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Abstract Aims The effectiveness of surgery depends on it being carried out safely, which allows patients to return to independent lives. Because gastrointestinal cancers are a major cause of morbidity and mortality in older people, we examined the dynamics of recuperation after elective, curative surgery. As disease parameters alone may not suffice to address geriatric patients' issues after onco-surgical interventions, Comprehensive Geriatric and QOL Assessments (CGA/QOL) were performed at four time points to gain information on clinical, functional, and cognitive aspects. Methods CGA/QOL including standard geriatric instruments, socio-demographic, clinical data, and the EORTCQLQ-C30 questionnaire were applied pre-operatively (T1), at discharge (T2), after three (T3), and after six months (T4). Results 200 patients gave their informed consent, 70 patients declined. At T1 n = 195, at T2 n = 155, at T3 n = 130, and at T4 n = 124 patients were actually assessed. Patients experienced a significant decline in most functional capabilities and increased symptoms at T2. While most parameters re-approached baseline results by T4, sophisticated abilities (instrumental ADL, IADL) remained impaired. Fatigue was the most prominent symptom that persisted in many at T4. Risk for malnutrition as well as BMI significantly decreased during regeneration. Global QOL correlated with parameters of independence (ADL, IADL) and low symptom burden. Role and social functions' correlation with global QOL increased from T1 to T4. Conclusions Longitudinal assessments before and after oncologic surgery highlight changes even after six months in QOL and independence that may be ameliorated by focused supportive care. Trial registry number: DRKS: 00000425. [ABSTRACT FROM AUTHOR]

Abstract: Prostaglandins (PGs) are generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2) and modulate several functions in the CNS such as the generation of fever, the sleep/wake cycle, and the perception of pain. Moreover, the induction of COX-2 and the generation of PGs has been linked to neuroinflammatory aspects of Alzheimer''s disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) that block COX enzymatic activity have been shown to reduce the incidence of AD in various epidemiological studies. While several reports investigated the expression of COX-2 in neurons and microglia, expression of COX-2 in astroglial cells has not been investigated in detail. Here we show that amyloid β peptide 25–35 (Aβ25–35) induces COX-2 mRNA and protein synthesis and a subsequent release of prostaglandin E2 (PGE2) in primary midbrain astrocytes. We further demonstrate that protein kinase C (PKC) is involved in Aβ25–35-induced COX-2/PGE2 synthesis. PKC-inhibitors prevent Aβ25–35-induced COX-2 and PGE2 synthesis. Furthermore Aβ25–35 rapidly induces the phosphorylation and enzymatic activation of PKC in primary rat midbrain glial cells and in primary human astrocytes from post mortem tissue. Our data suggest that the PKC isoforms α and/or β are most probably involved in Aβ25–35-induced expression of COX-2 in midbrain astrocytes. The potential role of astroglial cells in the phagocytosis of amyloid and the involvement of PGs in this process suggests that a modulation of PGs synthesis may be a putative target in the prevention of amyloid deposition. [Copyright &y& Elsevier]

Abstract: Objective: Memory complaints are a common finding in outpatients, especially in psychosomatic and neurological practice. In a substantial group of patients persistent memory complaints are found in the absence of abnormal neuropsychology. Different labels such as “functional memory complaint” have been suggested for this phenomenon. We characterise a group of patients with such memory complaints, which we termed functional memory disorder (FMD). The aim of the present study is to describe patients with FMD. Methods: Thirty-nine patients with FMD were compared to 38 control subjects. Data were collected on the German version of the Rey Auditory Verbal Learning test and the Zahlenverbindungstest (cognitive speed), subscales of the Metamemory in Adulthood questionnaire (MIA), the Perceived Stress Questionnaire (PSQ), the Global Severity Index (GSI) of the Symptom Checklist, the Beck Depression Inventory (BDI), and other psychological questionnaire measures. Results: We found significant group differences on all psychological questionnaire measures, with more pathological scores in the patient group. GSI and PSQ were the best predictors of memory self-efficacy. MIA-Memory Self-Efficacy (MSE), MIA-Achievement, and BDI were the best predictors of group membership (FMD vs. control group). When MSE was excluded, MIA-Achievement and BDI or GSI were the only predictors of group membership. Neuropsychological measures predicted neither MSE nor group membership. Conclusions: Pathological scores on measures of metamemory, stress, and depression are typical of FMD. Low MSE and a high memory-related achievement motivation seem to be key features of FMD. Other important features are increased perceived stress, general psychosomatic complaint, and elevated depression scores. Neuropsychological test performance is not associated with FMD symptoms. [Copyright &y& Elsevier]

