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1.
Nervenarzt ; 2021 Nov 04.
Artigo em Alemão | MEDLINE | ID: mdl-34735586

RESUMO

Alzheimer's disease is one the major common diseases but so far only with symptomatic treatment options. New insights define the disease as a slowly progressive continuum with very long preclinical and early symptomatic phases. Innovative molecular treatment strategies are based on an improved understanding of the molecular neurobiology of the disease, opening up a variety of therapeutic targets. For the first time, an anti-amyloid antibody has been approved in the USA in 2021 as a disease-modifying treatment for Alzheimer's disease, representing a first highly controversial step towards a molecular, cause-oriented treatment. This review presents the most advanced molecular treatment strategies and discusses the implications of the approved antibody treatment for the clinical practice. The special features of this long-term treatment with i.v. infusions in a particularly vulnerable population and a special side effect profile will impose significant challenges for implementation in the practice and will require a high degree of cooperation within the healthcare system. The future of Alzheimer's treatment with a multimodal therapeutic approach with different classes of drugs will probably reinforce these trends.

2.
BMC Geriatr ; 21(1): 343, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082710

RESUMO

BACKGROUND: Frailty is characterized by an age-related decline in multiple physiological systems, leading to a high vulnerability to stressors, adverse health outcomes, and low quality of life. Neuroscientific models of pathological aging emphasize the loss of sensorimotor stimulation and reduced neuromodulatory capacities as core processes in age-related cognitive and bodily decline, which may be associated with maladaptive plastic changes in the brain. We plan to increase sensorimotor stimulation in frail persons through a newly developed app-based training program and link the training trials to biological and psychological correlates of age-associated vulnerability and health indices. METHODS: We will conduct a randomized trial, applying an app-based sensorimotor home training (N = 30) in people suffering from frailty. An app-based relaxation training will serve as an active control condition (N = 30). Both interventions will last for 90 days each. The sensorimotor training includes unimodal and multimodal sensory discrimination tasks in the visual, auditory, and tactile domain, as well as sensorimotor precision tasks. The tasks will be implemented using an adaptive training algorithm and enriched with motivational components embedded in a virtual training environment. We expect a pre-post reduction of frailty status and associated functional decline related to refinement of representational maps within the sensorimotor system and improved sensorimotor function such as extremity function. Secondary analyses will study the influence of BDNF genotype as moderating variable. Additional outcomes will include measures of perceptual and cognitive functioning, quality of life as well as BDNF serum levels. Measurements will take place before training (baseline), after 60 days (assessment 1), and at the end of the training after 90 days (assessment 2). DISCUSSION: In our randomized trial, we aim to characterize a multidimensional concept of frailty and to target maladaptive behaviors and neuroplasticity using an app-based sensorimotor training. This type of intervention might provide further knowledge and new possibilities for preventing decline and preserving function in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 . Registered 11 September 2018 - Retrospectively registered. Protocol version: Version 4 revised (issue date: 19 May 2021).


Assuntos
Fragilidade , Aplicativos Móveis , Idoso , Envelhecimento , Fragilidade/diagnóstico , Fragilidade/terapia , Humanos , Plasticidade Neuronal , Qualidade de Vida
3.
Geriatrics (Basel) ; 6(1)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809840

