Study protocol of the OrkA project: orofacial and communicative activation in old age- a cluster randomized prevention study in long-term care facilities in Lower Saxony, Germany.

BACKGROUND: The process of aging involves numerous changes in the body, influencing physical, mental, and emotional well-being. Age-related changes and degradation can impact various functions of the swallowing process and lead to delayed word retrieval. Individuals with limited linguistic stimulation may experience a more rapid decline in cognitive performance. Thus, this project explores a preventive training program targeting swallowing and linguistic-communicative skills, aimed at preserving the social participation of older individuals residing in nursing homes. METHODS: A preventive intervention program, combining orofaciopharyngeal and linguistic-communicative components, will be offered twice weekly over 12 weeks in long-term care facilities in the greater Hanover area. The program will aim at: (a) activating sensitive and motor skills in the orofaciopharyngeal area to counter age-related swallowing disorders, and (b) enhancing communicative abilities through semantic-lexical activation. A cluster randomized controlled trial will be conducted to investigate whether the intervention program improves swallowing skills in older adults. Additionally, a secondary analysis will explore the impact on language skills and social participation, as well as program acceptance. DISCUSSION: The results will provide valuable insight into the effectiveness of preventive measures addressing swallowing and speech issues in older individuals. TRIAL REGISTRATION: The trial was registered with DRKS (German register for clinical trials) in June 2023 (study ID: DRKS00031594) and the WHO International Clinical Trail Registry Platform (secondary register).

An accurate fully automated panel of plasma biomarkers for Alzheimer's disease.

INTRODUCTION: There is a great need for fully automated plasma assays that can measure amyloid beta (Aß) pathology and predict future Alzheimer's disease (AD) dementia. METHODS: Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma Aß42/Aß40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. RESULTS: The best biomarker for discriminating Aß-positive versus Aß-negative participants was Aß42/Aß40 (are under the curve [AUC] 0.83-0.87). Combining Aß42/Aß40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (ΔAUC ≤0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and Aß42/Aß40 in MCI (AUC 0.87). DISCUSSION: The high accuracies for Aß pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.

[Alzheimer's disease-Which substances are at present in phase III studies?] / Alzheimer-Erkrankung ­ welche Substanzen befinden sich derzeit in Phase-III-Studien?

BACKGROUND: The recent approval of aduhelm/aducanumab by the US Food and Drug Administration (FDA) in June 2021 raised hopes that further substances against Alzheimer's disease might be approved in the near future. OBJECTIVE: The current status of phase III studies for Alzheimer's disease was evaluated. MATERIAL AND METHODS: The American database www. CLINICALTRIALS: gov was searched on 7 August 2021 for phase III studies which target the cognitive functions affected by Alzheimer's disease. The mode of action of the different substances was classified according to the Common Alzheimer's Disease Research Ontology (CADRO). RESULTS: With the applied search criteria 53 studies were found, 32 studies with 25 substances dealt with cognition, which was demonstrated by a cognition test as one of the primary outcome measures, 20 of the studies are recruiting, 4 are not yet recruiting and 8 studies are active but not recruiting. Of the studies seven target amyloid beta-peptide as well as tau protein. For 20 substances a disease modifying action is assumed. In 2022 and 2023 a total of 8 studies each are planned to be terminated. CONCLUSION: The mode of action of the substances, which are currently in studies, seems broad and for their action a modification of the disease is mostly assumed. Therefore, there is hope that in the next 2 years further drugs against Alzheimer's disease might be approved.

Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aß, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aß1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS: A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS: Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

Post-discharge adjustment of medication in geriatric patients : A prospective cohort study.

