Choice between decision-making strategies in human route-following.

To follow a prescribed route, we must decide which way to turn at intersections. To do so, we can memorize either the serial order of directions or the associations between spatial cues and directions ("at the drug store, turn left"). Here, we investigate which of these two strategies is used if both are available. In Task S, all intersections looked exactly alike, and participants therefore had to use the serial order strategy to decide which way their route continued. In Task SA, each intersection displayed a unique spatial cue, and participants therefore could use either strategy. In Task A, each intersection displayed a unique cue, but the serial order of cues varied between trips, and participants therefore had to use the associative cue strategy. We found that route-following accuracy increased from trip to trip, was higher on routes with 12 rather than 18 intersections, and was higher on Task SA than on the other two tasks, both with 12 and with 18 intersections. Furthermore, participants on Task SA acquired substantial knowledge about the serial order of directions as well as about cue-direction associations, both with 12 and with 18 intersections. From this we conclude that, when both strategies were available, participants did not pick the better one but rather used both. This represents dual encoding, a phenomenon previously described for more elementary memory tasks. We further conclude that dual encoding may be implemented even if the memory load is not very high (i.e., even with only 12 intersections).

Simulation-based training improves process times in acute stroke care (STREAM).

BACKGROUND: The objective of the STREAM Trial was to evaluate the effect of simulation training on process times in acute stroke care. METHODS: The multicenter prospective interventional STREAM Trial was conducted between 10/2017 and 04/2019 at seven tertiary care neurocenters in Germany with a pre- and post-interventional observation phase. We recorded patient characteristics, acute stroke care process times, stroke team composition and simulation experience for consecutive direct-to-center patients receiving intravenous thrombolysis (IVT) and/or endovascular therapy (EVT). The intervention consisted of a composite intervention centered around stroke-specific in situ simulation training. Primary outcome measure was the 'door-to-needle' time (DTN) for IVT. Secondary outcome measures included process times of EVT and measures taken to streamline the pre-existing treatment algorithm. RESULTS: The effect of the STREAM intervention on the process times of all acute stroke operations was neutral. However, secondary analyses showed a DTN reduction of 5 min from 38 min pre-intervention (interquartile range [IQR] 25-43 min) to 33 min (IQR 23-39 min, p = 0.03) post-intervention achieved by simulation-experienced stroke teams. Concerning EVT, we found significantly shorter door-to-groin times in patients who were treated by teams with simulation experience as compared to simulation-naive teams in the post-interventional phase (-21 min, simulation-naive: 95 min, IQR 69-111 vs. simulation-experienced: 74 min, IQR 51-92, p = 0.04). CONCLUSION: An intervention combining workflow refinement and simulation-based stroke team training has the potential to improve process times in acute stroke care.

Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET.

The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer's disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

Mechanical Thrombectomy with the Novel NeVa M1 Stent Retriever: Do the Drop Zones Represent a Risk or a Benefit?

OBJECTIVE: The NeVa M1 thrombectomy device is a novel hybrid-cell stent retriever with multifunctional zones for optimized retrieval of resistant clots located in the M1 segment of the middle cerebral artery. The objective was to evaluate the safety and efficacy of the NeVa in a "real-life" setting. METHODS: Twenty-nine consecutive patients (median age: 77 years) treated with the NeVa M1 for acute ischemic stroke of the M1 segement were retrospectively reviewed. First-pass and final modified thrombolysis in cerebral infarction (mTICI) scores, device-related complications, symptomatic intracranial hemorrhage, and 90-day modified Rankin scale (mRS) scores are reported. Primary outcome parameters were first-pass mTICI 2b-3 reperfusion and mRS 0-2 at 90 days. RESULTS: Median National Institutes of Health Stroke Scale scores decreased from 16 to 12 after treatment. mTICI 2b-3 reperfusion rates were 55% after the first pass, 79% after 1-2 passes, and 100% after the final pass. mTICI 2c-3 was obtained in 48% after the first pass, 62% after 1-2 passes, and 72% after the final pass. Rescue treatment was performed in 4 patients (14%). Device-related complications included 1 asymptomatic caroticocavernous fistula, 1 asymptomatic M2 dissection, and 1 symptomatic intracranial hemorrhage. The procedure-related vasospasm rate was 48%. A 90-day mRS of 0-2 was achieved by 31%. CONCLUSIONS: The NeVa M1 provides a high first-pass complete reperfusion rate with an adequate safety profile. To retrieve resistant clots, the stent design exerts high mechanical traction forces, which may trigger vasospasm and vessel wall damage. Large, comparative studies are warranted to draw a definite conclusion on this device.

One-Stop Shop: 18F-Flortaucipir PET Differentiates Amyloid-Positive and -Negative Forms of Neurodegenerative Diseases.

