Comparison of Clock Test Deficits Between Elderly Patients With Early and Late Onset Depression.

To compare clock test deficits in elderly patients with early onset depression (EOD) and late onset depression (LOD), we assessed 32 elderly healthy controls (HCs), 26 patients with EOD, and 27 patients with LOD with the clock drawing test (CDT), clock setting test, clock reading test, and the Tübingen Clock Questionnaire testing semantic memory about clock times. There was no significant difference in depression severity between patients with EOD and LOD. Patients with LOD had significantly lower scores on the CDT than patients with EOD and HCs. Semantic memory impairment concerning minute hand functionality was highly correlated with CDT performance and was significantly different between the EOD and the LOD groups. It can be suggested that significant differences in cognitive impairment severity between patients with EOD and LOD can be detected with CDT. Semantic memory impairment concerning minute hand functionality might affect CDT test results in elderly patients with depression.

Memory for past public events depends on retrieval frequency but not memory age in Alzheimer's disease.

Alzheimer's 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.

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.

Hashimoto's 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.

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.

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.

Thyroid peroxidase antibody positivity is associated with symptomatic distress in patients with Hashimoto's thyroiditis.

Previous studies suggest impairments of physical, mental, and psychic well-being in patients with Hashimoto's thyroiditis (HT), but these impairments have been shown to be independent of thyroid dysfunction. In 64 euthyroid patients with HT, symptomatic distress was assessed with the Symptom Checklist-90-Revised (SCL-90-R), a 90-item multidimensional self-report symptom inventory using a 5-point rating scale. In a subgroup of patients, endocrine testing 3 years prior to the current investigation was available. Anti-thyroid peroxidase antibodies (TPO-Abs) were associated with the three SCL-90-R global indices Global Severity Index (GSI), Positive Symptom Distress Index (PSDI), and Positive Symptom Total (PST) as well as with somatization and obsessive-compulsive symptoms after adjustment for age, gender, and thyroid function as assessed by TSH levels (all p<0.05). HT patients positive for TPO-Abs showed poorer results in the three SCL-90-R global indices as well as in the three domains: somatization, obsessive-compulsive symptoms, and depression (all p≤0.02), though the aforementioned associations did not withstand sequential Bonferroni correction for multiple testing. In contrast, TPO-Abs positivity, defined as TPO-Abs >100 IU/l, significantly predicted poorer psychosocial well-being in all of the three SCL-90-R global indices after three years, even after correction (all p≤0.02). In conclusion, high TPO-Abs are associated with poor physical and psychological well-being and appear to predict future health perception in HT patients.

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.

Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease.

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's 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.

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.

Deterioration of the memory for historic events in patients with mild cognitive impairment and early Alzheimer's disease.

Retrograde memory decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI) has been evaluated using tests of past public knowledge, such as famous personalities and events, and tests of autobiographical memory. Reports of temporal gradients (TG) in retrograde amnesia have been inconclusive. Here, we compared the remembrance of famous historic events by patients with amnesic MCI and early AD using the newly developed Historic Events Test (HET). The HET demands knowledge about famous public events of the past 60 years divided into five time segments, and consists of three tasks, Recognition, Dating Accuracy, and Contextual Memory. In both patient groups, the performance was worse than in healthy controls. Memory performance of all time segments was uniformly affected by this kind of retrograde amnesia. There was no evidence of a TG, and memory decline was similar in all three tasks of the HET. In contrast, for the same patients tested at the same time, we had previously found a TG for autobiographical memory with better preservation of remote than recent memories (Leyhe, Müller, Milian, Eschweiler, & Saur, 2009). We propose that recall of more frequently retrieved remote autobiographical facts and incidents has become independent of the hippocampus, whereas more seldomly retrieved recent autobiographical memory and knowledge of famous events remain dependent on the hippocampus and will thereby be susceptible to the early neurodegenerative damage of the hippocampus in AD. Our assumption may reconcile the Cortical Reallocation Theory and the Multiple Trace Theory.

Cortical activation during clock reading as a quadratic function of dementia state.

