Severity of white matter hyperintensities: Lesion patterns,cognition, and microstructural changes

White matter hyperintensity (WMH) is a common finding in aging population and considered to be a contributor to cognitive decline. Our study aimed to characterize the spatial patterns of WMH in different severities and explore its impact on cognition and brain microstructure in non-demented elderly. Lesions were both qualitatively (Fazekas scale) and quantitatively assessed among 321 community-dwelled individuals with MRI scanning. Voxel- and atlas-based analyses of the whole-brain white matter microstructure were performed. The WMH of the same severities was found to occur uniformly with a specific pattern of lesions. The severity of WMH had a significant negative association with the performance of working and episodic memory, beginning to appear in Fazekas 3 and 4. The white matter tracts presented significant impairments in Fazekas 3, which showed brain-wide changes above Fazekas 4. Lower FA in the superior cerebellar peduncle and left posterior thalamic radiation was mainly associated with episodic memory, and the middle cerebellar peduncle was significantly associated with working memory. These results support that memory is the primary domain to be affected by WMH, and the effect may potentially be influenced by tract-specific WM abnormalities. Fazekas scale 3 might be the critical stage predicting a future decline in cognition.     

Executive function mediates effects of white matter hyperintensities on episodic memory

This study examined the relationship between white matter hyperintensities (WMH) and executive functioning on episodic memory in a group of older adults who were cognitively normal or diagnosed with MCI or dementia. Volumetric magnetic resonance imaging (MRI) measures of total brain volume, white matter hyperintensity volume, and hippocampal volume along with age, education, and gender were evaluated as predictors of episodic memory. WMH were found to influence both episodic memory and executive functioning independently of other variables. The influence WMH on episodic memory was mediated by executive functioning and was completely eliminated when the interaction between executive functioning and hippocampal volume was entered in the regression model. The results indicate that executive functioning mediates the effects of WMH on episodic memory but that executive functioning and hippocampal volume can also interact such that executive functioning can exacerbate or ameliorate the influence of hippocampal volume on episodic memory.     

Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study

Neuroanatomical substrates of age-related differences in working memory and perseverative behavior were examined in a sample of healthy adults (50–81 years old). The participants, who were screened for history of neurological, psychiatric, and medical conditions known to be linked to poor cognitive performance, underwent magnetic resonance imaging (MRI) and were administered tests of working memory and perseveration. Regional brain volumes and the volume of white matter hyperintensities (WMH) were measured on magnetic resonance images. The analyses indicate that the volume of the prefrontal cortex (PFC) and the volume of white matter hyperintensities in the prefrontal region are independently associated with age-related increases in perseverative errors on the Wisconsin Card Sorting Test (WCST). When participants taking antihypertensive medication were excluded from the analysis, both the volume of the prefrontal cortex and the frontal white matter hyperintensities (FWMH) still predicted increases in perseveration. Neither reduced volume of the prefrontal cortex nor the FWMH volume was linked to age-associated declines in working memory. The volumes of the fusiform gyrus (FG) and the temporal white matter hyperintensities (TWMH) were unrelated to cognitive performance.     

Neural mechanisms of voluntary and involuntary recall: a PET study

Neuropsychological and neuroimaging studies on episodic memory retrieval have primarily focused on volitional memory tasks. However, some conscious memories arise involuntarily, i.e. without a strategic retrieval attempt, yet little is known about the neural network underlying involuntary episodic memory. The aim of this study was to determine whether voluntary and involuntary recall are mediated by separate cortical networks. We used positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) in 12 healthy subjects during voluntary and involuntary cued recall of pictures and a control condition with no episodic memory requirements. Involuntary recall was elicited by using an incidental memory task. Compared to the control condition, voluntary and involuntary recall were both associated with significant regional cerebral blood flow (rCBF) increases in posterior cingulate gyrus (PCG; BA 23), left precuneus (BA 7), and right parahippocampal gyrus (BA 35/36). In addition, rCBF in right dorsolateral prefrontal cortex (PFC; BA 8/9) and left precuneus (BA 7) was significantly larger during voluntary compared to involuntary recall, while rCBF was enhanced in left dorsolateral PFC (BA 9) during involuntary recall. The findings corroborate an association of the right PFC with a strategic component of episodic memory retrieval. Moreover, they show for the first time that it is possible to activate the medial temporal lobe, the PCG, and the precuneus, regions normally associated with retrieval success, without this strategic element. The relatively higher activity in precuneus during voluntary compared to involuntary recall suggests that activity in this region co-varies not only with retrieval success but also with retrieval intentionality.     