RESUMO

BACKGROUND: The COVID-19 pandemic and governmental lockdown measures disproportionally impact older adults. This study presents the results from a psychiatric helpline for older adults in Mannheim, Germany, during the lockdown, set up to provide information and psychosocial support. We aim to elucidate the needs of older adults, their reported changes, and the psychological impact during the initial stages of the health crisis. METHODS: A total of 55 older adults called the psychiatric helpline between April and June 2020. Information on demographics, medical and psychiatric history. as well as changes in daily life due to the pandemic was collected anonymously. Mental health status was assessed using the 7-Item Hamilton Depression Rating Scale (HAMD-7) and the Hamilton Anxiety Rating Scale (HAM-A). RESULTS: Most callers were women, older adults (M = 74.69 years), single, and retired. In total, 69% of callers reported new or an increase in psychiatric symptoms, with anxiety and depressive symptoms being the most common ones. Age was significantly negatively correlated to higher levels of anxiety and depression symptoms. Individuals with a previous diagnosis of a psychiatric disease reported significantly higher levels of depressive and anxiety symptoms than those without a diagnosis. CONCLUSION: In older adults, the perceived psychological impact of the COVID-19 crisis appears to ameliorate with age. Individuals with a history of psychiatric disease are most vulnerable to negative mental health outcomes. Rapid response in the form of a geriatric helpline is a useful initiative to support the psychosocial needs of older adults during a health crisis.

4.
In Vivo ; 35(2): 1177-1183, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33622918

RESUMO

BACKGROUND: Crossed cerebellar diaschisis (CCD) is a phenomenon with depressed metabolism and hypoperfusion in the cerebellum. Using arterial spin-labelling perfusion weighted magnetic resonance imaging (ASL PWI), we investigated the frequency of CCD in patients with Alzheimer's disease (AD) and differences between patients with and without CCD. PATIENTS AND METHODS: In patients with AD who underwent a standardized magnetic resonance imaging including ASL PWI cerebral blood flow was evaluated in the cerebellum, and brain segmentation/volumetry was performed using mdbrain (mediaire GmbH, Berlin, Germany) and FSL FIRST (Functional Magnetic Resonance Imaging of the Brain Software Library). RESULTS: In total, 65 patients were included, and 22 (33.8%) patients were assessed as being CCD-positive. Patients with CCD had a significantly smaller whole brain volume (862.8±49.9 vs. 893.7±62.7 ml, p=0.049) as well as white matter volume (352.9±28.0 vs. 374.3±30.7, p=0.008) in comparison to patients without CCD. CONCLUSION: It was possible to detect CCD by ASL PWI in approximately one-third of patients with AD and was associated with smaller whole brain and white matter volume.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Circulação Cerebrovascular , Alemanha , Humanos , Imageamento por Ressonância Magnética , Perfusão , Marcadores de Spin
5.
In Vivo ; 35(1): 429-435, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33402493

RESUMO

BACKGROUND/AIM: Sodium (23Na) MR imaging is a noninvasive MRI technique that has been shown to be sensitive to visualize biochemical information about tissue viability, their cell integrity, and cell function in various studies. The aim of this study was to evaluate differences in regional brain 23Na signal intensity between Alzheimer's disease (AD) and healthy controls to preliminarily evaluate the capability of 23Na imaging as a biomarker for AD. PATIENTS AND METHODS: A total of 14 patients diagnosed with AD were included: 12 in the state of dementia and 2 with mild cognitive impairment (MCI), and 12 healthy controls (HC); they were all scanned on a 3T clinical scanner with a double tuned 1H/23Na birdcage head coil. After normalizing the signal intensity with that of the vitreous humor, relative tissue sodium concentration (rTSC) was measured after automated segmentation in the hippocampus, amygdala, basal ganglia, white matter (WM) and grey matter (GM) in both cerebral hemispheres. RESULTS: Patients with AD showed a significant increase in rTSC in comparison to healthy controls in the following brain regions: WM 13.6%; p=0.007, hippocampus 12.9%; p=0.003, amygdala 18.9%; p=0.0007. CONCLUSION: 23Na-MRI has the potential to be developed as a useful biomarker for the diagnosis of AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Sódio
6.
Nervenarzt ; 92(7): 708-715, 2021 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-33025072