Tau protein aggregations are a hallmark of amyloid-associated Alzheimer disease and some forms of non-amyloid-associated frontotemporal lobar degeneration. In recent years, several tracers for in vivo tau imaging have been under evaluation. This study investigated the ability of 18F-flortaucipir PET not only to assess tau positivity but also to differentiate between amyloid-positive and -negative forms of neurodegeneration on the basis of different 18F-flortaucipir PET signatures. Methods: The 18F-flortaucipir PET data of 35 patients with amyloid-positive neurodegeneration, 19 patients with amyloid-negative neurodegeneration, and 17 healthy controls were included in a data-driven scaled subprofile model (SSM)/principal-component analysis (PCA) identifying spatial covariance patterns. SSM/PCA pattern expression strengths were tested for their ability to predict amyloid status in a receiver-operating-characteristic analysis and validated with a leave-one-out approach. Results: Pattern expression strengths predicted amyloid status with a sensitivity of 0.94 and a specificity of 0.83. A support vector machine classification based on pattern expression strengths in 2 different SSM/PCA components yielded a prediction accuracy of 98%. Anatomically, prediction performance was driven by parietooccipital gray matter in amyloid-positive patients versus predominant white matter binding in amyloid-negative patients. Conclusion: SSM/PCA-derived binding patterns of 18F-flortaucipir differentiate between amyloid-positive and -negative neurodegenerative diseases with high accuracy. 18F-flortaucipir PET alone may convey additional information equivalent to that from amyloid PET. Together with a perfusion-weighted early-phase acquisition (18F-FDG PET-equivalent), a single scan potentially contains comprehensive information on amyloid (A), tau (T), and neurodegeneration (N) status as required by recent biomarker classification algorithms (A/T/N).

Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury.

PURPOSE: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several ß-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG). METHODS: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0-60 min p.i.) and static [18F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. RESULTS: Highest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers. CONCLUSION: Early-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

Risk Factors of Procedural Complications Related to Woven EndoBridge (WEB) Embolization of Intracranial Aneurysms.

PURPOSE: The Woven EndoBridge (WEB) device has been proven to be a safe and efficient endovascular treatment option for wide-necked bifurcation aneurysms. The study aimed to evaluate the incidence and risk factors of procedural complications related to WEB embolization of ruptured and unruptured intracranial aneurysms. METHODS: This was a multicenter, observational study of consecutive patients with ruptured and unruptured aneurysms who were treated with the WEB at three German tertiary care centers between May 2011 and February 2018. Patient characteristics, anatomical details and procedural aspects were retrospectively collected and the impact on procedure-related complications was evaluated. RESULTS: Among 120 patients (mean age 58.5 ± 11.9 years) with 120 aneurysms (mean size: 8.5 ± 4.5 mm), WEB implantation was successful in 112 patients (93.3%). The rates for overall and symptomatic complications were 11.7% and 5.0%, respectively. At 6­month follow-up device-related morbidity was 1.2% among unruptured aneurysms and 2.6% among ruptured aneurysms. In the univariate analysis, a lower aspect ratio (p = 0.04) and an increased width-to-height ratio (p = 0.03) were significant risk factors for procedural complications. CONCLUSION: The results of this study confirmed the WEB to be a safe treatment option, which is associated with low complication rates and minimal morbidity. Complications tended to occur more often in aneurysms with an unfavorable ratio between aneurysm height and aneurysm/neck width.

In the Eye of the Storm: Immune-mediated Toxicities Associated With CAR-T Cell Therapy.

The success of chimeric antigen receptor (CAR)-T cell therapy with impressive response rates in hematologic malignancies but also promising data in solid tumors came along with the cognition of unexpected, potentially life-threatening immune-mediated toxicities, namely the cytokine release syndrome (CRS) and neurotoxicity recently referred to as "immune effector cell-associated neurotoxicity syndrome" (ICANS). These toxicities require urgent diagnostic and therapeutic interventions and targeted modulation of key cytokine pathways represents the mainstay of CRS treatment. However, as the underlying mechanisms of ICANS are not well understood, treatment options remain limited and further investigation is warranted. Importantly, after the recent market approval of 2 CAR-T cell constructs, the application of CAR-T cells will expand to nonacademic centers with limited experience in the management of CAR-T cell-associated toxicities. Here, we review the current evidence of CRS and ICANS pathophysiology, diagnostics, and treatment.

Level of education mitigates the impact of tau pathology on neuronal function.

PURPOSE: Using PET imaging in a group of patients with Alzheimer's disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function. METHODS: We included 38 patients with mild-to-moderate AD (mean age 67 ± 7 years, mean MMSE score 24 ± 4, mean years of education 14 ± 4; 20 men, 18 women) in whom a [18F]AV-1451 scan (a measure of tau pathology) and an [18F]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [18F]AV-1451 and [18F]FDG from healthy controls, and subsequently thresholded at a z-score of ≥3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates. RESULTS: Years of education were positively associated with tau-specific volume (ß = 0.362, p = 0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (ß = 0.303, p = 0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction. CONCLUSION: In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life.

