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.

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.

Examination of the current top candidate genes for AD in a genome-wide association study.

With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the 'Top Results' list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case-control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with 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.

[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.

[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.

[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.

Validation of the German revised Addenbrooke's cognitive examination for detecting mild cognitive impairment, mild dementia in alzheimer's disease and frontotemporal lobar degeneration.

BACKGROUND/AIMS: The diagnostic accuracy of the German version of the revised Addenbrooke's Cognitive Examination (ACE-R) in identifying mild cognitive impairment (MCI), mild dementia in Alzheimer's disease (AD) and mild dementia in frontotemporal lobar degeneration (FTLD) in comparison with the conventional Mini Mental State Examination (MMSE) was assessed. METHODS: The study encompasses 76 cognitively healthy elderly individuals, 75 patients with MCI, 56 with AD and 22 with FTLD. ACE-R and MMSE were validated against an expert diagnosis based on a comprehensive diagnostic procedure. Statistical analysis was performed using the receiver operating characteristic method and regression analyses. RESULTS: The optimal cut-off score for the ACE-R for detecting MCI, AD, and FTLD was 86/87, 82/83 and 83/84, respectively. ACE-R was superior to MMSE only in the detection of patients with FTLD [area under the curve (AUC): 0.97 vs. 0.92], whilst the accuracy of the two instruments did not differ in identifying MCI and AD. The ratio of the scores of the memory ACE-R subtest to verbal fluency subtest contributed significantly to the discrimination between AD and FTLD (optimal cut-off score: 2.30/2.31, AUC: 0.77), whereas the MMSE and ACE-R total scores did not. CONCLUSION: The German ACE-R is superior to the most commonly employed MMSE in detecting mild dementia in FTLD and in the differential diagnosis between AD and FTLD. Thus it might serve as a valuable instrument as part of a comprehensive diagnostic workup in specialist centres/clinics contributing to the diagnosis and differential diagnosis of the cause of dementia.

Carotid- intima media thickness is independently associated with cognitive decline. The INVADE study.

OBJECTIVES: Increased carotid intima-media thickness (C-IMT) is a non-invasive marker of atherosclerosis and predicts vascular events. Moreover, increasing evidence suggests an association between carotid atherosclerosis and cognitive decline. The purpose of this study is to investigate the relationship between C-IMT and the development of cognitive impairment in a large population-based sample. METHODS: This study was based on the data of the participants of the INVADE (Intervention project on cerebrovascular diseases and dementia in the district of Ebersberg, Bavaria) project. Vascular risk factors, Geriatric depression scale (GDS) and "6 Item Cognitive Impairment Test" (6CIT) were evaluated at baseline and after 2 years. The relationship between C-IMT and cognitive impairment was analysed using multivariate logistic regression. RESULTS: Complete baseline data were available in 3386 subjects (mean age 67.7 [95% confidence interval (CI): 67.5, 68.0] years, 41% male). During follow-up, 174 subjects developed a new cognitive impairment. In the subgroup without cognitive impairment at baseline a significant association between cognitive decline after 2 years and elevated C-IMT at baseline could be detected with a significantly higher baseline C-IMT in those with cognitive decline (0.87 mm vs. 0.78 mm; p < 0.0001). After adjustment for various risk factors only age, GDS baseline 6CIT and C-IMT were independently associated with the development of a new cognitive impairment. CONCLUSIONS: Our data indicate that an increased carotid intima-media thickness predicts a cognitive decline in an elderly population without prevalent cognitive impairment.

Turning principles into practice in Alzheimer's disease.