RESUMO

BACKGROUND: Memory clinics (MC) are institutions specialized in the (differential) diagnostics, treatment, education, management and counseling of diseases related to dementia and their risk stages. In Germany, they have a variety of different organizational forms. Due to the growing diagnostic options in neurodegenerative diseases, the increasing demand for early detection and prediction as well as foreseeable new diagnostic procedures and disease-modifying treatment, it is important to standardize the structural prerequisites and areas of responsibility of MC. OBJECTIVE: The article proposes structural and organizational requirements and procedures and a harmonized mode of operation for MC in Germany. METHOD: Expert consensus of psychiatrists, neurologists and geriatricians from academic and nonacademic institutions. RESULTS: The MC should provide the specialist standards of psychiatry and/or neurology. They need to implement the recommendations of the national guidelines on dementia (S3LL) with respect to the (differential) diagnostics and treatment of dementia. With respect to the early detection and prediction of neurodegenerative disorders, they extend beyond the current German guideline standards. In MC, mild cognitive impairment (MCI) is understood as an at-risk or prodromal stage of diseases related to dementia and biomarkers are consistently applied for etiological (early and differential) diagnostics. There is a requirement for close interaction with specialized diagnostic disciplines. Furthermore, MC should also offer comprehensive advice on social and legal issues and provide caregiver support. They should integrate current knowledge from research into care and serve as regional expert centers. CONCLUSION: The MC should implement evidence-based standards in diagnostics and treatment and introduce innovations in the care of patients with cognitive disorders and at-risk and prodromal stages. Their role in the German healthcare system must be strengthened. Sufficient and sustained funding needs to be established, since current reimbursement does not cover costs.


Assuntos
Transtornos Cognitivos , Disfunção Cognitiva , Demência , Doenças Neurodegenerativas , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/terapia , Demência/diagnóstico , Demência/terapia , Alemanha , Humanos
7.
Int J Geriatr Psychiatry ; 36(2): 324-333, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32896040

RESUMO

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico , Biomarcadores , Disfunção Cognitiva/diagnóstico , Aconselhamento , Revelação , Progressão da Doença , Europa (Continente) , Seguimentos , Humanos , Sensibilidade e Especificidade
8.
Artigo em Inglês | MEDLINE | ID: mdl-33380492

RESUMO

OBJECTIVE: Synaptic loss plays a major role in Alzheimer's disease (AD). However so far no neurochemical marker for synaptic loss has been introduced into clinical routine. By mass spectrometry beta-synuclein was established as a candidate marker. We now aimed to set up a novel ELISA for beta-synuclein for evaluation of its potential as a diagnostic and predictive marker for AD. METHODS: We analysed in total 393 patients from four specialised centres. The diagnostic groups comprised: AD (n=151), behavioural variant frontotemporal dementia (bvFTD, n=18), Parkinson syndrome (n=46), Creutzfeldt-Jakob disease (CJD, n=23), amyotrophic lateral sclerosis (ALS, n=29), disease control (n=66) and 60 non-neurodegenerative control patients. Results were compared with core AD biomarkers (total tau, phospho-tau and amyloid-ß peptide 1-42). Additionally, coexistence of beta-synuclein with vesicular glutamate transporter 1 (VGLUT1) was determined and beta-synuclein levels were quantified in brain homogenates. RESULTS: Beta-synuclein levels quantified with the newly established ELISA correlated strongly with antibody-free quantitative mass spectrometry data (r=0.92 (95% CI: 0.89 to 0.94), p<0.0001). Cerebrospinal fluid (CSF) beta-synuclein levels were increased in AD-mild cognitive impairment (p<0.0001), AD dementia (p<0.0001) and CJD (p<0.0001), but not in bvFTD, Parkinson syndrome or ALS. Furthermore, beta-synuclein was localised in VGLUT1-positive glutamatergic synapses, and its expression was significantly reduced in brain tissue from patients with AD (p<0.01). CONCLUSION: We successfully established a sensitive and robust ELISA for the measurement of brain-enriched beta-synuclein, which we could show is localised in glutamatergic synapses. We confirmed previous, mass spectrometry-based observations of increased beta-synuclein levels in CSF of patients with AD and CJD supporting its potential use as a marker of synaptic degeneration.