Correlates of memory function in community-dwelling elderly: the importance of white matter hyperintensities.

We sought to identify magnetic resonance- (MR)-imaged structures associated with declarative memory in a community-dwelling sample of elderly Mexican-American individuals with a spectrum of cognitive decline. Measured structures were the hemispheric volumes of the hippocampus (HC), parahippocampal gyrus, and remaining temporal lobes, as well as severity of white matter signal hyperintensities (WMH). Participants were an imaged subsample from the Sacramento Area Latino Study of Aging (SALSA), N = 122. Individuals were categorized as normal, memory impaired (MI), cognitively impaired non-demented (CIND), or demented. We show that WMH was the strongest structural predictor for performance on a delayed free-recall task (episodic memory) in the entire sample. The association of WMH with delayed recall was most prominent in elderly normals and mildly cognitively impaired individuals with no dementia or impairment of daily function. However, the left HC was associated with verbal delayed recall only in people with dementia. The right HC volume predicted nonverbal semantic-memory performance. We conclude that WMH are an important pathological substrate that affects certain memory functions in normal individuals and those with mild memory loss and discuss how tasks associated with WMH may rely upon frontal lobe function.     

Estimated Regional White Matter Hyperintensity Burden,Resting State Functional Connectivity,and Cognitive Functions in Older Adults

ObjectiveWhite matter hyperintensities (WMH) are linked to deficits in cognitive functioning, including cognitive control and memory; however, the structural, and functional mechanisms are largely unknown. We investigated the relationship between estimated regional disruptions to white matter fiber tracts from WMH, resting state functional connectivity (RSFC), and cognitive functions in older adults.DesignCross-sectional study.SettingCommunity.ParticipantsFifty-eight cognitively-healthy older adults.MeasurementsTasks of cognitive control and memory, structural MRI, and resting state fMRI. We estimated the disruption to white matter fiber tracts from WMH and its impact on gray matter regions in the cortical and subcortical frontoparietal network, default mode network, and ventral attention network by overlaying each subject's WMH mask on a normative tractogram dataset. We calculated RSFC between nodes in those same networks. We evaluated the interaction of regional WMH burden and RSFC in predicting cognitive control and memory.ResultsThe interaction of estimated regional WMH burden and RSFC in cortico-striatal regions of the default mode network and frontoparietal network was associated with delayed recall. Models predicting working memory, cognitive inhibition, and set-shifting were not significant.ConclusionFindings highlight the role of network-level structural and functional alterations in resting state networks that are related to WMH and impact memory in older adults.     

Different mechanisms of episodic memory failure in mild cognitive impairment

Mild cognitive impairment (MCI), defined as episodic memory impairment beyond what is expected in normal aging, is often associated with hippocampal atrophy (HA) and may represent incipient Alzheimer's disease. However, recent studies suggest that MCI is very heterogeneous and multiple etiologies likely exist. One possibility is small vessel cerebrovascular disease (CVD). Specifically, we hypothesized that white matter hyperintensities (WMH), an MRI marker for CVD, would lead to impairments in executive control processes critical for working memory that may, in turn, result in episodic memory impairment. To test this hypothesis, we examined a group of subjects clinically diagnosed with MCI and used MRI to further subcategorize individuals as either MCI with severe white matter hyperintensities (MCI-WMH) or MCI with severe hippocampal atrophy (MCI-HA). MCI-WMH, MCI-HA, and matched control subjects each performed a battery of working memory and episodic memory tasks. Results showed that MCI-HA and MCI-WMH were equally impaired on the episodic memory task relative to controls, but MCI-WMH were additionally impaired on tests tapping verbal and spatial working memory abilities and attentional control processes. These results suggest that CVD and hippocampal dysfunction are associated with distinct neuropsychological profiles. Although both syndromes are associated with episodic memory deficits, CVD is additionally associated with working memory and executive control deficits.     

Control of semantic interference in episodic memory retrieval is associated with an anterior cingulate-prefrontal activation pattern

Prefrontal activation is a consistent finding in functional neuroimaging studies of episodic memory retrieval. In the present study we aimed at a further analysis of prefrontal neural systems involved in the executive control of context-specific properties in episodic memory retrieval using an event-related fMRI design. Nine subjects were asked to learn two 20-item word lists that consisted of concrete nouns assigned to four semantic categories. Ten items of both word lists referred to the same semantic category. Subjects were instructed to determine whether nouns displayed in random order corresponded to the first 20-item target list. The interference evoked by the retrieval of semantically related items of the second list resulted in significantly longer reaction times compared to the noninterference condition. Contrasting the interference against the noninterference retrieval condition demonstrated an activation pattern that comprised a right anterior cingulate and frontal opercular area and a left-lateralized dorsolateral prefrontal region. Trial averaged time series revealed that the PFC areas were selectively activated at the interference condition and did not respond to the familiarity of learned words. These findings suggest a functionally separable role of prefrontal cortical areas mediating processes associated with the executive control of interfering context information in episodic memory retrieval.     

