A European Academy of Neurology guideline on medical management issues in dementia.

BACKGROUND AND PURPOSE: Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow-up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia. METHODS: A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated. RESULTS: Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk-benefit ratio should be performed at regular intervals. Regular, preplanned medical follow-up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non-pharmacological measures have been proven to be without benefit or in the case of severe self-harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first-line therapy (Good Practice statement). CONCLUSION: This GRADE-based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas.

Alzheimer's disease medication and outcomes of hospitalisation among patients with dementia.

AIMS: The use of Alzheimer disease medication for the treatment of dementia symptoms has shown significant benefits with regards to functional and cognitive outcomes as well as nursing home placement (NHP) and mortality. Hospitalisations in these patient groups are characterised by extended length of stays (LOS), frequent readmissions, frequent NHP and high-mortality rates. The impact of Alzheimer disease medication on the aforementioned outcomes remains still unknown. This study assessed the association of Alzheimer disease medication with outcomes of hospitalisation among patients with Alzheimer disease and other forms of dementia. METHODS: A dynamic retrospective cohort study from 2004 to 2015 was conducted which claims data from a German health insurance company. People with dementia (PWD) were identified using ICD-10 codes and diagnostic measures. The main predictor of interest was the use of Alzheimer disease medication. Hospitalisation outcomes included LOS, readmissions, NHP and mortality during and after hospitalisation across four hospitalisations. Confounding was addressed using a propensity score throughout all analyses. RESULTS: A total of 1380 users of Alzheimer disease medication and 6730 non-users were identified. The use of Alzheimer disease medication was associated with significantly shorter LOS during the first hospitalisations with estimates for the second, third and fourth showed a tendency towards shorter hospital stays. In addition, current users of Alzheimer disease medication had a lower risk of hospital readmission after the first two hospitalisations. These associations were not significant for the third and fourth hospitalisations. Post-hospitalisation NHP and mortality rates also tended to be lower among current users than among non-users but differences did not reach statistical significance. CONCLUSIONS: Our results indicate that Alzheimer disease medication might contribute to a reduction of the LOS and the number of readmissions in PWD.

Correlation of CSF- and MRI-Biomarkers and Progression of Cognitive Decline in an Open Label MCI Trial.

BACKGROUND: In several randomized controlled trials (RCT) acetylcholinesterase-inhibitors (AChE-I) were tested in patients with mild cognitive impairment (MCI) but were ineffective in delaying disease progression as determined by neuropsychological testing only. Here we present data from an open label observational extension of a multicenter RCT in order to assess if biomarkers are providing useful additional information about a drug's efficacy. We followed 83 amnestic MCI patients and performed correlational analyses of Aß 1-42 and total-Tau in the cerebrospinal fluid (CSF), hippocampal and amygdala volume at baseline, the total duration of blinded and open label AChE-I treatment and the outcome 24 months after inclusion into the RCT. Twelve out of 83 amnestic MCI (14%) had progressed to Alzheimer's disease (AD). Overall, worsening and disease progression as measured by the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) and Clinical Dementia Rating (CDR) did not correlate with the duration of AChE-I treatment. However, a specific multidimensional biomarker profile at baseline indicated more reliably than cognitive testing alone progression to AD. We conclude that pharmacological RCTs testing symptomatic treatment effects in MCI should include biomarker assessment.

Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment.

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ɛ4 (apolipoprotein E-ɛ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

[Therapy of dementia with antipsychotics and antidepressives]. / Therapie mit Antipsychotika und Antidepressiva bei Demenzen.

