Behavioral variant frontotemporal dementia: advanced disease stages and death. A step to palliative care.

OBJECTIVE: The aim of the present study was to gain insight into the living and care situation in advanced behavioral variant frontotemporal dementia (bvFTD), to describe symptoms and findings in advanced bvFTD, and to evaluate somatic comorbidities and circumstances of death. METHODS: Standardized interviews were conducted with family caregivers of 83 patients with bvFTD. Forty-four percent of the patients were already deceased at the time of the interview. RESULTS: At the time of the interview or death, respectively, 47% of the patients lived in a nursing home. The median time between symptom onset and nursing home admission was 5.0 ± 5.5 years. In moderate and severe dementia stages almost all patients suffered from severe disabilities including impairment of language, gait, swallowing, and of the ability to care for themselves. Sixteen percent of the patients had got enteral tube feeding. Comorbid somatic diseases were diagnosed in 46% of the patients. Twenty-three percent of the deceased patients had been admitted into a hospital before death. Cardiovascular disease and respiratory disease, mostly pneumonia, were the most frequent causes of death. CONCLUSIONS: Advanced bvFTD is characterized by severe cognitive impairment and physical disabilities. BvFTD leads to a premature death. Our findings stress the importance of strategies that maximize patient comfort in advanced disease stages and allow for a peaceful death. Copyright © 2016 John Wiley & Sons, Ltd.

[Connections between sleep and Alzheimer's disease : Insomnia, amnesia and amyloid]. / Wie Schlaf und Alzheimer-Krankheit zusammenhängen : Insomnie, Amnesie und Amyloid.

Sleep plays an essential role in memory consolidation. Although sleep problems are common in Alzheimer's disease, they are not usually thought to be key features of the disease; however, new experimental research has shown that sleep disturbances not only occur before the onset of typical cognitive deficits but are also associated with the pathogenesis of Alzheimer's disease and may have a decisive influence on the symptoms and course. Thus, sleep disturbances may be potentially modifiable risk factors for Alzheimer's disease that deserve more attention in research, diagnostics and treatment.

[Mechanisms of Alzheimer's disease : Neuronal hyperactivity and hypoactivity as new therapeutic targets]. / Mechanismen der Alzheimer-Krankheit : Neuronale Hyper- und Hypoaktivität als neue Therapieziele.

Alzheimer's disease (AD) is characterized by the pathological accumulation of amyloid-beta (Abeta) and tau peptides in the brain. Recent evidence suggests that the soluble peptide amyloid-eta (Aeta) may have an additional role in the pathogenesis of AD. The detailed investigation of the cellular and neurophysiological mechanisms underlying AD has revealed surprising results that may become highly relevant for the early diagnosis and treatment of the disease. By analyzing the function of single neurons and large-scale networks in intact brains in vivo it has been shown that A-beta, tau and A-eta abnormally modulate brain activity and obviously unfold contrasting effects: while A-beta promotes neuronal hyperactivity as well as epileptiform activity, tau and A-eta reduce the activity of neurons. Promising new evidence from animal studies and humans with AD indicates that the treatment of hyperactivity may improve cognitive dysfunctions and even slow the underlying disease process.

Over-the-counter-drugs for the treatment of mood and anxiety disorders--the views of German pharmacists.

INTRODUCTION: Depression, anxiety, agitation and sleep disorders are highly prevalent in the general population, but few persons receive psychiatric care. METHODS: Our aim was to study the views of 690 German pharmacists on "over-the counter" (OTC) drugs for these indications. RESULTS: They reported dispensing OTC medication to an average of 12 customers per day, and this corresponded to almost one quarter of the medications provided for these indications. Herbal drugs and complex homeopathic formulations were used most frequently. Patients preferring OTC substances were described as being younger, with shorter durations of illness and less severe symptoms, and more skeptical regarding psychopharmacology. While genuine pharmacological effects were considered as most relevant, pharmacists were highly aware of placebo and interpersonal factors. Symptoms, comorbidity and advice on drug intake were prominent topics during pharmacy consultations. CONCLUSION: German pharmacists report dispensing large amounts of OTC drugs for anxiety, agitation, sleep disturbances or depression. It is unclear whether this constitutes a rational and cost effective method to deal with mild courses of high prevalence diseases or must be seen critically.

The deceleration capacity - a new measure of heart rate variability evaluated in patients with schizophrenia and antipsychotic treatment.