Dissociating the “retrieval success” regions of the brain: Effects of retrieval delay

There is abundant evidence that the hippocampal formation critically supports episodic memory retrieval, the remembering of episodes including contextual details. Yet, a group of other brain regions has also been consistently implicated in successful episodic retrieval. This retrieval success network (RSN) includes the posterior midline region, medial prefrontal cortex (mPFC), and posterior parietal cortex (PPC). Despite these consistent findings, the functional roles of the RSN regions remain poorly understood. Given that vivid remembering leads to high-confidence retrieval decisions, it is unclear whether activity in these regions reflects episodic long-term memory, or is merely associated with retrieval confidence. In order to distinguish between these alternatives, we manipulated study-test delays within the context of a continuous recognition task during fMRI-scanning. The design was based on previous evidence indicating that retrieval at short delays is easier leading to high-evidence mnemonic decisions, whereas retrieval at longer delays is more difficult but also more hippocampus-dependent. Confirming previous findings, we found that retrieval decisions at short delays were more accurate and faster, and that the hippocampus showed greater activity at longer delays. Within the other RSN regions, we found three distinct activation patterns as a function of delay. Similar to the hippocampus, the retrosplenial cortex showed increased activity as a function of retrieval delay. Dorsal PPC and the precuneus showed decreased activity. Finally, the posterior cingulate, medial PFC and ventral PPC showed a V-shaped pattern. These findings support the idea that dorsal PPC and the precuneus are involved in decision-related retrieval processes rather than successful remembering.     

The relation of White Matter Hyperintensities to implicit learning in healthy older adults

OBJECTIVE: This study examined whether MRI evidence of cerebrovascular disease in the form of white matter hyperintensities (WMH) was associated with decreased implicit sequence learning performance in a high-functioning group of normal elderly volunteers. METHOD: One hundred and eight community-dwelling elderly individuals received an MRI and performed an implicit sequence learning task, the serial reaction time (SRT) task. RESULTS: Hyperintensities present in the white matter were associated with a decreased learning effect. This association was found with both deep white matter and periventricular changes. Other factors affecting SRT performance (i.e., baseline reaction time and switch-cost) were not significantly related to the presence of WMH. CONCLUSIONS: The results indicate that in addition to previously identified generalized cognitive deficits, WMH are also associated with a specific decrease in the implicit learning of sequences.     

Common prefrontal activations during working memory,episodic memory,and semantic memory

Regions of the prefrontal cortex (PFC) are typically activated in many different cognitive functions. In most studies, the focus has been on the role of specific PFC regions in specific cognitive domains, but more recently similarities in PFC activations across cognitive domains have been stressed. Such similarities may suggest that a region mediates a common function across a variety of cognitive tasks. In this study, we compared the activation patterns associated with tests of working memory, semantic memory and episodic memory. The results converged on a general involvement of four regions across memory tests. These were located in left frontopolar cortex, left mid-ventrolateral PFC, left mid-dorsolateral PFC and dorsal anterior cingulate cortex. These findings provide evidence that some PFC regions are engaged during many different memory tests. The findings are discussed in relation to theories about the functional contribution of the PFC regions and the architecture of memory.     

Mapping episodic memory

This paper presents an analysis of brain regions generally associated with a frequently used episodic memory task; visual word recognition. The results from five positron emission tomography studies of regional cerebral blood flow, involving a total of nine pairwise comparisons of brain activity related to episodic retrieval and to performance on non-episodic reference tasks, were considered. Across studies, increased activity has been observed in the right anterior and posterior prefrontal, anterior cingulate, bilateral parietal, and cerebellar regions. Decreased activity has been found in bilateral temporal and left midfrontal regions. Comparison of this activation pattern with those of other memory tasks, episodic and semantic, indicate that the right anterior and posterior prefrontal regions guide processes selectively demanded by episodic memory retrieval. There is suggestive evidence from subtraction analyses that these prefrontal regions are activated by different processing components, and analyses of functional connectivity provide further support for functional differentiation. These analyses also point to a critical role of medial-temporal brain regions in episodic retrieval. Taken together, these results show that episodic memory retrieval is mediated by an extensive set of brain regions, some of which seem to be specifically engaged by episodic remembering.     