In patients with Alzheimer's disease (AD), neuroimaging studies have demonstrated decreased brain activation, while increased activation was detected in patients with mild cognitive impairment (MCI). It can be hypothesized that increased cerebral activity seen in patients with MCI reflects neural compensation at the beginning of neurodegenerative processes. Later, as patients develop AD, neural integrity is increasingly impaired. This is accompanied by decreased neural activation. In this study we examined cognitive performance and functional magnetic resonance imaging activation on a Clock Reading task (CRT) and a Spatial Control task (SCT) in healthy controls, patients with MCI, and patients with early AD. Correlations between neural-functional activation and cognitive state, measured by the Mini Mental Status Examination, were determined using rank, linear and quadratic correlation models. It could be shown that CRT, in comparison to SCT, specifically activates brain regions in the ventral visual stream and precuneus known to be involved in conceptual processing and spatial imagery. The correlation between brain activity and cognitive state followed a quadratic rather than a linear pattern in several brain regions, including the lingual gyrus, cuneus, and precuneus. The strongest brain activity was found in patients with MCI and less severely impaired early AD subjects. These findings support the hypothesis that patients in early stages of dementia compensate for neuronal loss by the recruitment of additional neural resources reflected by increased neural activation, as measured by the blood oxygen level-dependent signal.

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.

Younger age is a good predictor of better executive function after surgery for pituitary adenoma in adults.

Pituitary adenomas, even after successful treatment, are associated with cognitive dysfunctions. We hypothesized that an association between the age of the patients at pituitary surgery and neuropsychological outcome may exist. Forty-two patients (mean age 51 +/- 10 years) who had been successfully treated for pituitary adenoma (surgery with or without subsequent radiotherapy) underwent neuropsychological testing. Age at treatment (mean 37 +/- 11 years) was significantly associated with Trail Making Test, Part B (TMT-B) results, a measure of executive control and attention (r = .60, p < .0001). This association remained significant after adjustment for age at testing and time since treatment (r = .42, p = .008). No associations were detected between age at treatment and Trail Making Test, Part A (TMT-A, attentional speed), the digit span test (acoustic working memory), and the German version of the Auditory Verbal Learning and Memory, and Memory Test (verbal memory, all p > or = .3). Our data suggest a favorable effect of younger age at treatment in adults on neurocognitive outcome after surgery for pituitary adenoma.

Clock test deficits are associated with semantic memory impairment in Alzheimer disease.

Based on previous findings, we hypothesized that Clock Test deficits in patients with Alzheimer disease (AD) are associated primarily with the impairment of semantic memory regarding the appearance and functionality of a clock. To scrutinize this hypothesis, we developed a Clock Questionnaire that examined the semantic knowledge of the concept of a ''Clock'' and correlated scores from the questionnaire with performance in Clock Drawing, Clock Setting, and Clock Reading by healthy control participants and patients with mild cognitive impairment, early AD, and progressed AD. The Rey-Osterrieth-Complex-Figure is known to measure both visuospatial abilities and executive functions, and was chosen as a control variable. We found that deteriorated semantic memory best predicted Clock Test performance. In progressed AD, degraded knowledge regarding the appearance of a clock can explain the reduced ability to draw a clock face, while in early AD, impaired access to semantic knowledge about the minute hand might explain observed difficulties in drawing, setting, and reading the minute hand.

Impairment of episodic and semantic autobiographical memory in patients with mild cognitive impairment and early Alzheimer's disease.

Autobiographical memory includes the retrieval of personal semantic data and the remembrance of incident or episodic memories. In retrograde amnesias, it has been observed that recall of autobiographical memories of recent events is poorer than recall of remote memories. Alzheimer's disease (AD) may also be associated with a temporal gradient (TG) in memory decline, though studies have yielded inconsistent results on this point. They have also yielded inconsistent results on whether AD might differentially affect semantic and episodic remembrance. Here, we compared autobiographical memory of childhood, early adulthood, and recent life among healthy control (HC) subjects, patients with early AD, and patients with amnesic mild cognitive impairment (aMCI). Both the aMCI and AD patients exhibited declines in recall of autobiographical incidents and semantic information. In AD patients, both components of autobiographical memory had a clear TG, with better preservation of memories of childhood than those of early adulthood and recent life. The TG of autobiographical memory decline in AD patients is more compatible with the Cortical Reallocation Theory than with the Multiple Trace Theory of memory consolidation. In contrast to AD patients, aMCI patients exhibited impaired recall of personal facts and autobiographical incidents relating only to recent life. The significant decline in autobiographical memory for recent life that occurred in aMCI patients suggests that deterioration of consolidation of personal facts and events begins with commencement of functional impairment in the hippocampus.