Clinical Outcome After Mechanical Thrombectomy in Patients with Diabetes with Major Ischemic Stroke of the Anterior Circulation.

BACKGROUND: Among patients with acute ischemic stroke treated with mechanical thrombectomy (MT), patients with diabetes (DP) show a poorer outcome compared with patients without diabetes (NDP). This study aims to provide a comprehensive analysis of factors associated with unfavorable outcome in DP receiving MT for stroke of the anterior circulation. METHODS: This study included 317 of 498 consecutive patients who received interventional treatment for acute ischemic stroke in the terminal internal carotid artery and/or middle cerebral artery, including 46 DP. The study data included pre- and posttreatment stroke computed tomography, including perfusion data, collateral status, treatment data including treatment times, pre-existing cardiovascular risk factors, cerebrovascular events, comorbidities, laboratory parameters, and medication. Neurologic status was assessed at baseline (National Institute of Health Stroke Scale [NIHSS]/modified Rankin Scale [mRS]) and after 90 days (mRS 90). RESULTS: Compared with NDP, DP showed a significantly poorer outcome (mRS90 >2) (P < 0.05). Collateralization and infarct core size did not differ between groups, whereas the penumbra was significantly smaller in DP than in NDP (P < 0.05). The poorer mRS90 outcome (mRS90 > 2) in DP was associated with poor collaterals (P = 0.01) and hyperglycemia on admission (P < 0.05). Shorter time to reperfusion was associated with favorable mRS90 in the NDP (P < 0.001) but not the DP (P = 0.49) group. In univariate logistic regression, the following parameters were significantly associated with mRS90: diabetes, hyperglycemia at admission, time to reperfusion, and the NIHSS score (P < 0.05 each). In multivariate analyses and partition regression models of all variables, DP with admission hyperglycemia (≥132 mg/dL) and older age (≥66 years) showed a particularly poor outcome. CONCLUSIONS: The main factors for an unfavorable outcome of DP after MT are admission hyperglycemia, age, and NIHSS score.

Networks of tau distribution in Alzheimer's disease.

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.

Thrombus Enhancement Is a Predictor of Clinical Outcome in Acute Ischemic Stroke after Mechanical Thrombectomy.

BACKGROUND: Ex vivo computed tomography (CT) studies of artificial blood thrombi showed that contrast enhancement (CE) is determined by fibrin-content, while unenhanced density is associated with red blood cells. Thus, the present study investigates patient outcome in association with combined thrombus density measures in native and contrast-enhanced CT (CECT) of acute ischemic stroke patients. METHODS: This retrospective study includes 137 patients with M1 occlusions treated by mechanical thrombectomy (MT) between 2010 and 2016. Clinical outcome was determined with modified Rankin Scale (mRS) at 90 days. Differentiation of complete and incomplete large vessel occlusion (CLVO/ILVO) was based on CT and angiography. Two blinded readers classified blood thrombi based on native non-enhanced CT (NECT) as (a) hypo-, (b) iso-, and (c) hyperdense and in CECT angio measurements as (d) not-enhancing, (e) intermediate and (f) enhancing. To make sure that the mean is not represented in any of the maximum/minimum groups, thresholds in both cases were selected in a way that all values within one SD around the mean value form the isodense/intermediate group. In addition, the CE per se was correlated with the outcome. Correlations between imaging and clinical scales were performed with Spearman's Rho. For the group testing Pearson chi-square test, Mann-Whitney U, as well parametric and nonparametric one-factor ANOVA "Kruskal-Wallis" test including Bonferroni correction for multiple tests ware used. RESULTS: Twenty-three patients with ILVO (16.8%) differed significantly from patients with CLVO in mRS at admission (median 4 vs. 5) and after 90 days (median 1 vs. 4; p < 0.05) and thus were excluded. In the ILVO cohort, the classification according to NECT did not show statistical difference between hypo-, iso- and hyperdense CLVOs in regard to outcome. Classification of CLVOs according to CECT allowed an outcome prediction between the intermediate (median 3) and enhancing group (median 5) and between the enhancing and non-enhancing group (median 3; both p < 0.05) with a correlation of 291 between CE and higher mRS after 90 days (p < 0.005). CONCLUSIONS: CE of thrombi - especially in a range from over 18.4 to 40.35 Hounsfield Units - is an independent predictor of poor clinical outcome in patients undergoing MT due to acute middle cerebral artery occlusion.

Functional Disintegration of the Default Mode Network in Prodromal Alzheimer's Disease.

Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer's disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus de-coupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker.

Resting-state fMRI evidence for early episodic memory consolidation: effects of age.

