Ralf Saur

Monitoring coordination during bimanual movements: Where is the mastermind?

One remarkable aspect of the human motor repertoire is the multitude of bimanual actions it contains. Still, the neural correlates of coordinated movements, in which the two hands share a common goal, remain debated. To address this issue, we designed two bimanual circling tasks that differed only in terms of goal conceptualization: a “coordination” task that required movements of both hands to adapt to each other to reach a common goal and an “independent” task that imposed a separate goal to each hand. fMRI allowed us to pinpoint three areas located in the right hemisphere that were more strongly activated in the coordination condition: the superior temporal gyrus (STG), the SMA, and the primary motor cortex (M1). We then used transcranial magnetic stimulation (TMS) to disrupt transiently the function of those three regions to determine their causal role in bimanual coordination. Right STG virtual lesions impaired bimanual coordination, whereas TMS to right M1 enhanced hand independence. TMS over SMA, left STG, or left M1 had no effect. The present study provides direct insight into the neural correlates of coordinated bimanual movements and highlights the role of right STG in such bimanual movements.

Similar autobiographical memory impairment in long-term secondary progressive multiple sclerosis and Alzheimer’s disease

Background: Memory disturbance is a common symptom of multiple sclerosis (MS), but little is known about autobiographical memory deficits in the long-term course of different MS subtypes. Inflammatory activity and demyelination is pronounced in relapsing–remitting multiple sclerosis (RRMS) whereas, similar to Alzheimer’s disease, neurodegeneration affecting autobiographical memory-associated areas is seen in secondary progressive multiple sclerosis (SPMS). Objective: In light of distinct disease mechanisms, we evaluated autobiographical memory in different MS subtypes and hypothesized similarities between elderly patients with SPMS and Alzheimer’s disease. Methods: We used the Autobiographical Memory Interview to assess episodic and semantic autobiographical memory in 112 education- and gender-matched participants, including healthy controls and patients with RRMS, SPMS, amnesic mild cognitive impairment (aMCI) and early Alzheimer’s dementia (AD). Results: Patients with SPMS, AD, and aMCI, but not with RRMS, exhibited a pattern of episodic autobiographical memory impairment that followed Ribot’s Law; older memories were better preserved than more recent memories. In contrast to aMCI and AD, neither SPMS nor RRMS was associated with semantic autobiographical memory impairment. Conclusion: Our neuropsychological findings suggest that episodic autobiographical memory is affected in long-term patients with SPMS, possibly due to neurodegenerative processes in functional relevant brain regions.

Changes in Cortical Activation during Retrieval of Clock Time Representations in Patients with Mild Cognitive Impairment and Early Alzheimer's Disease

Objective: We investigated healthy controls (HCs), and patients with mild cognitive impairment (MCI) and early Alzheimer’s disease (AD) to identify neuronal correlates of clock time representation and changes resulting from neurodegenerative processes using functional magnetic resonance imaging. Methods: Two clock-specific tasks demanding conceptual knowledge of clock hands, i.e. a minute hand and an hour hand task, were compared with a semantic control task. Results: We observed that the minute hand task provoked a stronger activation of areas in the parietal lobes known to be involved in spatial mental imagery, while the semantic task primarily activated regions of the superior temporal lobes associated with verbal conceptual knowledge. The performance of the MCI group did not differ from that of the HC group, but additional activation was found in several brain regions. Decreased activation was detected during the minute hand task in the right middle temporal gyrus. Patients with early AD showed deteriorated performance in both clock tasks along with reduced activation in the occipital lobes and the left fusiform gyrus. Additional activation was detected in the precuneus. Conclusions: The fusiform gyrus might be crucial for the visual-semantic retrieval of clock time representation. In patients with early AD, access to this visual-semantic knowledge appears to be reduced.

Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimers Disease

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimers disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.

Clock Test Deficits Related to the Global Cognitive State in Alzheimer’s and Parkinson’s Disease

Background/Aims: Clock drawing (CD) seems to be impaired quite early in the process of cognitive decline in Parkinson’s disease (PD). Methods: We assessed performance on the CD test (CDT), clock setting test (CST) and clock reading test (CRT) in 32 elderly healthy controls, 41 patients with PD, 23 patients with amnestic mild cognitive impairment (aMCI) and 40 patients with Alzheimer’s dementia (AD). Our focus was on comparing the performance of PD and aMCI/AD patients in relation to their global cognitive states (operationalized by the Mini Mental Status Examination). We also analyzed qualitative differences in errors of drawing, setting and reading clocks. Results: We found that performance in CDT, but not in the CST or CRT, was impaired earlier in PD than in aMCI/AD. Incorrect placement of the minute hand was the most prominent error in both patient groups. We found no specific influence of visuospatial dysfunction in PD on clock drawing. Conclusion: Our findings suggest that executive function related to retrieval of semantic memory about the minute hand is compromised early in PD.

Recognition performance differentiates between elderly patients in the long term course of secondary progressive multiple sclerosis and amnestic mild cognitive impairment.