The prevalence of dementia is reaching epidemic proportions globally, but there remain a number of issues that prevent people with dementia, their families and caregivers, from taking control of their condition. In 2008, Alzheimer's Disease International (ADI) launched a Global Alzheimer's Disease Charter, which comprises six principles that underscore the urgency for a more ambitious approach to diagnosis, treatment and care. This review highlights some of the most important aspects and challenges of dementia diagnosis and treatment. These issues are reviewed in light of the six principles of the recent ADI Charter: promoting dementia awareness and understanding; respecting human rights; recognizing the key role of families and caregivers; providing access to health and social care; stressing the importance of optimal diagnosis and treatment; and preventing dementia through improvements in public health. The authors continue to hope that, one day, a cure for Alzheimer's disease will be found. Meanwhile, healthcare professionals need to unite in rising to the challenge of managing all cases of dementia, using the tools available to us now to work toward improved patient care.

[SSRI - treatment and bleeding. What risks do we take?]. / Blutungsrisiko unter SSRI-Behandlung.

Treatment with selective serotonin reuptake inhibitors (SSRI) increases the risk of gastrointestinal bleeding. The combination with non-steroidal anti-inflammatory drugs (NSAIDs) further augments this hazard. Particular precaution is also necessary in patients on platelet aggregation inhibitors, with a known bleeding disorder or preceding gastrointestinal lesions. The incidence of bleeding events apart from the gastrointestinal tract, e.g. intracerebral hemorrhages, is not cumulated under SSRI treatment. This also applies for the combination of SSRI and coumarin or aspirin. Prescribing doctors have to be aware of the bleeding risks of SSRI and should explain this to their patients. High-risk patients have to be followed up closely and an SSRI with a low potential for drug interaction should be used. The prescription of gastroprotective agents and a change of the antidepressant should be considered in particular cases. We provide a literature survey and recommendations for the clinical routine.

[Car driving ability of patients with frontotemporal lobar degeneration and Alzheimer's disease]. / Fahrtauglichkeit bei Patienten mit frontotemporaler und Alzheimer-Demenz.

BACKGROUND: The following study presents in detail newly occurring changes in driving ability of patients with Alzheimer's disease (AD) and dementia due to frontotemporal lobar degeneration (FTLD). PATIENTS AND METHODS: The caregivers of 30 patients with FTLD (20 with FTD, 10 with SD) and 26 matched patients with AD were interviewed on potential alterations in driving ability using a standardized questionnaire. RESULTS: Of the patients 90% with FTLD and 58% with AD showed changes in driving behavior. In AD the predominating alteration was an unsteady style of driving with increased lack of orientation. Patients with FTLD presented an aggressive and risky style of driving including various traffic rule violations. Significant differences between the two groups were observed regarding speeding, disregarding red traffic lights, inappropriate behavior and driving despite being forbidden by the family Of the patients with FTLD 37% were responsible for at least one accident since disease onset in comparison to 19% of patients with AD (p=0.24). Most patients with AD showed a reasonable attitude to their change in driving behavior, however the majority of patients with FTLD showed a lack of understanding for the fact that their style of driving presented a potential risk and did not accept the need to stop driving (p=0.023). CONCLUSION: Patients with FTLD should cease driving as soon as possible in the course of the disease. With patients suffering from mild AD an individual assessment should be made.

[Dying demented. Concepts of care and palliative medicine]. / Sterben mit Demenz. Versorgungssituation und palliativmedizinischer Ausblick.

A third of the elderly population dies with dementia. This poses major and partly unmet needs on relatives, professional carers and medical specialists. Our review summarizes epidemiological risk factors for the increased mortality in demented patients (age, somatic co-morbidity, neuropsychiatric symptoms), current practice (place of death, decision making, complications, medical treatment, course of dying, cause of death, suicide, bereaved relatives), and instruments for the assessment of pain, burden, prognosis and treatment planning in the terminal stage of illness. We describe the current legal situation in Germany and present a brief outline of practical management issues. We also list a number of areas offering leeway for improvement regarding research, training, psycho-education, preparation, diagnosis, treatment and support.

[The German Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD): more than Parkinson]. / Die "German study on the epidemiology of Parkinson's disease with dementia" (GEPAD): mehr als nur Parkinson.