The relationship between episodic long-term memory and white matter integrity in normal aging

It has been proposed that episodic long-term memory (LTM) declines in normal aging and may be affected by disruption of white matter networks. This was explored in 104 healthy adults aged 50-90 years in the GENIE study; white matter integrity was assessed using diffusion tensor imaging (DTI) in large regions of interest, with additional measures of white matter hyperintensities (WMH), normalized brain and hippocampal volumes. LTM was compared with executive function, working memory and information processing speed. LTM correlated significantly with DTI, WMH and whole brain volume, but not with hippocampal volume. Using linear regression, only DTI measures explained the variance (approximately 19%) in LTM; mediational analyses explored the extent to which other cognitive functions mediate the association between DTI changes and memory. The results suggest that reduced LTM performance in normal aging is related to reduced integrity of a distributed network dependent on white matter pathways supporting episodic memory.     

White matter pathways associated with working memory in normal aging

Introduction

Previous studies by our group have found that white matter integrity as determined by Diffusion Tensor Imaging (DTI) is associated with working memory decline. It has been proposed that subtle white matter integrity loss may lead to the disruption of working memory in particular because it relies on the dynamic and reiterative activity of cortico-cortical pathways.

Methods

DTI and working memory measurement were acquired for 99 adults from our GENIE study of healthy middle aged and elderly individuals. Voxel-based statistics were used to identify clusters of voxels in mean diffusivity images specifically associated with variations in working memory performance. Tractography then identified the cortico-cortical white matter pathways passing through these clusters, between the temporal, parietal and frontal cortices.

Results

Significant clusters were identified which were associated with working memory in the white matter of the temporal and frontal lobes, the cingulate gyrus, and in the thalamus. The tracts that passed through these clusters included the superior parietal lobule pathway, the medial temporo-frontal pathway, the uncinate fasciculus, the fronto-parietal fasciculus, and the cingulum.

Conclusions

Significant clusters were identified in the white matter that were associated with working memory performance. Tractography performed through these clusters identified white matter fiber tracts which pass between grey matter regions known to be activated by working memory tasks and also mirror working memory pathways suggested by previous functional connectivity imaging.     

The Impact of Strategic White Matter Hyperintensity Lesion Location on Language

ObjectiveThe impact of white matter hyperintensities (WMH) on language possibly depends on lesion location through disturbance of strategic white matter tracts. We examined the impact of WMH location on language in elderly Asians.DesignCross-sectional.SettingPopulation-based.ParticipantsEight-hundred nineteen residents of Singapore, ages (≥65 years).MeasurementsClinical, cognitive and 3T magnetic resonance imaging assessments were performed on all participants. Language was assessed using the Modified Boston Naming Test (MBNT) and Verbal Fluency (VF). Hypothesis-free region-of-interest-based (ROI) analyses based on major white matter tracts were used to determine the association between WMH location and language. Conditional dependencies between the regional WMH volumes and language were examined using Bayesian-network analysis.ResultsROI-based analyses showed that WMH located within the anterior thalamic radiation (mean difference: ?0.12, 95% confidence interval [CI]: ?0.22; ?0.02, p = 0.019) and uncinate fasciculus (mean difference: ?0.09, 95% CI: ?0.18; ?0.01, p = 0.022) in the left hemisphere were significantly associated with worse VF but did not survive multiple testing. Conversely, WMH volume in the left cingulum of cingulate gyrus was significantly associated with MBNT performance (mean difference: ?0.09, 95% CI: ?0.17; ?0.02, p = 0.016). Bayesian-network analyses confirmed the left cingulum of cingulate gyrus as a direct determinant of MBNT performance.ConclusionOur findings identify the left cingulum of cingulate gyrus as a strategic white matter tract for MBNT, suggesting that language – is sensitive to subcortical ischemic damage. Future studies on the role of sporadic ischemic lesions and vascular cognitive impairment should not only focus on total WMH volume but should also take WMH lesion location into account when addressing language.     