Background: Cognitive impairment is a common symptom of multiple sclerosis (MS), but little is known about cognitive decline in patients in the long-term course of progressive MS. Because advancing age is the most significant risk factor for Alzheimer’s Disease (AD), AD-related pathology must be considered in elderly patients with MS. Amnestic mild cognitive impairment (aMCI) represents the prodromal phase of AD with subjects showing memory impairment that does not improve with recognition testing. Objective: We sought to identify disease-dependent deterioration patterns by comparing elderly patients with secondary progressive MS (SPMS) and with aMCI using the Consortium to Establish a Registry for Alzheimer’s Disease test battery. Methods: This study included 120 age-, education- and gender-matched participants, including healthy controls (n=40), SPMS patients (n=40), and aMCI patients (n=40). Results: Episodic memory deficits appeared in the long-term course of SPMS. Deficits were associated with deterioration of executive function, but not impairment of memory storage as recognition was preserved in SPMS in contrast to the patients with aMCI. Conclusion: Through neuropsychological testing, MS-related episodic memory impairment due to deteriorated executive function can be distinguished from AD-related encoding and storage deficits. Hence, neuropsychological testing may help to identify AD-related pathology in SPMS patients.

Low performance in attention testing is associated with reduced grey matter density of the left inferior frontal gyrus in euthyroid patients with Hashimoto's thyroiditis

Hashimotos thyroiditis (HT) can casually co-occur with an encephalopathy associated with autoimmune thyroid disease. Recently we found an increased occurrence of weaknesses in sustained attention and response inhibition in a subgroup of euthyroid patients with HT as obtained by the d2 attention test. Previous studies in healthy subjects and patients with brain lesions demonstrated a pivotal role for the left inferior frontal gyrus (LIFG) in these skills. Therefore, we studied the association between the performance in the d2 test and grey matter (GM) density of the LIFG in 13 euthyroid patients with HT compared to a control group of 12 euthyroid patients with other thyroid diseases. A significant correlation between GM density and d2 test total score was detected for the opercular part of the LIFG in patients with HT (p<0.001), but not in the control group (p=0.94). Regression in patients with HT was significantly stronger than in the control group (p=0.02). Moreover, GM density was significantly reduced when comparing HT patients with control patients that scored in the lower third during d2 attention testing (p<0.05). It can be concluded that in HT performance in the d2 test correlated with GM density of the LIFG. Particularly low achievement was associated with reduced GM density of this brain region suggesting an influence of autoimmune processes on the frontal cortex in this disease. This could be due to not yet known antibodies affecting brain morphology or an influence of thyroid antibodies themselves.

Deteriorated executive functions in patients with successful surgery for pituitary adenomas compared with other chronically ill patients.

Pituitary adenomas, even after successful treatment, are associated with cognitive impairments. It is unclear whether these deficits are a consequence of unspecific factors associated with having a chronic illness and whether the cognitive dysfunctions exceed those of other chronically ill patients. Thirty-eight patients with transsphenoidal surgery for pituitary adenomas and 38 patients undergoing L-thyroxine replacement therapy after thyroid surgery were studied neuropsychologically with established tests. Executive function was examined with the Trail-Making Test A and B, working memory with the digit span test, attention with the digit symbol test, verbal memory with the German version of the Auditory Verbal Learning and Memory Test, and general verbal intelligence by a vocabulary test. Attention (p = .007), attentional speed (p = .0004), executive control (p = .04), and working memory (p = .01), were significantly reduced in patients with pituitary adenomas compared with other chronically ill patients. In contrast, no differences were found between the groups for verbal memory (all subtests: p ≥ .06). Patients with successful surgery for pituitary adenomas show also in comparison with other chronically ill patients an increased risk for deficits in certain aspects of cognitive function, including attention and working memory, supporting the relevance of the brain lesion and its treatment for these dysfunctions.

Memory for Past Public Events Depends on Retrieval Frequency but not Memory Age in Alzheimer's Disease

Alzheimers disease (AD) is characterized by retrograde memory deficits primarily caused by dysfunction of the hippocampal complex. Unresolved questions exist concerning the time course of hippocampal involvement in conscious recollection of declarative knowledge, as reports of temporal gradients of retrograde amnesia have been inconclusive. The aim of this study was to examine whether the extent and severity of retrograde amnesia is mediated by retrieval frequency or, in contrast, whether it depends on the age of the memory according to the assumptions of the main current theories of memory formation. We compared recall of past public events in patients with AD and healthy control (HC) individuals using the Historic Events Test (HET). The HET assesses knowledge about famous public events of the past 60 years divided into four time segments and consists of subjective memory rating, dating accuracy, and contextual memory tasks. Although memory for public events was impaired in AD patients, there was a strong effect of retrieval frequency across all time segments and both groups. As AD and HC groups derived similar benefits from greater retrieval frequency, cortical structures other than the hippocampal complex may mediate memory retrieval. These findings suggest that more frequently retrieved events and facts become more independent of the hippocampal complex and thus better protected against early damage of AD. This could explain why cognitive activity may delay the onset of memory decline in persons who develop AD.

Impairment in proverb interpretation as an executive function deficit in patients with amnestic mild cognitive impairment and early Alzheimer's disease.

Background/Aims: Proverb interpretation is assumed to reflect executive functions. We hypothesized that proverb interpretation is impaired in patients with amnestic mild cognitive impairment (aMCI) diagnosed as single-domain impairment by common neuropsychological testing. Methods: We compared performance in a proverb interpretation test in single-domain aMCI patients and patients with early Alzheimer’s disease (EAD). Results: The groups with aMCI and EAD performed significantly worse than healthy controls. Both patient groups gave concrete answers with a similar frequency. However, patients with EAD tended to give senseless answers more frequently. Conclusions: Our data suggest that in patients diagnosed as single-domain aMCI, deterioration of executive functions is detectable with subtle and appropriate neuropsychological testing. Implementation of these procedures may improve the early prediction of AD.