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Event-relating to potential dementia. Semantic processing in the course of healthy and pathological aging
No full textWhile most healthy elderly are able to manage their everyday activities, studies showed that there are both stable and declining abilities during healthy aging. For example, there is evidence that semantic memory processes which involve controlled retrieval mechanism decrease, whereas the automatic functioning of the semantic network remains intact. In contrast, patients with Alzheimer’s disease (AD) suffer from episodic and semantic memory impairments aggravating their daily functioning. In AD, severe episodic as well as semantic memory deficits are observable. While the hallmark symptom of episodic memory decline in AD is well investigated, the underlying mechanisms of semantic memory deterioration remain unclear. By disentangling the semantic memory impairments in AD, the present thesis aimed to improve early diagnosis and to find a biomarker for dementia. To this end, a study on healthy aging and a study with dementia patients were conducted investigating automatic and controlled semantic word retrieval. Besides the inclusion of AD patients, a group of participants diagnosed with semantic dementia (SD) – showing isolated semantic memory loss – was assessed.
Automatic and controlled semantic word retrieval was measured with standard neuropsychological tests and by means of event-related potentials (ERP) recorded during the performance of a semantic priming (SP) paradigm. Special focus was directed to the N400 or N400-LPC (late positive component) complex, an ERP that is sensitive to the semantic word retrieval. In both studies, data driven topographical analyses were applied. Furthermore, in the patient study, the combination of the individual baseline cerebral blood flow (CBF) with the N400 topography of each participant was
employed in order to relate altered functional electrophysiology to the pathophysiology of dementia. Results of the aging study revealed that the automatic semantic word retrieval remains stable during healthy aging, the N400-LPC complex showed a comparable topography in contrast to the young participants. Both patient groups showed automatic SP to some extent, but strikingly the ERP topographies were altered compared to healthy controls. Most importantly, the N400 was identified as a putative marker for dementia. In particular, the degree of the topographical N400 similarity was
demonstrated to separate healthy elderly from demented patients. Furthermore, the marker was significantly related to baseline CBF reduction in brain areas relevant for semantic word retrieval. Summing up, the first major finding of the present thesis was that all groups showed semantic priming, but that the N400 topography differed significantly between healthy and demented elderly. The second major contribution was the identification of the N400 similarity as a putative marker for dementia. To conclude, the present thesis added evidence of preserved automatic processing during healthy aging. Moreover, a possible marker which might contribute to an improved diagnosis and lead consequently to a more effective treatment of dementia was presented and has to be further developed
Contralateral functional connectivity of temporal lobes in Alzheimer’s disease and semantic dementia
Full text linkIntroduction: The hippocampus (Hp) is the core region of atrophy in Alzheimer’s disease (AD), leading to
episodic memory deficits in patients. In semantic dementia (SD), degeneration of the temporal pole (Tp) has been
found to contribute to the typical semantic memory deterioration (Galton, 2001). Besides, the Hp is affected also
in SD, despite relatively spared episodic memory abilities (Good, 2002). Recent studies on network connectivity
including these two core regions showed mainly decreased functional connectivity (fc) of the Tp in SD (Guo,
2013), and of the Hp as part of networks relevant for episodic memory processes in AD (Allen, 2007). Yet other
studies have suggested that neuronal loss is accompanied by cortical reorganization which might reflect
compensatory processes to maintain cognitive functioning to some degree (Kenny, 2012). The influence of such
neuroplasticity mechanisms of the Hp and Tp in AD and SD are not well understood. To this end, the present
study investigated the fc of the Hp and the superior Tp in AD and SD as compared to healthy elderly controls
(EC).
Methods: We analyzed resting-state fMRI data from 15 patients with early AD (mean age 68, range 53–83; mean
MMSE 25.1, range 13–28), 5 with SD (age 64, 56–69; MMSE 21.4, 14–27), and 19 EC (age 68, 62–73; 28.8, 27–
30) after excluding 5 subjects with head movements (3 AD, 1 SD, 1 EC). The reason for the small SD group was
its rare prevalence. Data were acquired with a 3T scanner, using an EPI sequence (400 volumes, 26 slices, 3.0 x
3.0 x 4 mm3, TR/TE 1600ms/35ms. Prepocessing was performed in SPM8 and included slice-time correction,
realignment, coregistration, normalization, and smoothing (FWHM 8 mm). Data was high-pass filtered (1/128 Hz)
and we modeled 14 nuisance parameters (6 movement parameters and its first derivative, white matter, and
CSF). For the fc analysis, we extracted time-series from 7 AAL ROIs from the temporal lobe (Fig. 1B) to calculate
Pearson correlations. Further, the signal from the two core regions superior Tp and Hp were subjected to a seedbased
whole brain analysis.