Increased prevalence of antibodies to central nervous system tissue and gangliosides in Hashimoto's thyroiditis compared to other thyroid illnesses.

BACKGROUND: Previous studies point to central nervous system (CNS) alterations in euthyroid patients with Hashimoto's thyroiditis (HT). The aim of the present study was to investigate the prevalence and clinical significance of antibodies (Abs) against CNS tissue and gangliosides in female patients with HT compared to patients with other non-autoimmune thyroid disorders, comprising diffuse or nodular goitre and thyroid surgery for goitre. METHODS: 58 HT patients (mean age: 46+/-17 years) and 89 patients with other thyroid disorders (mean age: 51+/-15 years) were recruited consecutively from our endocrine outpatient clinic. Serum Abs against CNS tissue and gangliosides were determined using an enzyme-linked immunosorbent assay (ELISA). In a subgroup of 23 HT patients, neurocognitive function was studied using established neuropsychological tests. RESULTS: In HT patients, the prevalence of serum anti-ganglioside-Abs and anti-CNS-Abs were significantly higher compared to patients with other thyroid disorders (p<0.05 and p<0.005, respectively). In both cases, the number of Ab-positive HT patients was twice that of Ab-positive controls. Reactivity of IgM-Abs to gangliosides and IgG-Abs to CNS tissue was significantly higher in HT patients than in controls (p<0.05 and p<0.01, respectively). However, prevalence and reactivity of Abs to gangliosides and CNS tissue were associated neither with the prevalence of depression nor with impairment of neurocognitive function in HT patients. CONCLUSION: Ab reactivity towards CNS tissue and gangliosides is markedly enhanced in patients with HT as compared to patients with other thyroid disorders. Whether these Abs could be of prognostic value to evaluate the risk of future neurocognitive impairment has to be investigated in longitudinal studies.

Perisylvian white matter connectivity in the human right hemisphere.

BACKGROUND: By using diffusion tensor magnetic resonance imaging (DTI) and subsequent tractography, a perisylvian language network in the human left hemisphere recently has been identified connecting Brocas's and Wernicke's areas directly (arcuate fasciculus) and indirectly by a pathway through the inferior parietal cortex. RESULTS: Applying DTI tractography in the present study, we found a similar three-way pathway in the right hemisphere of 12 healthy individuals: a direct connection between the superior temporal and lateral frontal cortex running in parallel with an indirect connection. The latter composed of a posterior segment connecting the superior temporal with the inferior parietal cortex and an anterior segment running from the inferior parietal to the lateral frontal cortex. CONCLUSION: The present DTI findings suggest that the perisylvian inferior parietal, superior temporal, and lateral frontal corticies are tightly connected not only in the human left but also in the human right hemisphere.

The minute hand phenomenon in the Clock Test of patients with early Alzheimer disease.

Common scoring systems for the Clock Test do not sufficiently emphasize the correct time representation by the clock hands. We compared Clock Drawing, Clock Setting, and Clock Reading in healthy control persons, patients with mild cognitive impairment, early Alzheimer disease and progressed Alzheimer disease particularly analyzing clock time representation. We found that healthy control persons and participants with mild cognitive impairment did not show any impairment in Clock Test performance. Patients with early Alzheimer disease could be discriminated from healthy control persons and participants with mild cognitive impairment solely by misplacement of the minute hand in Clock Drawing and Clock Setting. The progressed Alzheimer disease group showed significantly more impairments in all Clock Test variants. It is assumed that early stage Alzheimer disease patient deficits in Clock Tests are mainly determined by a reduced access to semantic memory about the appearance and functionality of a clock.