R. Dodel

Effect of minocycline in experimental autoimmune encephalomyelitis.

With interest we read the report by Popovic and colleagues showing the effect of minocycline in experimental autoimmune encephalomyelitis (EAE). Minocycline is a secondgeneration tetracycline, which recently was shown by us and others to have antiinflammatory as well as neuroprotective properties. The authors demonstrated that minocycline suppressed disease activity and inflammation in the central nervous system in association with immune deviation in the periphery. In their experiments, minocycline was dissolved in distilled water or saline and injected daily intraperitoneally (45mg/kg). We recently performed similar experiments in female SJL mice using an adoptive transfer EAE model. Mice were immunized with proteolipid protein 139-151 (200 g) plus adjuvant. After 10 days, draining lymph node cells were prepared, cultured for 4 days with antigen (10 g/ml), and injected intravenously (5 10) into naı̈ve mice. In contrast with the study by Popovic and colleagues, we had an oral treatment group in addition to an intraperitoneal treatment group. Intraperitoneal treatment led to a marked suppression of EAE, whereas, in orally treated animals, the effect of minocycline was markedly reduced (Fig). Also, we found that intraperitoneal application of minocycline may cause painful peritoneal irritation despite rigorous pH adjustment. In in vitro experiments on encephalitogenic lymph node cells and T-cell clones, we found that up to 10 M minocycline did not suppress proliferation or production of tumor necrosis factor– , interferon, or interleukin-10 (not shown). Minocycline is a compelling new therapeutic approach for multiple sclerosis, and our data support the findings by Popovic and colleagues that intraperitoneal minocycline suppresses EAE. However, our observation that oral dosing is less effective is remarkable and raised our concerns about the mechanisms involved and the impact on a potential application in humans. Tetracyclines distribute widely throughout the body as a function of their lipophilicity. Oral resorption of minocycline is approximately 95 to 100% with a half-life of 12 to 18 hours. Plasma levels are similar after oral or parenteral application. A concern relates to the observation that minocycline solutions are toxic and painful after injection mainly because of a rather low pH and also, though less so, after pH adjustment. We hypothesize that stress-induced immunosuppression, an established phenomenon in EAE, may have contributed to the effect of intraperitoneal minocycline. In conclusion, we advise that the mechanisms of EAE suppression by minocycline are investigated in more detail and intraperitoneal experiments are interpreted with caution before a potential (oral) application in humans.

NF-κB mediates IL-1β-induced synthesis/release of α2-macroglobulin in a human glial cell line

Abstract Increasingly, inflammatory responses in localized areas of brain parenchyma in response to the extracellular deposition of the Aβ peptides are thought to play a causative role in Alzheimer’s disease (AD) progression. Anti-inflammatory agents, in particular non-steroid anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, have been shown to be associated with a delayed onset or slowed rate of disease progression in several epidemiological studies. Activation of glial cells and the subsequent expression of a number of proteins including α 2 -macroglobulin (α 2 M) are associated with the induction of brain tissue inflammation. Additionally cytokines, such as interleukin-1α (IL-1α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are co-localized to senile plaques, a neuropathological hallmark of AD. α 2 M binds various cytokines, including IL-1β, as well as Aβ. In this study, we demonstrate that IL-1β induces α 2 M synthesis/release from a human astroglial cell line (U373) via the activation of the nuclear transcription factor NF-κB. Our data suggest that attenuation of IL-1β-induced α 2 M synthesis/release by blocking NF-κB activation may potentially be ‘protective’ against the development of late-onset AD.

Depression and care-dependency in Parkinson’s disease: Results from a nationwide study of 1449 outpatients

Parkinsons disease (PD) is frequently compounded by neuropsychiatric complications, increasing disability. The combined effect of motor and mental status on care-dependency in PD outpatients is not well characterized. We conducted a cross-sectional study of 1449 PD outpatients. The assessment comprised the Montgomery-Asberg Depression Rating Scale (MADRS) and the diagnostic criteria for dementia. PD severity and treatment complications were rated using Hoehn and Yahr staging and the Unified Parkinsons Disease Rating Scale (UPDRS) IV. The acknowledged level of care-dependency was documented. Care-dependency was present in 18.3% of all patients. A total of 13.9% had dementia, 18.8% had depression, and 14.3% had both. Regression analyses revealed increasing effects of age, PD duration, and PD severity on care-dependency in all three mental-disorder subgroups with the strongest effects in patients with depression only. Depressed patients with antidepressive treatment still had significantly higher PD severity, higher MADRS and UPDRS-IV scores but were not more likely to be care-dependent than non-depressed patients. Older age, longer duration and increased severity of PD contribute to care-dependency in patients with untreated depression. Treatment of depression is associated with lower rates of care-dependency.

