarker levels could not account for group differences in brain morphometry at baseline but that CSF biomarker levels showed moderate relationships to longitudinal atrophy rates in numerous brain areas, not restricted to medial temporal structures. Baseline morphometry was at least as predictive of atrophy as were CSF biomarkers. Even MCI patients with levels of Aβ42 comparable to controls and of p-tau lower than controls showed more atrophy than the controls. Morphometry predicted change in CDR-sb better than did CSF biomarkers. These results indicate that morphometric changes in MCI and AD are not secondary to CSF biomarker changes, and that the two types of biomarkers yield complementary information.
Alzheimer's disease; Magnetoencephalography; ABeta-peptide; Phosphorylation; Hippocampus; Cerebral cortex; Entorhinal cortex; Parahippocampal cortex
An accurate description of changes in the brain in healthy aging is needed to understand the basis of age-related changes in cognitive function. Cross-sectional magnetic resonance imaging (MRI) studies suggest thinning of the cerebral cortex, volumetric reductions of most subcortical structures and ventricular expansion. However, there is a paucity of detailed longitudinal studies to support the cross-sectional findings. In the present study, 142 healthy elderly participants (60–91 years) were followed with repeated MRI, and were compared to 122 patients with mild to moderate Alzheimer's disease (AD). Volume changes were measured across the entire cortex and in 48 regions of interest (ROIs). Cortical reductions in the healthy elderly were extensive after only one year, especially evident in temporal and prefrontal cortex where annual decline was about 0.5%. All subcortical and ventricular regions except caudate nucleus and the 4th ventricle changed significantly over one year. Some of the atrophy occurred in areas vulnerable to AD, while other changes were observed in areas less characteristic of the disease in early stages. This suggests that the changes are not primarily driven by degenerative processes associated with AD, although it is likely that preclinical changes associated with AD are superposed on changes due to normal aging in some subjects, especially in the temporal lobes. Finally, atrophy was found to accelerate with increasing age, and this was especially prominent in areas vulnerable to AD. Thus, it is possible that the accelerating atrophy with increasing age is due to preclinical AD.
MRI; aging; longitudinal; ADNI; cerebral cortex; hippocampus
Medial temporal lobe (MTL) atrophy is associated with increased risk for conversion to Alzheimer's disease (AD), but manual tracing techniques and even semi-automated techniques for volumetric assessment are not practical in the clinical setting. In addition, most studies that examined MTL atrophy in AD have focused only on the hippocampus. It is unknown the extent to which volumes of amygdala and temporal horn of the lateral ventricle predict subsequent clinical decline. This study examined whether measures of hippocampus, amygdala, and temporal horn volume predict clinical decline over the following 6-month period in patients with mild cognitive impairment (MCI). Fully-automated volume measurements were performed in 269 MCI patients. Baseline volumes of the hippocampus, amygdala, and temporal horn were evaluated as predictors of change in Mini-mental State Exam (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR SB) over a 6-month interval. Fully-automated measurements of baseline hippocampus and amygdala volumes correlated with baseline delayed recall scores. Patients with smaller baseline volumes of the hippocampus and amygdala or larger baseline volumes of the temporal horn had more rapid subsequent clinical decline on MMSE and CDR SB. Fully-automated and rapid measurement of segmental MTL volumes may help clinicians predict clinical decline in MCI patients.