BACKGROUND: Schizophrenia is associated with increased cardiac mortality. A disturbed autonomic modulation of heart rate (HR) has been described in patients with schizophrenia in whom antipsychotic medication may represent an additional cardiac risk. The novel measure deceleration capacity (DC) of heart rate predicts cardiac mortality in patients with cardiovascular illnesses. The aim of the present paper was to calculate DC in patients with schizophrenia and to compare this measure with established parameters of heart rate variability (HRV). METHODS: HRV and DC were calculated in 24-hour electrocardiogram (ECG) recordings of 20 unmedicated, 40 medicated patients with schizophrenia and 40 controls. As activity has a major influence on HRV, 4-hour periods of "sleep-" and "wake-" ECG were evaluated as additional parameters. Actigraphy was used to ensure comparable levels of activity in patients and controls. RESULTS: The DC as well as the other established HRV measures were not significantly different comparing unmedicated patients with schizophrenia to healthy controls. However, medicated patients showed a significant reduction of DC calculated from ECG recordings during 4 hour over night periods. CONCLUSION: Calculation of DC might contribute to a better monitoring and identification of an increased risk of cardiac mortality in patients with schizophrenia undergoing antipsychotic treatment.

Agomelatine improves sleep in a patient with fatal familial insomnia.

A young patient with FFI was started on agomelatine 25 mg to medicate nocturnal insomnia. Under this treatment sleep efficiency was improved, slow wave sleep was high and awakenings during sleep period time were far less than before. Clinically the patient was less restless during nighttime.

Deficits of spatial and task-related attentional selection in mild cognitive impairment and Alzheimer's disease.

Visual selective attention was assessed with a partial-report task in patients with probable Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI), and healthy elderly controls. Based on Bundesen's "theory of visual attention" (TVA), two parameters were derived: top-down control of attentional selection, representing task-related attentional weighting for prioritizing relevant visual objects, and spatial distribution of attentional weights across the left and the right hemifield. Compared with controls, MCI patients showed significantly reduced top-down controlled selection, which was further deteriorated in AD subjects. Moreover, attentional weighting was significantly unbalanced across hemifields in MCI and tended to be more lateralized in AD. Across MCI and AD patients, carriers of the apolipoprotein E ε4 allele (ApoE4) displayed a leftward spatial bias, which was the more pronounced the younger the ApoE4-positive patients and the earlier disease onset. These results indicate that impaired top-down control may be linked to early dysfunction of fronto-parietal networks. An early temporo-parietal interhemispheric asymmetry might cause a pathological spatial bias which is associated with ApoE4 genotype and may therefore function as early cognitive marker of upcoming AD.

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 (κ = 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.

Depression and care-dependency in Parkinson's disease: results from a nationwide study of 1449 outpatients.

Parkinson's 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 Parkinson's 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.

[German consortium for frontotemporal lobar degeneration]. / Konsortium zur Erforschung der frontotemporalen Lobärdegeneration.

Frontotemporal lobar degeneration (FTLD) is an umbrella term for an aetiologically diverse group of neurodegenerative disorders with prominent lobar cortical atrophy. First this disease group was restricted to Pick's disease or Pick's complex. Several updates of the clinical classification systems were performed and discussed. Currently we summarize the following diseases under the FTLD spectrum: frontotemporal dementia (FTD) as a behavioural variant, primary non-fluent aphasia (PNFA) and semantic dementia as language variants, amyotrophic lateral sclerosis with FTD (ALS-FTD), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP).From the pathophysiological aspect major progress was made. Neuropathologically FTLDs are now defined based on the molecular composition of these protein accumulations. A major distinction of tau-associated (FTLD-tau) and TDP43-associated (FTLD-TDP43) and to a lesser extend FUS-associated (FTLD-FUS) has been made. Additional risk genes were described. However from the therapeutic perspective even symptomatic therapy is under discussion. A major aim of our consortium is to develop parameters allowing an early diagnosis and follow-up, thus providing effective and objective parameters for therapeutic strategies.

CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease.

OBJECTIVE: To explore if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient Alzheimer disease (AD) in a group of patients with mild cognitive impairment (MCI). METHODS: A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with frontotemporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. CSF concentrations of sAPPα, sAPPß, tau, and Aß(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves. RESULTS: The MCI-AD group had significantly higher sAPPß concentrations than the MCI-NAD and the FTD groups. A combination of sAPPß, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.00% and a specificity of 81.00%. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPß and tau, and showed a sensitivity of 95.20% and a specificity of 81.20%. Aß(1-42) and sAPPα did not significantly contribute to the models. CONCLUSION: These findings suggest that sAPPß may be clinically useful, and superior to Aß(1-42), in the early and differential diagnosis of incipient AD.

[Dementia and depression determine care dependency in Parkinson's disease: analysis of 1,449 outpatients receiving nursing care in Germany]. / Demenz und Depression determinieren Pflegebedürftigkeit bei M. Parkinson : Untersuchung an 1449 Patienten im ambulanten Versorgungssektor in Deutschland.

BACKGROUND: Parkinson's 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.