In dementia depressive symptoms, anxiety, hallucinations and delusions often occur and are accompanied by unspecific behavioral changes. A targeted pharmacotherapy is complicated by the underlying cognitive impairment and physical comorbidities. The current review focusses on recent evidence on the use of antidepressives and antipsychotics for psychotic disturbances, agitation and depression in dementia and analyzes currently published randomized controlled clinical trials and meta-analyses. The evidence on the use of antipsychotics for different indications favors risperidone, with lower evidence levels for quetiapine and aripiprazole, whereas haloperidol should be avoided. Increased mortality and the risk of cerebrovascular events due to antipsychotics are of major concern. With respect to antidepressives, the benefit of antidepressive pharmacotherapy in dementia is critically discussed because of limited efficacy and increased side effects; however, selective serotonin reuptake inhibitors (SSRI), such as citalopram and sertraline have demonstrated efficacy on neuropsychiatric behavioral symptoms in general. These conclusions on the risk-benefit ratio of antidepressives and antipsychotics in dementia are in accordance with the recommendations of the German Society of Neurology and German Association for Psychiatry, Psychotherapy and Psychosomatics (DGN/DGPPN) S3 guidelines on the treatment of dementia.

Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer's Disease.

OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.

[Guidelines on "pharmacotherapy of neurodegenerative dementia": an update]. / Leitlinien zur "Pharmakotherapie neurodegenerativer Demenzen" : Ein Update.

This article presents the evidence-based pharmacotherapeutic options for the most common forms of neurodegenerative dementia. The aim is to present the recommendations derived from the relevant studies on the neurological, psychiatric and geriatric practice of treatment for dementia patients. The text is derived from the 2009 guidelines of the German Society of Neurology (DGN, lead management: K. Fassbinder), the S3 guidelines of the DGN/German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN, lead management: G. Deuschl and W. Maier) and the latest amendments of the European Federation of Neurological Societies/European Society of Neurology (EFNS-ENS, Sorbi et al. Eur J Neurol 19:1159-1179, 2012) guidelines. The forms of neurodegenerative dementia addressed are Alzheimer's disease, frontotemporal dementia and Lewy body dementia. Specific statements on the treatment of dementia in Parkinson's disease and vascular dementia can be found in separate guidelines. An analogous article on psychosocial interventions was recently published in Der Nervenarzt (Kurz, Nervenarzt 84:93-103, 2013).

Progression of Alzheimer disease in Europe: data from the European ICTUS study.

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden.

[Attitudes toward dementia management in Germany - Data from the IMPACT survey (Important Perspectives on Alzheimer's Care and Treatment)]. / Einstellungen und Wahrnehmungen zur Demenz-Versorgung in Deutschland. Daten aus der IMPACT-Umfrage.

AIM: To assess attitudes and opinions of primary care physicians, neuropsychiatrists, care givers, and community members regarding the management of dementia in Germany. METHODS: The IMPACT survey, a 30-minute web-based questionnaire conducted between April and May 2009, queried 350 subjects in Germany (200 community members, 100 physicians, 50 caregivers of patients with dementia) as a subpopulation of 1800 subjects involved in the management of dementia subjects across Europe. RESULTS: Community members favored dementia-screening (p < 0.001) in healthy elderly and wanted to know a diagnosis of dementia as early as possible (p = 0.092). German physicians regarded dementia as underdiagnosed and undertreated, they acknowledged the effectiveness of available antidementia drugs and saw the major reason for not-prescribing in the costs of drugs. CONCLUSION: Professional knowledge about dementia has to be enhanced and financial restrictions have to be reduced to improve dementia management on all levels of medical care.

A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI.

OBJECTIVES: Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory. DESIGN, SETTING AND PARTICIPANTS: For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized. INTERVENTION: Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo. MEASUREMENTS: The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog. RESULTS: After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2-52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the combination regimen or as mono treatment, resulted in a transient decline of the ADAScog score in amnestic MCI of presumed AD etiology, while discontinuation of Memantine did not change the cognitive status. CONCLUSION: In an interrupted trial with amnestic MCI subjects the combination of galantamine plus memantine were generally well tolerated. In the subgroup of MCI subjects with presumed AD etiology, a cognitive benefit of a short-term combination treatment of galantamine plus memantine was observed, and cognitive decline occurred after discontinuation of galantamine.

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease.

OBJECTIVE: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). METHODS: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale-Revised. CSF was obtained from all patients. RESULTS: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aß(1-42)/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD- patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. CONCLUSIONS: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

Venlafaxin-associated post-ictal asystole during electroconvulsive therapy.