BACKGROUND: Little is known to what extent general practitioners (GP) change hospital discharge medications in older patients. OBJECTIVE: This prospective cohort study aimed to analyze medication changes at the interface between hospital and community in terms of quality, quantity and type of drugs. METHODS: A total of 121 out of 248 consecutively enrolled patients admitted to an acute geriatric hospital unit participated in the study. Medication regimens were recorded at admission and discharge and 4 weeks after hospital discharge the general practitioners in charge were contacted to provide the current medication charts. Changes in the extent of polypharmacy, in the type of drugs using anatomical therapeutic chemical classification (ATC) codes and potentially inappropriate medications (PIM) were analyzed. RESULTS: Medication charts could be obtained for 98 participants in primary care. Only 21% of these patients remained on the original discharge medication. Overall, the average number of medications rose from hospital admission (6.58 SD ± 3.45) to discharge (6.96 SD ± 3.49) and again post-discharge in general practice (7.22 SD ± 3.68). The rates of patients on excessive polypharmacy (≥10 drugs) and on PIM were only temporarily reduced during hospital stay. The GPs stopped anti-infective drugs (ATC-J) and prescribed more antirheumatic drugs (ATC-M). Although no significant net changes occurred in other ATC groups, a substantial number of drugs were interchanged regarding the subgroups. CONCLUSION: The study found that GPs extensively adjusted geriatric discharge medications. Whereas some changes may be necessary due to alterations in patients' state of health, a thorough communication between hospital doctors and GPs may level off different prescribing cultures and contribute to consistency in medication across sectors.

Living with and dying from advanced heart failure: understanding the needs of older patients at the end of life.

BACKGROUND: Heart failure (HF) is a life-limiting illness and patients with advanced heart failure often suffer from severe physical and psychosocial symptoms. Particularly in older patients, HF often occurs in conjunction with other chronic diseases, resulting in complex co-morbidity. This study aims to understand how old and very old patients with advanced HF perceive their disease and to identify their medical, psychosocial and information needs, focusing on the last phase of life. METHODS: Qualitative longitudinal interview study with old and very old patients (≥70 years) with severe HF (NYHA III-IV). Interviews were conducted at three-month intervals over a period of up to 18 months and were analysed using qualitative methods in relation to Grounded Theory. RESULTS: A total of 95 qualitative interviews with 25 patients were conducted and analysed. The following key categories were developed: (1a) dealing with advanced heart failure and ageing, (1b) dealing with end of life; (2a) perceptions regarding care, and (2b) interpersonal relations. Overall, our data show that older patients do not experience HF as a life-limiting disease. Functional restrictions and changed conditions leading to problems in daily life activities were often their prime concerns. The needs and priorities of older HF patients vary depending on their disease status and individual preferences. Pain resulting in reduced quality of life is an example of a major symptom requiring treatment. Many older HF patients lack sufficient knowledge about their condition and its prognosis, particularly concerning emergency situations and end of life issues, and many expressed a wish for open discussions. From the patients' perspective, there is a need for improvement in interaction with health care professionals, and limits in treatment and medical care are not openly discussed. CONCLUSION: Old and very old patients with advanced HF often do not acknowledge the seriousness and severity of the disease. Their communication with physicians predominantly focuses on curative treatment. Therefore, aspects such as self-management of the disease, dealing with emergency situations and end-of-life issues should be addressed more prominently. An advanced care planning (ACP) programme for heart disease in older people could be an option to improve patient-centred care.

Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease.

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1alpha, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc(-/-)). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc(-/-) mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to gamma-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease.

Lipoic acid as a novel treatment for Alzheimer's disease and related dementias.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-alpha-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-alpha-enantiomer, may be effective to treat AD and related dementias.

Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer's disease: post-hoc analysis of a randomized placebo-controlled study.

BACKGROUND: A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer's disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome. METHODS: Randomized patients (N = 2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints. RESULTS: Overall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p = 0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p < 0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p < 0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n = 1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores. CONCLUSION: This post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00679627 . Registered 15 May 2008.

Identification of novel biomarker candidates by differential peptidomics analysis of cerebrospinal fluid in Alzheimer's disease.