9.
Alzheimers Res Ther ; 12(1): 124, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008436

RESUMO

BACKGROUND: Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer's disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD. METHODS: The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts. We profiled LPA-derived metabolites using liquid chromatography-mass spectrometry. We evaluated the association of LPAs with CSF biomarkers of AD, Aß-42, p-tau, and total tau levels overall and stratified by APOE genotype and with MCI to AD progression. RESULTS: Five LPAs (C16:0, C16:1, C22:4, C22:6, and isomer-LPA C22:5) showed significant positive association with CSF biomarkers of AD, Aß-42, p-tau, and total tau, while LPA C14:0 and C20:1 associated only with Aß-42 and alkyl-LPA C18:1, and LPA C20:1 associated with tau pathology biomarkers. Association of cyclic-LPA C16:0 and two LPAs (C20:4, C22:4) with Aß-42 levels was found only in APOE ε4 carriers. Furthermore, LPA C16:0 and C16:1 also showed association with MCI to AD dementia progression, but results did not replicate in an independent cohort. CONCLUSIONS: Our findings provide evidence that LPAs may contribute to early AD pathogenesis. Future studies are needed to determine whether LPAs play a role in upstream of AD pathology or are downstream markers of neurodegeneration.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Biomarcadores , Disfunção Cognitiva/genética , Estudos de Coortes , Progressão da Doença , Humanos , Lisofosfolipídeos , Fragmentos de Peptídeos , Proteínas tau
10.
JAMA Netw Open ; 3(5): e206027, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32463470

RESUMO

Importance: Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed. Objective: To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Design, Setting, and Participants: This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. Interventions: Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. Main Outcomes and Measures: Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. Results: A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups. Conclusions and Relevance: Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood. Trial Registration: EU Clinical Trials Register Identifier: 2007-005352-17.


Assuntos
Doença de Alzheimer/psicologia , Antidepressivos de Segunda Geração/uso terapêutico , Apatia/efeitos dos fármacos , Bupropiona/uso terapêutico , Idoso , Doença de Alzheimer/tratamento farmacológico , Antidepressivos de Segunda Geração/efeitos adversos , Bupropiona/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência
11.
J Proteome Res ; 19(3): 1310-1318, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32101007

RESUMO

Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read-out for patient diagnosis and possible follow-up in clinical trials. Several synaptic markers for AD are described in cerebrospinal fluid (CSF), but studies in blood have failed so far. Using quantitative mass spectrometry (IP-MS, MRM) we observed increased concentrations of the presynaptic protein beta-synuclein (ßSyn) in CSF and blood of AD patients (n = 64, p < 0.01) and confirmed this finding in two validation cohorts (AD: n = 40 and n = 49, controls: n = 44 and n = 25). ßSyn was already increased in patients with mild cognitive impairment (p < 0.01) and was also markedly increased in Creutzfeldt-Jakob disease (CJD; n = 25, p < 0.001) but not behavioral variant frontotemporal dementia (n = 16), dementia with Lewy bodies/Parkinson's disease dementia (n = 13), Parkinson's disease (n = 25), or amyotrophic lateral sclerosis (n = 30). The diagnostic sensitivity and specificity for CJD versus other neurodegenerative diseases was ≥96%. These findings suggest ßSyn as a candidate blood marker for synaptic degeneration that might be used in clinical AD trials and patient follow-up as part of the recently suggested ATN biomarker panel. It can also serve in the differential diagnosis of CJD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico , Biomarcadores , Diagnóstico Diferencial , Humanos , Espectrometria de Massas , beta-Sinucleína , Proteínas tau
12.
BMC Psychiatry ; 19(1): 274, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488095