[Cognitive reserve and its relevance for the prevention and diagnosis of dementia]. / Kognitive Reservekapazität und ihre Bedeutung für Auftreten und Verlauf der Demenz.

Progressive brain damage is undoubtedly the main cause of clinical symptoms of dementia in neurodegenerative disorders such as Alzheimer's disease. However, the association between brain damage and cognitive symptoms is not linear. Certain interindividual differences such as a good school education or a greater brain volume are associated with a higher resilience against brain damage that is usually referred to as cognitive reserve (CR). Individuals with high CR have a diminished risk for dementia and both active and passive concepts for this phenomenon are discussed. In the concept of passive CR, peculiarities of brain structure such as higher synapse or neuron counts are regarded as buffers against brain damage. Symptoms of dementia do not occur until a certain threshold of damage is passed. In addition to the passive concepts, active mechanisms are also discussed that are associated with the ability to maintain a certain level of cognitive performance in the face of progressive neurodegeneration for a longer period. In subjects with healthy cognitive function, these active mechanisms contribute to the adaptation of brain activity when task difficulty level is increased. Confronted with progressive neurodegeneration, these active mechanisms help to compensate for brain damage. Individuals with higher CR show more efficient activation for solving the same task, which helps them to preserve normal levels of cognitive performance for a longer period.

Lack of evidence to support the association of polymorphisms within the alpha- and beta-secretase genes (ADAM10/BACE1) with Alzheimer's disease.

Cleavage of the amyloid precursor protein (APP) occurs through either an amyloidogenic or a non-amyloidogenic pathway. The first results in the generation of beta-amyloid (Aß) and is initiated through cleavage by the beta-site amyloid beta A4 precursor protein-cleaving enzyme 1 (BACE1). The second precludes the formation of Aß through cleavage by alpha-secretase, an enzyme's activity demonstrated in a disintegrin metalloproteinase, ADAM10. To assess the contribution of variants in the BACE1 and ADAM10 genes we used a detailed fine mapping approach. Genotyping of 11 single nucleotide polymorphisms covering the complete BACE1 gene, and 27 covering the entire ADAM10 gene, revealed no single-marker or haplotypic association with AD. We conclude that, in this present study, neither ADAM10 nor BACE1 present with any evidence to suggest that they are major candidate genes involved in conferring risk for AD.

No association of Tachykinin receptor 2 (TACR2) polymorphisms with Alzheimer's disease.

The Tachykinin Receptor 2 (TACR2) located at chromosome 10q21.3 belongs to a class of receptors that bind members of the tachykinin neurotransmitter family. The TACR2 binds neurokinin A, also known as substance K, and is expressed in distinct parts of the human brain. Functionally, the TACR2 has been implicated in stress induced hippocampal acetylcholine release and the gene TACR2 is located within a previously identified linkage region for Alzheimer's disease (AD) on chromosome 10q21. Together, both facts make the TACR2 a reasonable positional and functional candidate gene for AD. Genotyping of 13 single nucleotide polymorphisms (SNPs) covering the entire gene and haplotypic analysis revealed no association with AD. Thus, we conclude that TACR2 can be excluded as a major susceptibility gene conferring risk to AD.

Memantine in everyday clinical practice: a comparison of studies in Germany and Greece.

BACKGROUND/AIMS: Results from German and Greek non-interventional studies were compared to investigate possible differences concerning efficacy, tolerability and compliance between both countries. METHODS: In two open-label, multicentre, non-interventional studies, 4,305 patients with mild to severe Alzheimer's disease (AD) were treated with daily doses of 20 mg memantine for 6 months. Efficacy was assessed using the Mini-Mental State Examination (MMSE) and instrumental activities of daily living (IADL) scales. Safety and tolerability were recorded. RESULTS: After 6 months, the patients showed an improvement of their cognitive performance by 2 MMSE points compared to baseline (p < 0.001). MMSE values were improved in 67.4% of the patients, while 15.1% remained stable, and MMSE deteriorated in 17.5% only. The ability to perform IADL increased, as is indicated by lower values (baseline: 70.5; after 6 months: 66.6 points). Improvement of cognition and IADL was nearly identical in both countries. Treatment discontinuation was significantly more frequent in the Greek population, mainly due to non-adherence (9.4% of the safety population). 345 adverse events were recorded in 245 patients (6.3%), and they were significantly associated with country and age. CONCLUSION: The results correspond to those of clinical trials and support the efficacy and good tolerability of memantine in a realistic setting. Differences between the countries were observed regarding the baseline characteristics of patients (more female, older and more severe patients in Germany as well as less pretreatment with cholinesterase inhibitors) and regarding premature discontinuation and reported adverse drug reactions, which were both higher in Greece.