Corrigendum to “Cost of disorders of the brain in Europe 2010” [Eur. Neuropsychopharmacol. 21 (2011) 718–779]

Corrigendum to “Cost of disorders of the brain in Europe 2010” [Eur. Neuropsychopharmacol. 21 (2011) 718–779]

Alzheimer's Disease: Differences of Transdermal versus Oral Treatment on Caregiving Time

Background: Data on indirect effects of dementia treatment on caregiver burden obtained from naturalistic studies are still lacking. We explored differences between patients with oral and transdermal application of acetylcholine esterase inhibitors regarding caregiver’s time burden and psychopathology. Methods: A cross-sectional naturalistic cohort study of 403 patients in outpatient care with three treatment groups (none, oral, and transdermal) was conducted. Assessments included a standardized clinical burden questionnaire and a standardized caregiver interview. Results: Any treatment was associated with lower burden in most measures. Transdermal treatment was superior regarding (1) administration time (p < 0.001); (2) rates of administration problems (p = 0.031); (3) burden in activities of daily living (p = 0.008), and (4) caregiver anxiety (OR 0.25; 95% CI 0.05–0.99). Caregivers did not report better quality of life regarding mental/physical health. Physicians’ and caregivers’ ratings of patients’ improvements were not associated (ĸ = 0.01–0.06). Conclusions: Benefits associated with transdermal treatment do not translate into a better ‘generic quality of life’ of the caregiver. The substantially different perceptions of patients’ improvements need to be considered in future studies.

[Dementia and depression determine care dependency in Parkinson's disease: analysis of 1,449 outpatients receiving nursing care in Germany]

BACKGROUND Parkinsons disease (PD) is frequently accompanied by dementia or depression which can aggravate the clinical picture of the disease and increase the risk of care dependency (CD). Little is known about the associations between PD, these neuropsychiatric comorbidities and CD in outpatients. PATIENTS AND METHODS A nationwide sample of outpatients (n=1,449) was examined by office-based neurologists (n=315) comprising the documentation of the general, neurological status and the degree of CD. The dementia status was clinically rated according to the established DSM-IV criteria. Depression was screened with the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS Overall, 18.3% of all patients were care dependent. Even after adjustment for PD severity, patients with depression (OR=2.8; 95% CI 1.8-4.3), dementia (OR=2.7; 95% CI 1.8-4.1) or both (OR=3.9; 95% CI 2.5-60,0) were at higher risk for CD than patients without dementia or depression. Patients aged ≥76 years were fourfold more likely to be care dependent than patients aged ≤65 years (OR=3.5; 95% CI 2.3-5.5). Across all age groups, patients with depression featured the highest increments (from 11.9 to 42.0%). CONCLUSION The risk for CD is substantially elevated in outpatients with PD when further neuropsychiatric symptoms are present. The data suggest that depression contributes equally to disability as does dementia.

Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.

BACKGROUND Data on gender-specific profiles of cognitive functions in patients with Parkinsons disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered. METHOD The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates. RESULTS Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis. CONCLUSIONS Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.

Psychometric properties of the apathy evaluation scale in patients with Parkinson's disease

Parkinsons disease (PD) frequently entails non‐motor symptoms, worsening the course of the disease. Apathy is one of the core neuropsychiatric symptoms that has been investigated in recent years; research is however hampered by the limited availability of well‐evaluated apathy scales for these patients. We evaluated the psychometric properties of the Apathy Evaluation Scale (AES) in a sample of PD patients. Psychometric properties, convergent and discriminant validity and sensitivity/specificity were evaluated in patients with (n = 582) or without dementia/depression (n = 339). Internal consistency was high in the entire sample as well as in patients without dementia/depression. Correlations were moderate for convergent validity (UPDRS I item 4: motivation). While apathy could be differentiated from cognitive decline, it was related to depression (Geriatric Depression Scale, GDS‐15). The overall classification accuracy based on the UPDRS I item 4 was comparable for AES and GDS scores. The AES exhibits good psychometric properties in PD patients with and without dementia and/or depression. Commonly used screenings on the presence of apathy had low detection rates compared to the AES and reflected both apathetic and depressive symptoms. Psychometric evaluation of available instruments will support further research on the clinical relevance of apathy for disease progression and treatment approaches in PD patients.

Psychometric Properties of an Abbreviated Version of the Apathy Evaluation Scale for Parkinson Disease (AES-12PD)

BACKGROUND Apathy is a frequent symptom in Parkinsons disease (PD), substantially aggravating the course of PD. Regarding the accumulating evidence of the key role of apathy in PD, time-efficient assessments are useful for fostering progress in research and treatment. The Apathy Evaluation Scale (AES) is widely used for the assessment of apathy across different nosologies. OBJECTIVE To facilitate the application of the AES in PD, we reduced the AES to two-thirds its length and validated this abbreviated version. DESIGN Data sets of 339 PD patients of the DEMPARK/LANDSCAPE study without dementia and depression were randomly split into two samples. Data of sample 1 were used to develop a brief version of the AES (AES-12PD). A cross-validation was conducted in sample 2 and in a subsample of 42 PD patients with comorbid dementia and depressive symptomatology. Receiver operating characteristic analysis was applied to determine the optimal cutoff of the AES-12PD as an indicator of apathy. RESULTS The AES-12PD featured high internal consistency that was better compared to the AES. The abbreviated scale was well differentiated from motor impairment and cognitive deficits. The AES-12PD cutoff of 27/28 was the optimal cutoff for apathy in PD patients without dementia and depression. The cutoff of 25/26 indicated apathy in PD patients with comorbid dementia and depression. CONCLUSION Results confirm a high internal consistency and good discriminant validity of the AES-12PD. The AES-12PD represents a reliable tool for the efficient assessment of apathy that can be applied in PD patients with and without dementia and depression.