RESUMO

BACKGROUND: Intracranial arachnoid cysts are usually benign congenital findings of neuroimaging modalities, sometimes however, leading to focal neurological and psychiatric comorbidities. Whether primarily clinically silent cysts may become causally involved in cognitive decline in old age is neither well examined nor understood. CASE PRESENTATION: A 66-year old caucasian man presenting with a giant left-hemispheric frontotemporal cyst without progression of size, presented with slowly progressive cognitive decline. Neuropsychological assessment revealed an amnestic mild cognitive impairment (MCI) without further neurological or psychiatric symptoms. The patient showed mild medio-temporal lobe atrophy on structural MRI. Diffusion tensor and functional magnetic resonance imaging depicted a rather sustained function of the strongly suppressed left hemisphere. Amyloid-PET imaging was positive for increased amyloid burden and he was homozygous for the APOEε3-gene. A diagnosis of MCI due to Alzheimer's disease was given and a co-morbidity with a silent arachnoid cyst was assumed. To investigate, if a potentially reduced CSF flow due to the giant arachnoid cyst contributed to the early manifestation of AD, we reviewed 15 case series of subjects with frontotemporal arachnoid cysts and cognitive decline. However, no increased manifestation of neurodegenerative disorders was reported. CONCLUSIONS: With this case report, we illustrate the necessity of a systematic work-up for neurodegenerative disorders in patients with arachnoid cysts and emerging cognitive decline. We finally propose a modus operandi for the stratification and management of patients with arachnoid cysts potentially susceptive for cognitive dysfunction.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Cistos Aracnóideos/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Idoso , Doença de Alzheimer/etiologia , Cistos Aracnóideos/psicologia , Disfunção Cognitiva/etiologia , Humanos , Masculino , Testes Neuropsicológicos , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia
13.
J Alzheimers Dis ; 71(3): 993-1004, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31450503

RESUMO

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is challenging, and easily accessible biomarkers are an unmet need. Blood platelets frequently serve as peripheral model for studying AD pathogenesis and might represent a reasonable biomarker source. OBJECTIVE: In the present study, we investigated the potential to differentiate AD patients from healthy controls (HC) based on blood count, platelet morphology, and function as well as molecular markers at the time of first clinical diagnosis. METHODS: Blood samples from 40 AD patients and 29 age-matched HC were included for determination of 78 parameter by blood counting, platelet morphometry, aggregometry, flow cytometry (CD62P, CD63, activated fibrinogen receptor), protein quantification of nicotinic acetylcholine receptor α7 (nAChRα7) and caveolin-1 (CAV-1), and miRNA quantification (miR-26b, miR-199a, miR-335). Group comparison between patients and controls was performed in univariate and multivariate statistical analyses. RESULTS: AD patients showed significantly lower aggregation response to ADP and arachidonic acid and significantly decreased CD62P and CD63 surface expression induced by ADP and U46619 compared to HC. Relative nAChRα7 and CAV-1 expression was significantly higher AD platelets than in HC. Multivariate analysis of 63 parameter revealed significant differences between AD patients and healthy controls. The best performing feature model revealed a sensitivity of 96.6%, a specificity of 80.0%, and a positive predictive value of 89.3%. No grouping could be achieved by using single parameter groups. CONCLUSION: Significant differences between platelet characteristics from AD patients and HC at the time of first clinical diagnosis were observed. The best performing parameter can be used as a blood-based biomarker for AD diagnosis in a multivariate model in addition to the standardized mental tests.


Assuntos
Doença de Alzheimer/sangue , Plaquetas/química , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Biomarcadores/análise , Plaquetas/ultraestrutura , Diagnóstico Precoce , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Agregação Plaquetária , Contagem de Plaquetas , Valor Preditivo dos Testes , Sensibilidade e Especificidade
14.
BMJ Open ; 9(8): e028632, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31377702