The objective of this work was the application of peptidomics technologies for the detection and identification of reliable and robust biomarkers for Alzheimer's disease (AD) contributing to facilitate and further improve the diagnosis of AD. Using a new method for the comprehensive and comparative profiling of peptides, the differential peptide display (DPD), 312 cerebrospinal fluid (CSF) samples from AD patients, cognitively unimpaired subjects and from patients suffering from other primary dementia disorders were analysed as four independent analytical sets. By combination with a cross validation procedure, candidates were selected from a total of more than 6,000 different peptide signals based on their discriminating power. Twelve candidates were identified using mass-spectrometric techniques as fragments of the possibly neuroprotective neuroendocrine protein VGF and another one as the complement factor C3 descendent C3f. The combination of peptide profiling and cross validation resulted in the detection of novel potential biomarkers with remarkable robustness and a close relation to AD pathophysiology.

Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease.

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease.

BACKGROUND: Currently available treatments for Alzheimer's disease (AD) can produce mild improvements in cognitive function, behavior, and activities of daily living in patients, but their influence on long-term survival is not well established. This study was designed to assess patient survival and drug efficacy following a 2-year galantamine treatment in patients with mild to moderately severe AD. METHODS: In this multicenter, double-blind study, patients were randomized 1:1 to receive galantamine or placebo. One primary end point was safety; mortality was assessed. An independent Data Safety Monitoring Board monitored mortality for the total deaths reaching prespecified numbers, using a time-to-event method and a Cox-regression model. The primary efficacy end point was cognitive change from baseline to month 24, as measured by the Mini-Mental State Examination (MMSE) score, analyzed using intent-to-treat analysis with the 'last observation carried forward' approach, in an analysis of covariance model. RESULTS: In all, 1,024 galantamine- and 1,021 placebo-treated patients received study drug, with mean age ~73 years, and mean (standard deviation [SD]) baseline MMSE score of 19 (4.08). A total of 32% of patients (661/2,045) completed the study, 27% (554/2,045) withdrew, and 41% (830/2,045) did not complete the study and were discontinued due to a Data Safety Monitoring Board-recommended early study termination. The mortality rate was significantly lower in the galantamine group versus placebo (hazard ratio [HR] =0.58; 95% confidence interval [CI]: 0.37; 0.89) (P=0.011). Cognitive impairment, based on the mean (SD) change in MMSE scores from baseline to month 24, significantly worsened in the placebo (-2.14 [4.34]) compared with the galantamine group (-1.41 [4.05]) (P<0.001). Functional impairment, based on mean (SD) change in the Disability Assessment in Dementia score (secondary end point), at month 24 significantly worsened in the placebo (-10.81 [18.27]) versus the galantamine group (-8.16 [17.25]) (P=0.002). Incidences of treatment-emergent adverse events were 54.0% for the galantamine and 48.6% for the placebo group. CONCLUSION: Long-term treatment with galantamine significantly reduced mortality and the decline in cognition and daily living activities, in mild to moderate AD patients. IDENTIFICATION: This study is registered at ClinicalTrials.gov (NCT00679627).

'Who is going to explain it to me so that I understand?' Health care needs and experiences of older patients with advanced heart failure.

Heart failure is a leading cause of death and can result in significant palliative care needs. The aim of this study was to explore the needs of older patients with advanced heart failure, and their experiences with health care delivery in Germany. Qualitative interviews were carried out with 12 patients (6 men, 6 women; age 73-94 years; heart failure in an advanced stage according to the New York Heart Association Functional Classification) recruited in two geriatric hospitals. The interviews were analyzed by a qualitative descriptive approach. The main categories derived from the patient interviews were: understanding of illness and prognosis, health care services and social life. The patients expressed the need for better information and communication regarding illness and prognosis, and the desire for more respectful treatment by health care providers. Heart failure was not recognized as a potentially life-limiting disease, and the patients had no experience with palliative care services. The study emphasizes the need for improving communication with patients with advanced heart failure. To achieve this, strengthening the palliative care approach in all relevant services that deliver care for these patients and introducing advanced care planning appear to be promising strategies.