Results: We compared temporal lobe fc among groups and found twice as many regions with a high ipsilateral fc
in the right hemisphere in SD (temp. lobe right 6; left 3) and AD (right 5; left 3) as compared to the left hemisphere
(Fig. 1A). Moreover, both patient groups demonstrated contralateral fc (SD 3; AD 2). In contrast, EC showed a
symmetric fc pattern across both hemispheres. To compare the two patient groups, we performed Wilcoxon ranksum
tests that demonstrated the largest group effect between SD and AD, which was a 20% reduction in fc
strength in SD patients between the left superior and left temporal gyrus (W = 28, p = 0.036, see Fig. 1A). Wholebrain
analysis with Hp as seed showed lower fc in the temporal pole in AD compared to EC (Fig. 2A). With Tp as
seed, SD exhibited a more distributed fc pattern than the other groups, who mainly showed insular fc (Fig. 2B).
Discussion: The strongest connected regions of the seven ROIs in the EC group can be found ipsilateral. This
favors the view of a distinct functional differentiation of the hemispheres, which is common in healthy adults. Brain
regions affected by atrophy, however, appear to reorganize the functional network by recruitment of not only
proximate and more preserved, but also distal regions such as contralateral temporal regions as found in the
patient groups of this study. Furthermore, the case of SD showed that the less atrophied right temporal lobe
generates more and stronger connections, possibly to compensate for the damage in the left hemisphere. Taken
together, our results suggest that despite a decrease of fc in degenerated brain areas shown in numerous studies
before, the preserved tissue appears to strengthen the connection to other regions previously not connected as
strongly. This mechanism might reflect the reorganization of functional networks in AD and SD, which could
improve personalized therapy.
References:
Allen, G. et al. (2007), ‘Reduced Hippocampal Functional Connectivity in Alzheimer’s disease’, Archives in
Neurology, vol. 64, no. 10, pp. 1482-1487.
Galton, C.J. et al. (2001), ‘Differing patterns of temporal atrophy in Alzheimer’s disease and semantic dementia’,
Neurology, vol. 57, pp. 216–225.
Good, C.D. et al. (2002), ‘Automatic Differentiation of Anatomical Patterns in the Human Brain: Validation with
Studies of Degenerative Dementias’, NeuroImage, vol. 17, pp. 29-46.
Guo, C.C. et al. (2013), ‘Anterior temporal lobe degeneration produces widespread network-driven dysfunction’,
Brain, vol. 136, pp. 2979-2991.
Kenny, E.R. et al. (2012), ‘Functional connectivity in cortical regions in dementia with Lewy bodies and
Alzheimer’s disease’, Brain, vol. 135, pp. 569-581
Increased sensitivity in mapping task demand in visuospatial processing using reaction-time-dependent hemodynamic response predictors in rapid event-related fMRI
No full textSearching for the neural correlates of visuospatial processing using functional magnetic resonance imaging (fMRI) is usually done in an event-related framework of cognitive subtraction, applying a paradigm comprising visuospatial cognitive components and a corresponding control task. Besides methodological caveats of the cognitive subtraction approach, the standard general linear model with fixed hemodynamic response predictors bears the risk of being underspecified. It does not take into account the variability of the blood oxygen level-dependent signal response due to variable task demand and performance on the level of each single trial. This underspecification may result in reduced sensitivity regarding the identification of task-related brain regions. In a rapid event-related fMRI study, we used an extended general linear model including single-trial reaction-time-dependent hemodynamic response predictors for the analysis of an angle discrimination task. In addition to the already known regions in superior and inferior parietal lobule, mapping the reaction-time-dependent hemodynamic response predictor revealed a more specific network including task demand-dependent regions not being detectable using the cognitive subtraction method, such as bilateral caudate nucleus and insula, right inferior frontal gyrus and left precentral gyrus
Local signal complexity and dynamic functional connectivity associated with Alzheimer’s severity
Full text linkIntroduction: Alzheimer’s disease (AD) has been characterized as a disconnection-syndrome (Villain, 2010). Depending on the disease severity, atrophy in grey matter and disruptions in white matter (WM) are observed. These structural changes are accompanied by functional decline on a symptomatic level, and in intrinsic functional connectivity (FC) of brain networks. In AD, FC alterations are found in several resting-state networks (RSN) such as default mode network (DMN), salience network (SAL) or executive control networks (ECNs). These RSNs can be characterized by their properties of region to region static FC across the duration of an MRI BOLD scan, the variability of the dynamic modulations of this FC (dynFC). In addition to the relation between signal fluctuations between brain areas, the regularity/complexity of BOLD signal fluctuations can be assessed by means of multi-scale entropy (MSE; Smith, 2014) and has been shown to be related to cognitive function in elderly controls (Yang, 2013). Hence, we investigated alterations of dynFC between and MSE of signals within brain regions of these RSNs in early AD patients as compared to elderly controls (EC). Furthermore, we were interested in the relationship of these network characteristics and the MMSE score.