• Calcium/Calmodulin-dependent kinase alpha is essential for learning and memory. • We tested the association of CAMK2A SNPs with verbal logical memory in elderly people with cognitive impairments. • rs919741 predicted a higher hippocampal volume and better logical memory in the elderly. • No such association was found in healthy adults. Calcium/Calmodulin-dependent kinase alpha (αCaMKII) has been shown to play an essential role in synaptic plasticity and in learning and memory in animal models. However, there is little evidence for an involvement in specific memories in humans. Here we tested the potential involvement of the αCaMKII coding gene CAMK2A in verbal logical memory in two Caucasian populations from Germany, in a sample of 209 elderly people with cognitive impairments and a sample of 142 healthy adults. The association of single nucleotide polymorphisms (SNPs) located within the genomic region of CAMK2A with verbal logical memory learning and retrieval from the Wechsler Memory Scale was measured and hippocampal volume was assessed by structural MRI. In the elderly people, we found the minor allele of CAMK2A intronic SNP rs919741 to predict a higher hippocampal volume and better logical memory retrieval. This association was not found in healthy adults. The present study may provide evidence for an association of a genetic variant of the CAMK2A gene specifically with retrieval of logical memory in elderly humans. This effect is possibly mediated by a higher hippocampal volume. [ABSTRACT FROM AUTHOR]

The exploration and retrieval of words during category fluency involves different strategies to improve or maintain performance. Deficits in that task, which are common in patients with amnestic mild cognitive impairment (aMCI), mirror either impaired semantic memory or dysfunctional executive control mechanisms. Relating category fluency to tasks that place greater demands on either semantic knowledge or executive functions might help to determine the underlying cognitive process. The aims of this study were to compare performance and strategy use of 20 patients with aMCI to 30 healthy elderly controls (HC) and to identify the dominant component (either executive or semantic) for better task performance in category fluency. Thus, the relationship between category fluency, design fluency and naming was examined. As fluency tasks have been associated with the superior frontal gyrus (SFG), the inferior frontal gyrus (IFG), and the temporal pole, we further explored the relationship between gray matter volume in these areas and both performance and strategy use. Patients with aMCI showed significantly lower performance and significantly less strategy use during fluency tasks compared to HC. However, both groups equally improved their performance when repeatedly confronted with the same task. In aMCI, performance during category fluency was significantly predicted by design fluency performance, while in HC, it was significantly predicted by naming performance. In HC, volume of the SFG significantly predicted both category and design fluency performance, and strategy use during design fluency. In aMCI, the SFG and the IFG predicted performance during both category and design fluency. The IFG significantly predicted strategy use during category fluency in both groups. The reduced category fluency performance in aMCI seems to be primarily due to dysfunctional executive control mechanisms rather than impaired semantic knowledge. This finding is directly relevant to patients in the different stages of Alzheimer's disease as it links the known semantic fluency deficit in this population to executive functions. Although patients with aMCI are impaired in both performance and strategy use compared to HC, they are able to increase performance over time. However, only HC were able to significantly improve the utilization of fluency strategies in both category and design fluency over time. HC seem to rely more heavily on the SFG during fluency tasks, while in patients with aMCI additional frontal brain areas are involved, possibly reflecting compensational processes. [ABSTRACT FROM AUTHOR]

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1–42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline. [ABSTRACT FROM AUTHOR]

Abstract: Language deficits are regularly found in cortical neurodegenerative diseases. The progression of language deficits shows a considerable inter-individual variability even within one diagnostic group. We aimed at detecting patterns of altered diffusion as well as atrophy of cerebral gray and white matter which underlie ongoing language-related deterioration in patients with cortical neurodegenerative diseases. Diffusion tensor imaging and T1-weighted MRI data of 26 patients with clinically diagnosed neurodegenerative disorders were acquired at baseline and 14 months later in this prospective study. Language functions were assessed with a confrontation naming test and the Token Test. Diffusion and voxel-based morphometric measures were calculated and correlates of language performance were evaluated. Across all patients, the naming impairment was related to diffusion (false discovery rate-corrected P<0.05 at baseline) and atrophy abnormalities (family-wise error (FWE)-corrected P<0.05 at follow-up) primarily in the left temporal lobe. Deficits in the Token Test were correlated with predominantly left frontal MRI abnormalities (FWE-corrected P<0.05). The Token Test performance decline over 14 months was accompanied by further increasing abnormalities in the frontal cortex, left caudate, parietal cortex (all FWE-corrected P<0.05), and posterior callosal body (FWE-corrected P=0.055). Both diffusion and structural MRI were apt to elucidate the underpinnings of inter-individual differences in language-related deficits and to detect longitudinal changes that accompanied ongoing cognition and language decline, with mean diffusivity appearing most sensitive. This might indicate the usefulness of diffusion measures as markers for successful intervention in therapy studies. [Copyright &y& Elsevier]

