Current Alzheimer Research - Volume 15, Issue 1, 2018

Background: Primary care services frequently provide the initial contact between people with dementia and health service providers. Early diagnosis and screening programmes have been suggested as a possible strategy to improve the identification of such individuals and treatment and planning health and social care support. Objective: To determine what early diagnostic and screening programmes have been adopted in primary care practice, to explore who should deliver these and to determine the possible positive and negative effects of an early diagnostic and screening programme for people with dementia in primary care. Methods: A systematic review of the literature was undertaken using published and unpublished research databases. All papers answering our research objectives were included. A narrative analysis of the literature was undertaken, with the CASP tools used appropriately to assess study quality. Results: Thirty-three papers were identified of moderate to high quality. The limited therapeutic options for those diagnosed with dementia means that even if such a programme was instigated, the clinical value remains questionable. Furthermore, accuracy of the diagnosis remains difficult to assess due to poor evidence and this raises questions regarding whether people could be over- or under-diagnosed. Given the negative social and psychological consequences of such a diagnosis, this could be devastating for individuals. Conclusion: Early diagnostic and screening programmes have not been widely adopted into primary care. Until there is rigorous evidence assessing the clinical and cost-effectiveness of such programmes, there remains insufficient evidence to support the adoption of these programmes in practice.

Background: The use of imaging markers for the diagnosis of predementia and early dementia stages of Alzheimer's disease (AD) has widely been explored in research settings and specialized care. The use of these markers in primary care has yet to be established. Objective: Summarize current evidence for the usefulness of imaging markers for AD in primary compared to specialized care settings. Method: Selective overview of the literature, and pilot data on the use of MRI-based hippocampus and basal forebrain volumetry for the discrimination of AD dementia and mild cognitive impairment (MCI) cases from healthy controls in 58 cases from a primary care cohort and 58 matched cases from a memory clinic's sample. Results: Molecular imaging marker of amyloid pathology, and volumetric markers of regional and whole brain atrophy support the diagnosis of AD dementia and MCI due to AD, and contribute to confidence in the differential diagnosis of AD and non-AD related dementias in specialized care. Limited evidence from the literature and our primary care cohort suggests that the diagnostic accuracy of volumetric imaging markers may be similar in the dementia stage of AD, but may be inferior for cases with MCI in primary compared with specialized care. Conclusion: Evidence is still widely lacking on the use of imaging markers for early and differential diagnosis of AD dementia, and detection of prodromal AD in primary care. Further progress to fill this gap will depend on the availability of international multimodal data from well-defined primary care cohorts.

Objectives: Based on an analysis of the potential consequences of disclosing AD suspicions from respective research and using the research ethical principle of non-maleficence, the authors of this paper argue for the thesis that the benefits of early AD detection in research outweigh the risk of potential adverse effects only in cases where studies are conducted with symptomatic people actively seeking for support, e.g. as they utilize the services of memory clinics. Conclusion: In the case of non-symptomatic volunteers, the result of the risk-benefit-assessment seems to be less distinctive. Given that disclosing results can, at least initially, cause severe distress and harm and taking into account that research examinations have a significantly increased risk of producing false-positive findings, we suggest to make use of a research-ethical “princple of caution” that supports a restrictive disclosure policy for the second group of potential study participants. This differentiated view on the benefits of disclosed findings in AD research is reflected in recommendations for the set-up of return of result processes.

Objective: The primary aim of the study was to determine accuracy, sensitivity and specificity of the Clock Drawing Test (CDT) in detecting probable dementia as compared to the multi-domain dementia screening test DemTect. Methods: The sample was derived from the general practitioner (GP)-based, cluster-randomized controlled intervention trial DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania). Selected from 6.440 patients systematically screened for dementia in primary care, we examined three groups (a,b,c) where the CDT (as index test) as well as the DemTect (as reference standard) were available. After excluding cases with missing values, we included a sample of n=462 with “probable dementia”, n=586 with “mild cognitive impairment” and n=553 with “no cognitive impairment” matched for age and gender. We analyzed the accuracy of the CDT in identifying people with probable dementia by the DemTect and report sensitivity, and specificity for the CDT. We further analyzed age and gender differences associated with the groups. Results: In comparison to the DemTect the CDT identified more than twice as many of the screened patients as cognitively impaired (63.1% in the CDT vs. 28.9% in the DemTect). The sensitivity and specificity for the CDT were 84.4% and 45.6% respectively. We found considerable age and gender differences for the performance of the CDT. Higher age (p < 0.001) and female sex (p < 0.001) were associated with incorrect clock drawings. Conclusion: The CDT shows a considerably high rate of false positive screening outcomes compared to the DemTect and disadvantages older people and women. Thus, in contrary to previous findings our results indicate that the CDT should not be used as exclusive instrument to screen for probable dementia in primary care.