White matter network damage mediates association between cerebrovascular disease and cognition

To determine whether white matter network disruption mediates the association between MRI markers of cerebrovascular disease (CeVD) and cognitive impairment. Participants (n = 253, aged ≥60 years) from the Epidemiology of Dementia in Singapore study underwent neuropsychological assessments and MRI. CeVD markers were defined as lacunes, white matter hyperintensities (WMH), microbleeds, cortical microinfarcts, cortical infarcts and intracranial stenosis (ICS). White matter microstructure damage was measured as fractional anisotropy and mean diffusivity by tract based spatial statistics from diffusion tensor imaging. Cognitive function was summarized as domain-specific Z-scores.Lacunar counts, WMH volume and ICS were associated with worse performance in executive function, attention, language, verbal and visual memory. These three CeVD markers were also associated with white matter microstructural damage in the projection, commissural, association, and limbic fibers. Path analyses showed that lacunar counts, higher WMH volume and ICS were associated with executive and verbal memory impairment via white matter disruption in commissural fibers whereas impairment in the attention, visual memory and language were mediated through projection fibers.Our study shows that the abnormalities in white matter connectivity may underlie the relationship between CeVD and cognition. Further longitudinal studies are needed to understand the cause-effect relationship between CeVD, white matter damage and cognition.     

Lateralization of prefrontal activity during episodic memory retrieval: evidence for the production-monitoring hypothesis

We propose a new hypothesis concerning the lateralization of prefrontal cortex (PFC) activity during verbal episodic memory retrieval. The hypothesis states that the left PFC is differentially more involved in semantically guided information production than is the right PFC, and that the right PFC is differentially more involved in monitoring and verification than is the left PFC. This "production-monitoring hypothesis" differs from the existing "systematic-heuristic hypothesis," which proposes that the left PFC is primarily involved in systematic retrieval operations, and the right PFC in heuristic retrieval operations. To compare the two hypotheses, we measured PFC activity using positron emission tomography (PET) during the performance of four episodic retrieval tasks: stem cued recall, associative cued recall, context recognition (source memory), and item recognition. Recall tasks emphasized production processes, whereas recognition tasks emphasized monitoring processes. Stem cued recall and context-recognition tasks underscored systematic operations, whereas associative cued recall and item-recognition tasks underscored heuristic operations. Consistent with the production-monitoring hypothesis, the left PFC was more activated for recall than for recognition tasks and the right PFC was more activated for recognition than for recall tasks. Inconsistent with the systematic-heuristic hypothesis, the left PFC was more activated for heuristic than for systematic tasks and the right PFC showed the converse result. Additionally, the study yielded activation differences outside the PFC. In agreement with a previous recall/recognition PET study, anterior cingulate, cerebellar, and striatal regions were more activated for recall than for recognition tasks, and the converse occurred for posterior parietal regions. A right medial temporal lobe region was more activated for stem cued recall and context recognition than for associative cued recall and item recognition, possibly reflecting perceptual integration. In sum, the results provide evidence for the production-monitoring hypothesis and clarify the role of different brain regions typically activated in PET and functional magnetic resonance imaging (fMRI) studies of episodic retrieval.     

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.     

Prefrontal and parietal cortex in human episodic memory: an interference study by repetitive transcranial magnetic stimulation

Neuroimaging findings, including repetitive transcranial magnetic stimulation (rTMS) interference, point to an engagement of prefrontal cortex (PFC) in learning and memory. Whether parietal cortex (PC) activity is causally linked to successful episodic encoding and retrieval is still uncertain. We compared the effects of event-related active or sham rTMS (a rapid-rate train coincident to the very first phases of memoranda presentation) to the left or right intraparietal sulcus, during a standardized episodic memory task of visual scenes, with those obtained in a fully matched sample of subjects who received rTMS on left or right dorsolateral PFC during the same task. In these subjects, specific hemispheric effects of rTMS included interference with encoding after left stimulation and disruption of retrieval after right stimulation. The interference of PC-rTMS on encoding/retrieval performance was negligible, lacking specificity even when higher intensities of stimulation were applied. However, right PC-rTMS of the same intensity lengthened reaction times in the context of a purely attentive visuospatial task. These results suggest that the activity of intraparietal sulci shown in several functional magnetic resonance studies on memory, unlike that of the dorsolateral PFC, is not causally engaged to a useful degree in memory encoding and retrieval of visual scenes. The parietal activations accompanying the memorization processes could reflect the engagement of a widespread brain attentional network, in which interference on a single 'node' is insufficient for an overt disruption of memory performance.     

Serum anticholinergic activity, white matter hyperintensities, and cognitive performance

The authors investigated whether the cognitive impairments associated with white matter hyperintensities (WMH) in normal elderly subjects are exacerbated by any anticholinergic medications being taken by the subjects. Results showed serum anticholinergic activity (SAA) and WMH volume to have a synergistic interaction such that the cognitive decrements associated with increasing WMH volume were greatest in those older individuals in the highest quartile of the SAA distribution.