RESUMO

INTRODUCTION: Dementia (particularly Alzheimer's disease, AD) is a major cause of impaired cognitive functions in the elderly. Amnestic mild cognitive impairment (aMCI) is a prodromal stage of AD, if substantiated by Alzheimer biomarkers. A neuroscientific model of pathological ageing emphasises the loss of brain plasticity, sensorimotor capacities and subsequent cognitive decline. A mechanistic treatment targeting dysfunctional plastic changes associated with ageing should be efficacious in delaying AD. In this trial, we aim to evaluate the effectiveness of a newly developed sensorimotor training, delivered at home, combined with personalised reinforcement, on the progression of aMCI-related cognitive impairments. METHODS AND ANALYSIS: In a randomised trial, we will compare two aMCI groups (30 subjects each), randomly allocated to a sensorimotor or a cognitive control training. Both trainings consist of an adaptive algorithm, and will last 3 months each. We hypothesise that both trainings will have positive effects on cognitive function with the sensorimotor training being superior compared with the control training based on its improvement in basic perceptual skills underlying memory encoding and retrieval. The primary outcome is episodic memory function, improved hippocampal function during memory tasks will be a secondary outcome. As further exploratory outcomes, we expect improved segregation in sensory and motor maps, better sensory discrimination only in the sensorimotor training and reduced transition to dementia (examined after completion of this study). We expect the experimental training to be evaluated more positively by the users compared with the cognitive training, resulting in reduced rates of discontinuation. ETHICS AND DISSEMINATION: The Ethics Committee of the Medical Faculty Mannheim, Heidelberg University, approved the study (2015-543N-MA), which adheres to the Declaration of Helsinki. The results will be published in a peer-reviewed journal. Access to raw data is available on request. TRIAL REGISTRATION NUMBER: DRKS00012748.


Assuntos
Disfunção Cognitiva/reabilitação , Idoso , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Computadores de Mão , Progressão da Doença , Serviços de Assistência Domiciliar , Humanos , Testes Neuropsicológicos , Desempenho Psicomotor
15.
Dtsch Med Wochenschr ; 144(3): 156-160, 2019 02.
Artigo em Alemão | MEDLINE | ID: mdl-30703832

RESUMO

Antidementia therapy: The clinical use of acetylcholinesterase inhibitors (AChE-I) for the symptomatic treatment of mild to moderate Alzheimer's dementia is recognized worldwide, despite its modest effectiveness. AChE-I may be continued to be used into severe stages of the dementia. In moderate to severe Alzheimer's dementia, the NMDA-receptor-antagonist Memantin is indicated.Lewy body dementia is treated as Alzheimer's disease; for Parkinson's dementia, there is a separate indication for rivastigmin. A worsening in motor symptoms may occur. There is no evidence-based antidementia drug therapy for frontotemporal or vascular dementia.Future Therapeutic Strategies: Disease modification is a major focus of current clinical trials. There are several clinical trials targeting anti-amyloid (phase 3) or anti-tau strategies. However, other therapeutic targets are persued, too. In current clinical trials, mild cognitive impairment due to Alzheimer's disease is targeted as the most meaningful study population.Implications for practice: At present, there just is symptomatic anti-dementive drug therapy available for Alzheimer's dementia, Parkinson's dementia and Lewy body dementia. Despite its modest effect sizes, treatment with these drugs is clinically relevant and seems to be cost-effective.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Demência Vascular/tratamento farmacológico , Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Memantina/uso terapêutico
16.
J Alzheimers Dis ; 66(2): 639-652, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30320580

RESUMO

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aß1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aß1-42 is decreased due to the accumulation of Aß1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aß1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Biomarcadores/líquido cefalorraquidiano , Variação Genética/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Proteínas do Citoesqueleto/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosforilação/genética , Locos de Características Quantitativas , Proteínas tau/líquido cefalorraquidiano
17.
J Alzheimers Dis ; 63(1): 353-363, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29614658

RESUMO

Older patients with depression or Alzheimer's disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n = 28) or moderate and severe depression (n = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of AD versus depression. We found that our algorithm learned discriminative patterns in the subject's grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one-out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Depressão/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos
18.
J Alzheimers Dis ; 60(3): 1119-1128, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28984585