Methods: Data from 14 EC (age=67.9, SD=3.7; MMSE=28.6, SD=0.8) and 16 patients with AD (age=67.3, SD=9.7; MMSE=25.2, SD=3.6; Mann-Whitney UEC-AD=19.5, p<0.001) were analyzed. BOLD fMRI acquisition was done on a Siemens 3T scanner (400 volumes, 26 slices, 3x3x4mm, TR/TE 1600ms/35ms). Preprocessing included motion realignment, regression of 12 motion parameters and WM and CSF signal fluctuations, normalization to MNI space and smoothing (8mm FWHM Gaussian kernel). DMN, ECNs and SAL nodes were defined from template-RSNs (Shirer, 2012; Fig. 1). Using a sliding window approach (length 20TRs), the dynamic changes in interregional FC was computed. MSE was calculated with the average sample-entropy across 30 coarse-sampled temporal scales (pattern length m=2, matching threshold r=0.3). We first tested for differences in MSE and dynFC between networks and groups using ANOVA. Second, a potential global association between network connectivity and network complexity was investigated with a correlation of overall dynFC and overall MSE. Finally, we correlated dynFC with MMSE scores to identify aberrant connections related to AD severity.
Results: The ANOVA for MSE yielded a group effect, but no network effect (F(network)=0.38 p=n.s. F(group)=4.00 p<0.05). The DMN showed a reduced MSE in AD compared to EC (t=2.23, p<0.05). No differences in dynFC were found on the network level. For the combined groups a correlation between MSE and dynFC (Fig. 1) was observed for SAL and both ECNs (rLECN=-0.58 p<0.001, rRECN=-0.42 p<0.05, rSAL=-0.46 p=0.01). In other words, the more variable the connections, the less predictable the network. The correlation between MMSE and MSE/dynFC was negative in the DMN and SAL between MMSE and global dynFC (rDMN=-0.40 p<0.05, rSAL=-0.46 p<0.05). No correlation was found for the ECNs and MMSE. A detailed region-to-region analysis (Fig. 2) revealed that the dynFC specifically in LECN was positively correlated with MMSE in EC whereas in AD this was lacking. In contrast, the AD group showed overall negative relations between MMSE and dynFC within the other networks (except LECN).
Discussion: We did not find any dynFC differences between the groups in any RSN. This unexpected outcome might be explained by the mild AD severity and small sample size; however, future studies need to investigate this speculation. Nevertheless, there is a negative relation between the signal complexity within network nodes and variability in connectivity, which indicates a reduced potential to establish stable connections with remote areas. This is in line with the finding that in AD most networks displayed an inverse relation between MMSE and dynFC suggesting that communication between network nodes is impaired.
References:
Shirer, W. R. et al. (2012), ‘Decoding subject-driven cognitive states with whole-brain connectivity patterns’, Cerebral Cortex, vol. 22, no. 1, pp. 158-165.
Smith, R. X. et al. (2014), ‘Multiple time scale complexity analysis of resting state FMRI’, Brain Imaging and Behavior, vol. 8, no. 2, pp. 284-291.
Villain, N. et al. (2010), ‘Sequential relationships between grey matter and white matter atrophy and brain metabolic abnormalities in early Alzheimer’s disease’, Brain, vol. 133, no. 11, pp. 3301-3314.
Yang, A. C. et al. (2013), ‘Complexity of spontaneous BOLD activity in default mode network is correlated with cognitive function in normal male elderly: a multiscale entropy analysis’, Neurobiology of Aging, vol. 34, no. 2, pp. 428-438
Does Age Matter? Semantic Memory in Healthy Young and Elderly Adults
No full textBackground: Semantic memory processes have been well described in literature. However, the available findings are mostly
based on relatively young subjects and concrete word material (e.g. tree). Comparatively little information exists about semantic
memory for abstract words (e.g. mind) and possible age related changes in semantic retrieval. In this respect, we developed a
paradigm that is useful to investigate the implicit (i.e. attentionindependent) access to concrete and abstract semantic memory.
These processes were then compared between young and elderly healthy subjects. Methods: A well established tool for investigating
semantic memory processes is the semantic priming paradigm, which consists both of semantically unrelated and related
word pairs. In our behavioral task these noun-noun word pairs were further divided into concrete, abstract and matched pronounceable non-word conditions. With this premise, the young and elderly participants performed a lexical decision task: they
were asked to press a choice of two buttons as an indication for whether the word pair contained a non-word or not. In order to
minimize controlled (i.e. attention-dependent) retrieval strategies, a short stimulus onset asynchrony (SOA) of 150ms was set.
Reaction time (RT) changes and accuracy to related and unrelated words (priming effect) in the abstract vs. concrete condition
(concreteness effect) were the dependent variables of interest. Results and Discussion: Statistical analysis confirmed both a
significant priming effect (i.e. shorter RTs in semantically related compared to unrelated words) and a concreteness effect (i.e. RT
decrease for concrete compared to abstract words) in the young and elderly subjects. There was no age difference in accuracy. The
only age effect was a commonly known general slowing in RT over all conditions. In conclusion, age is not a critical factor in the
implicit access to abstract and concrete semantic memory
Altered N400 correlates with reduced neuronal activity in anterior temporal lobes in dementia
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