Abstract: To address the potential impact of presenilin mutations on the prostaglandin metabolism in a neurodegenerative model of glutamatergic excitotoxicity, we injected kainic acid intraperitoneally (30mg/kg body weight) into mice over-expressing the human N141I mutation of presenilin-2, which is known to cause an early-onset form of Alzheimer''s disease. We compared the seizure activity as well as seizure lethality in 2- and 6-month-old mice, transgenic for the above-mentioned point mutation, and their wildtype littermates and found that mice harboring the hN141I mutation showed a relative resistance to excitotoxic treatment. This was associated with a constituitively reduced expression of the cyclooxygenases COX-1 and COX-2 in the hippocampus of N141I presenilin-2 mice and a reduced induction of COX-2 expression post-kainate injection. In the past, clinical trials have suggested that both non-steroidal anti-inflammatory drugs, which impact upon a cell''s prostaglandin metabolism, and glutamatergic antagonists might be of benefit to patients suffering from Alzheimer''s-type dementias. Yet, the exact mechanism by which these drugs are beneficial remains unclear, although it seems possible that presenilins might be implicated in the process, at least in the case of early-onset forms. The data presented here strongly support the notion of an implication of presenilins in the alterations in the prostaglandin system, which have been observed in Alzheimer''s disease and may contribute to the underlying pathogenesis of the disease. [Copyright &y& Elsevier]

Abstract: Inhibition of neuronal cyclooxygenase-2 (COX-2) and hence prostaglandin E2 (PGE2) synthesis by non-steroidal anti-inflammatory drugs has been suggested to protect neuronal cells in a variety of pathophysiological situations including Alzheimer''s disease and ischemic stroke. Ascorbic acid (vitamin C) has also been shown to protect cerebral tissue in a variety of experimental conditions, which has been attributed to its antioxidant capacity. In the present study, we show that ascorbic acid dose-dependently inhibited interleukin-1β (IL-1β)-mediated PGE2 synthesis in the human neuronal cell line, SK-N-SH. Furthermore, in combination with aspirin, ascorbic acid augmented the inhibitory effect of aspirin on PGE2 synthesis. However, ascorbic acid had no synergistic effect along with other COX inhibitors (SC-58125 and indomethacin). The inhibition of IL-1β-mediated PGE2 synthesis by ascorbic acid was not due to the inhibition of the expression of COX-2 or microsomal prostaglandin E synthase (mPGES-1). Rather, ascorbic acid dose-dependently (0.1–100 μM) produced a significant reduction in IL-1β-mediated production of 8-iso-prostaglandin F2α (8-iso-PGF2α), a reliable indicator of free radical formation, suggesting that the effects of ascorbic acid on COX-2-mediated PGE2 biosynthesis may be the result of the maintenance of the neuronal redox status since COX activity is known to be enhanced by oxidative stress. Our results provide in vitro evidence that the neuroprotective effects of ascorbic acid may depend, at least in part, on its ability to reduce neuronal COX-2 activity and PGE2 synthesis, owing to its antioxidant properties. Further, these experiments suggest that a combination of aspirin with ascorbic acid constitutes a novel approach to render COX-2 more sensitive to inhibition by aspirin, allowing an anti-inflammatory therapy with lower doses of aspirin, thereby avoiding the side effects of the usually high dose aspirin treatment. [Copyright &y& Elsevier]

Abstract: Little and controversial evidence is available from neuroimaging studies in progressive nonfluent aphasia (PNA). The goal of this study was to combine information from different imaging modalities in PNA compared with Alzheimer''s disease (AD). Chemical shift imaging (CSI), voxel-based morphometry (VBM) and fluorodeoxyglucose positron emission tomography (FDG-PET) were used in 5 PNA, 10 AD patients and 10 normal subjects. Group comparisons revealed left anterior lateral temporal abnormalities (BA20/21) in PNA using CSI, VBM and PET in comparison to normal subjects. AD patients showed more limited hypometabolism within the same area. In addition left lateral parietal (BA40) abnormalities were demonstrated in our PNA as well as our AD group using PET and VBM (AD group only). Combining information from all imaging modalities on a single case basis revealed pathology within the left anterior lateral temporal and lateral parietal lobe both in PNA and AD. PNA and AD patients differed significantly, however, with respect to the frequency of medial temporal lobe and posterior cingulate/precuneus involvement. Although our results might not be generalizable to all subgroups of PNA, we conclude that medial temporal and posterior cingulate/precuneus cortex pathology as assessed by CSI and VBM or PET distinguish PNA from AD, whereas lateral temporal and parietal areas are involved in both conditions. [Copyright &y& Elsevier]