While post-stimulus asystoles occur quite often during electroconvulsive therapy (ECT) post-ictal or post-seizure sinus bradycardias or even asystoles are rare events. We report the case of an 82-year-old female patient with a current major depressive episode, who developed the rare event of a post-ictal asystole of 6 s and 4 ventricular escape beats during ECT. In the past this patient with a bipolar disorder and mild Alzheimer's disease had already been frequently treated with ECT with good success and no adverse events. Relevant comedication was venlafaxin, quetiapine, donepezil and clonidine, anesthesia was performed with ketamine and succinylcholine. Concurrent medication was completely unchanged compared to previous ECT sessions with the exception of venlafaxine, presumably at high serum levels. In summary, in line with some already existing reports, we expect the noradrenergic action of venlafaxin to have contributed substantially to the post-ictal asystole and want to indicate that the combination of ECT and venlafaxin might be harmful--especially in the elderly population.

Regional differences in effects of APOE ε4 on cognitive impairment in non-demented subjects.

BACKGROUND: The APOE ε4 allele is a risk factor for Alzheimer's disease (AD). APOE ε4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE ε4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. METHODS: Data from 16 centers across Europe were analyzed. RESULTS: A north-south gradient in APOE ε4 prevalence existed in the total sample (62.7% for APOE ε4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE ε4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. CONCLUSION: The APOE ε4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE ε4 allele and cognition is region dependent.

Assessing physician attitudes and perceptions of Alzheimer's disease across Europe.

Given the important role that physicians play in clinical care, disease advocacy, national health policy making and clinical research, the IMPACT survey sought to assess the attitudes and perceptions of physicians in 3 general categories: diagnosis and treatment of Alzheimer's disease (AD); caregivers and families of patients with AD; and the role of government in dealing with this disease and its consequences. Survey respondents comprised a total of 250 generalists and 250 specialists (neurologists, geriatricians, neuro-psychiatrists, psychiatrists and psychogeriatricians) from France, Germany, Italy, Spain and the United Kingdom. Physicians were aged 25 to 69 years, in practice for between 5 and 30 years and currently spending more than 50% of their time in direct patient care. Results showed that a sizable majority of physicians throughout Europe, specialists and generalists alike, agree that: 1) AD is underdiagnosed and undertreated; 2) patients and families are not prepared to recognise the early symptoms of the disease; 3) early treatment can help to slow the progression of the disease; and 4) more effective treatments are needed. Attitudes were statistically significantly different between some groups of physicians regarding disclosure of the diagnosis of AD, the benefits of lifestyle modification, and the value of AD-specific medication in patients whose symptoms are worsening. Differences in attitudes and perceptions of AD between specialists and generalists were limited; differences between countries were more common and of greater magnitude, particularly with respect to barriers to the use of prescription medications.

[S3 guidelines on dementia. Symptomatic therapy of dementia]. / S3-Leitlinie "Demenzen". Symptomatische Therapie der Demenzen.

Current treatment of Alzheimer's disease comprises pharmacological therapy and psychosocial interventions for patients and caregivers in the context of a symptom and severity dependent management concept. Treatment is targeted towards the core symptoms of dementia (cognitive and functional deficits) and if necessary, towards the behavioral symptoms of dementia. The treatment of Alzheimer's dementia with acetylcholine esterase inhibitors (AChE-I; donepezil, galantamine, rivastigmine) and memantine is evidence-based and recommended. For all drugs, the highest tolerable dose should be given. The choice of AChE-I depends on the side-effects and interaction profile, as there is no convincing evidence of a relevant superiority of one of the drugs over another. Mixed dementia should be treated as Alzheimer's dementia. Treatment of vascular dementia with AChE-I or memantine is off-label and without convincing evidence. There is no convincing evidence for the treatment of frontotemporal dementia or Lewy body dementia. Rivastigmine is effective for the treatment of dementia with Parkinson's disease.

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.