UNLABELLED: It is unknown, how frequently Parkinson's disease (PD) is complicated by dementia, depression and other neuropsychiatric conditions. An epidemiologic characterisation of the situation in specialised neurologic settings is lacking. The Geman Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD) isa national representative epidemiological study of n=1449 PD patients in n=315 office-based neurological settings, designed to estimate the prevalence of dementia, depression and other neuropsychiatric conditions in patients with PD of all stages by using standardized clinical assessments. RESULTS: 28.6% met DSM-IV criteria for dementia. 33.6% met criteria for depression and 61% additionally had other clinically significant psychopathological syndromes. Only 29.4% had no neuropsychiatric conditions. GEPAD reveals for the first time comprehensively that the neuropsychiatric burden of PD patients in all stages and even early stages is considerable, posing challenging questions for research and clinical management.

Prevention of interferon-stimulated gene expression using microRNA-designed hairpins.

RNA interference allows selective gene silencing, and is widely used for functional analysis of individual genes in vertebrate cells and represents an attractive therapeutic option for treating central nervous system diseases. However, growing evidence exists that the expression of short hairpin RNAs (shRNAs) can trigger cellular immune response resulting in unspecific cellular phenotypes and severe side effects. We found that lentiviral vector (LV)-mediated expression of shRNAs in primary cortical cultures resulted in strong expression of the interferon-stimulated gene oligoadenylate synthetase 1 (Oas1), which was accompanied by accelerated apoptosis and substantial net neuron loss. Modification of the shRNA construct by implementing features of the naturally occurring microRNA-30 (miR-30) precursor avoided Oas1 induction in transduced primary cultures, whereby modification of the passenger strand seems to be a crucial feature to circumvent interferon-stimulated gene expression. This work represents the first experimental study showing that an miR-30-based shRNA construct prevents Oas1 pathway associated off-target effects, which we consider as an essential prerequisite for shRNA use in future gene therapeutic approaches.

[Neuro-enhancement. Brain doping]. / Neuro-Enhancement. Gehirndoping.

Cognitive enhancement, the increase in the mental ability by psychoactive substances and other interventions has received a renewed boost through the development of innovative principle. More than 100 drugs are currently being developed, tested or used for cognitive enhancement. Cholinesterase inhibitors, memantine, dimebon, ampakines, fluoxetine and other antidepressants, methylphenidate and modafinil are candidates awaiting a larger distribution as cognitive enhancers in healthy individuals, if their advantages can be demonstrated. Beyond more general neuro-ethical reservations regarding neuro-enhancement, future research will need to address the following neuropsychiatric issues: (1) will the benefits of longer term neuro-enhancement outweigh potential disadvantages such as rebound effects and other neurobiological and psychosocial trade-offs? (2) What will be the neuropsychiatric sequelae of a soft coercion towards drug usage at work and for recreational purposes? (3) Will there be new and specific neuropsychiatric diseases due to long-term usage of neuro-enhancers in a larger population? Novel strategies of neuro-enhancement will have to demonstrate their superiority compared with more traditional and well-established interventions such as coffee and cake.

[Personality in old age]. / Persönlichkeit im höheren Lebensalter.

Modern developmental psychology tends to draw a positive, resource-based picture of human aging. We will however focus on more difficult aspects of personality in old age which are of psychiatric relevance: the persistence of cluster A and C personality disorders, antisocial personality in the elderly; the interaction of personality and a detection of mild cognitive impairment (MCI); personality features as risk or protective factors or early signs of Alzheimer's dementia; changes of personality in Parkinson's disease and frontotemporal dementia. We will briefly mention recent neuroimaging studies which appear to suggest a functional neuroanatomy of personality. A quote from Cicero's cato major, de senectute indicates that some of his perceptions regarding classic personality characteristics of the elderly can be recognized in our patients and can be prevented or treated with modern interventions.