Aging-related episodic memory decline is often attributed to insufficient encoding of new information, although the underlying neural processes remain elusive. We here tested the hypothesis that impaired memory consolidation contributes to aging-related memory decline. To this end, we used resting state functional magnetic resonance imaging in healthy young and older adults and investigated neural network connectivity underlying episodic memory consolidation and the effects of aging thereon. During postencoding rest, connectivity increased in subregions of temporobasal and temporo-occipital networks but decreased in a precuneal network. These connectivity changes predicted subsequent memory performance thereby constituting functional correlates of early memory consolidation. Furthermore, these consolidation-related regional connectivity changes partially overlapped with encoding-related neural activity changes, suggesting a close relationship between encoding- and consolidation-related activity. Older when compared to young participants failed to increase connectivity in the right lingual gyrus as part of an extended default mode network during consolidation, thereby providing a functional correlate for spatial contextual memory deficits. In conclusion, results are consistent with previous reports of persistent activity in regions mediating memory encoding as a core mechanism underlying episodic memory consolidation. Our data extend previous findings suggesting that aging-related memory decline results from a reduction of consolidation processes.

Aberrant functional connectivity differentiates retrosplenial cortex from posterior cingulate cortex in prodromal Alzheimer's disease.

The posterior cingulate cortex (PCC) is a key hub of the default mode network, a resting-state network involved in episodic memory, showing functional connectivity (FC) changes in Alzheimer's disease (AD). However, PCC is a cytoarchitectonically heterogeneous region. Specifically, the retrosplenial cortex (RSC), often subsumed under the PCC, is an area functionally and microanatomically distinct from PCC. To investigate FC patterns of RSC and PCC separately, we used resting-state functional magnetic resonance imaging in healthy aging participants, patients with subjective cognitive impairment, and prodromal AD. Compared to the other 2 groups, we found higher FC from RSC to frontal cortex in subjective cognitive impairment but higher FC to occipital cortex in prodromal AD. Conversely, FC from PCC to the lingual gyrus was higher in prodromal AD. Furthermore, data indicate that RSC and PCC are characterized by differential FC patterns represented by hub-specific interactions with memory and attentions scores in prodromal AD compared to cognitively normal individuals, possibly reflecting compensatory mechanisms for RSC and neurodegenerative processes for PCC. Data thus confirm and extend previous studies suggesting that the RSC is functionally distinct from PCC.

Aging-related changes of neural mechanisms underlying visual-spatial working memory.

Capacities of the prefrontal cortex (PFC) such as working memory (WM) are known to decline with increasing age. However, it is unclear which neurofunctional mechanisms may underlie this aging-related cognitive decline. The finding that PFC activity tends to be less lateralized in older subjects has led to the assumption of a hemispheric asymmetry reduction in the PFC associated with aging (HAROLD). Using functional magnetic resonance imaging (fMRI), we here investigated aging-related neurofunctional alterations during the performance of a visual-spatial WM task with differential levels of difficulty. Older volunteers activated dorsolateral PFC regions bilaterally while young subjects recruited these areas only in the left hemisphere. These data corroborate the hemispheric asymmetry reduction in the PFC associated with aging (HAROLD) account. However, we also observed functional reorganizations in parieto-occipital areas, and with increasing WM demands, an aging-related reversed hemispheric asymmetry of prefrontal activations. Importantly, neither PFC nor parieto-occipital reorganizations prevented older participants from showing worse WM performance than young volunteers. We conclude that frontal-parietal functional reorganizations may reflect compensational mechanisms related to aging, but do not obviate diminished visual-spatial WM performance in older people.

Modulatory effects of levodopa on cognitive control in young but not in older subjects: a pharmacological fMRI study.

Older individuals show decline of prefrontal cortex (PFC) functions which may be related to altered dopaminergic neurotransmission. We investigated the effects of aging and dopaminergic stimulation in 15 young and 13 older healthy subjects on the neural correlates of interference control using fMRI. In a double-blind, placebo-controlled within-subject design, subjects were measured after levodopa (100 mg) or placebo administration. In each session, subjects performed a visual-spatial interference task based on a Stroop/Simon-like paradigm. Across age groups, interference (incongruent relative to congruent trials) was associated with activations in the presupplementary motor area, ACC, and intraparietal cortex. Increased interference was found behaviorally in older volunteers. Differential activation in left dorsolateral PFC in young subjects and bilateral PFC activity in older subjects was observed to be associated with interference control. Performance deteriorated under levodopa only in young subjects. This was accompanied by an increase of neural activity in ACC (p < .05; small-volume correction for multiple comparisons). Worsening of performance under levodopa in young subjects and the associated effect on ACC may indicate that overstimulation of the dopaminergic system compromises interference control. This supports the inverted-U-shaped model of neurotransmitter action.