RESUMO

BACKGROUND: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer's disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression. OBJECTIVE: To examine the association between amyloid-ß 1-42 (Aß42) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline. METHODS: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR study. Assessment included CSF Aß42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline. RESULTS: At baseline, decreased CSF Aß42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aß42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis. CONCLUSION: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Memória , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos
19.
J Alzheimers Dis ; 60(3): 1025-1034, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28984603

RESUMO

BACKGROUND: Impaired olfactory function is an early characteristic of Alzheimer's disease (AD), but it remains unclear if odor identification also relates to early markers of AD in cerebrospinal fluid (CSF). OBJECTIVE: To investigate the association between odor identification and amyloid-ß 1-42 (Aß42) and total tau (t-tau) concentrations in CSF. In addition, to examine the relation between odor identification and cognitive function at baseline and at follow-up, and whether these associations are moderated by CSF Aß42 and t-tau and apolipoprotein E (APOE) genotype. METHODS: We included 160 individuals (40 with normal cognition, 45 with mild cognitive impairment (MCI), 42 with AD-type dementia, and 26 individuals with non-AD dementia) from the EDAR study. Individuals were recruited from six memory clinics across Europe. Odor identification was tested with the brief University of Pennsylvania Smell Identification Test. CSF Aß42 and t-tau were assessed with INNO-BIA AlzBio3 Luminex assay. Neuropsychological assessment included tests for verbal memory, verbal fluency, attention, executive function, and visuoconstruction. Follow-up was performed within 3 years after baseline. RESULTS: Lower odor identification scores correlated with increased CSF t-tau concentrations and with lower scores on all cognitive measures at baseline independent of diagnostic group. Lower odor identification scores predicted decline on the MMSE in the total group, and decline on wordlist learning and delayed recall in APOE ɛ4 carriers and in individuals with abnormal Aß42. CONCLUSION: Odor identification impairment may be an indicator of neuronal injury rather than amyloid pathology.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cognição , Percepção Olfatória , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Cognição/fisiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Odorantes , Percepção Olfatória/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia
20.
Alzheimers Res Ther ; 9(1): 22, 2017 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-28335810

RESUMO

BACKGROUND: Errorless learning (EL) is a method for optimizing learning, which uses feed-forward instructions in order to prevent people from making mistakes during the learning process. The majority of previous studies on EL taught patients with dementia artificial tasks of little or no relevance for their daily lives. Furthermore, only a few controlled studies on EL have so far been performed and just a handful of studies have examined the long-term effects of EL. Tasks were not always trained in the patients' natural or home environment, limiting the external validity of these studies. This multicenter parallel randomized controlled trial examines the effects of EL compared with trial and error learning (TEL) on the performance of activities of daily living in persons with Alzheimer's or mixed-type dementia living at home. METHODS: Patients received nine 1-hour task training sessions over eight weeks using EL or TEL. Task performance was measured using video observations at week 16. Secondary outcome measures were task performance measured at week 26, satisfaction with treatment, need for assistance, challenging behavior, adverse events, resource utilization and treatment costs. RESULTS: A total of 161 participants were randomized, of whom 71 completed the EL and 74 the TEL arm at week 11. Sixty-nine EL patients and 71 TEL patients were assessed at the 16-week follow-up (the primary measurement endpoint). Intention-to-treat analysis showed a significantly improved task performance in both groups. No significant differences between the treatment groups were found for primary or secondary outcomes. CONCLUSIONS: Structured relearning improved the performance of activities of daily living. Improvements were maintained for 6 months. EL had no additional effect over TEL. TRIAL REGISTRATION: German Register of Clinical Trials DRKS00003117 . Registered 31 May 2011.


Assuntos
Atividades Cotidianas , Biorretroalimentação Psicológica/métodos , Demência/diagnóstico , Demência/reabilitação , Reabilitação Neurológica/métodos , Desempenho Psicomotor , Idoso , Feminino , Humanos , Aprendizagem , Masculino , Países Baixos , Método Simples-Cego , Resultado do Tratamento
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