Background: Main objective was to analyze the associations of patient variables (depression, quality of life, anti-dementia drug treatment, knowledge about dementia) with the assignment of a formal diagnosis of dementia to community-dwelling primary care patients who have screened positive for dementia. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner based randomized controlled intervention trial. Present analyses are based on cross-sectional data of 319 positively screened patients (age 70+, living at home) who had not been formally diagnosed with dementia before the screening. The medical diagnoses (ICD-10) were retrieved from the patient's medical records. Depression (Geriatric Depression Scale; GDS), quality of life in Alzheimer's disease (Qol-AD), knowledge about dementia, and anti-dementia drug treatment were assessed after the screening test at the baseline examination. Results: At the baseline examination, 171 out of 319 patients (54%) had been formally diagnosed with dementia after they have screened positive. Univariate comparisons showed no statistically significant differences between diagnosed and undiagnosed patients regarding depression (GDS≥6: 11% vs. 15%; p=0.396), quality of life (mean (SD): 2.8 (0.3) vs. 2.8 (0.4); p=0.833), and the knowledge about dementia (75% vs. 75%; p>0.999). Patients who had received a formal diagnosis were more often treated with anti-dementia drugs (20% vs. 11%; p=0.040). Multivariate analyses controlled for confounding variables confirmed these findings. Conclusion: Present findings do not support concerns that the assignment of a formal dementia diagnosis after screening is associated with potential harms. If confirmed in a prospective study, our data would suggest that patients may benefit from being formally diagnosed regarding anti-dementia drug treatment.

Objectives: To measure older adults acceptability of dementia screening and assess screening test results of a racially diverse sample of older primary care patients in the United States. Design: Cross-sectional study of primary care patients aged 65 and older. Setting: Urban and suburban primary care clinics in Indianapolis, Indiana, in 2008 to 2009. Participants: Nine hundred fifty-four primary care patients without a documented diagnosis of dementia. Measurements: Community Screening Instrument for Dementia, the Mini-Mental State Examination, and the Telephone Instrument for Cognitive Screening. Results: Of the 954 study participants who consented to participate, 748 agreed to be screened for dementia and 206 refused screening. The overall response rate was 78.4%. The positive screen rate of the sample who agreed to screening was 10.2%. After adjusting for demographic differences the following characteristics were still associated with increased likelihood of screening positive for dementia: age, male sex, and lower education. Patients who believed that they had more memory problems than other people of their age were also more likely to screen positive for dementia. Conclusion: Age and perceived problems with memory are associated with screening positive for dementia in primary care.

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterised by a progressive decline in cognitive function and represents a major healthcare challenge worldwide. Increasing evidence indicates that mitochondrial dysfunction mediated oxidative stress plays a significant role in the pathophysiological process of AD. Therefore, the physiological activation of antioxidant enzymes that respond to increased oxidative stress is thought to prevent neuropathology. One of those endogenous defences is NADPH quinone oxidoreductase 1 (NQO1). NQO1 is a cytosolic homodimeric flavoprotein that catalyses the two-electron reduction of quinones and related molecules aimed at increasing their solubility and excretion. In line with its role as a phase II stress response protein, altered NQO1 expression is associated with several pathological conditions and disorders including AD. Conclusion: This review summarizes the association between NQO1 and AD pathology. Understanding this association will provide further insight into the pathogenesis of the disease. More importantly, recent interest in drugs that affect NQO1 expression or its activity provides hope that this approach could lead to novel therapeutic options for the treatment of AD.

Background: Feature extraction in medical image processing still remains a challenge, especially in high-dimensionality datasets, where the expected number of available samples is considerably lower than the dimension of the feature space. This is a common problem in real-world data, and, specifically, in medical image pro- cessing as, while images are composed of hundreds of thousands voxels, only a reduced number of patients are available. Objective: Extracting descriptive and discriminative features to represent each sample (image) by a small number of features, which is particularly important in classification task, due to the curse of dimensionality problem. Methods: In this paper we solve this recognition problem by means of sparse representations of the data, which also provides an arena to multimodal image (PET and MRI) data classification by combining specialized classifiers. Thus, a novel method to effectively combine SVC classifiers is presented here, which uses the distance to the hyperplane computed for each class in each classifier allowing to select the most discriminative image modality in each case. The discriminative power of each modality also provides information about the illness evolution; while functional changes are clearly found in Alzheimer’s diagnosed patients (AD) when compared to control subjects (CN), structural changes seem to be more relevant at the early stages of the illness, affecting Mild Cognitive Impairment (MCI) patients. Results: Classification experiments using 68 CN, 70 AD and 111 MCI images from the Alzheimer's Disease Neuroimaging Initiative database have been performed and assessed by cross-validation to show the effectiveness of the proposed method. Accuracy values of up to 92% and 84% for CN/AD and CN/MCI classification are achieved. Conclusions: The method presented in this work shows that sparse representations of brain images are of importance for codifying and transferring relevant image features, as they may capture the salient features while maintaining lightweight data transactions. In fact, the method proposed in this work outperforms the classification results obtained using projection methods such as Principal Component Analysis for extracting representative features of the images.

Background: Decreased heart rate variability (HRV) indexes indicate low vagal activity and may be associated with development of dementia. The neurodegenerative process is associated with the cardiovascular autonomic control. Objective: The aim of this systematic review was to investigate the effect size (ES) magnitude of the HRV indexes in the evaluation of autonomic dysfunction in older persons with dementia. Methods: PubMed (Medline), Web of Science, Scopus, Scielo, Lilacs, and APA Psycnet were consulted. Complete original articles published in English or Portuguese, investigating the association between autonomic dysfunction and dementia, using the HRV indexes were included. Results: The search identified 97 potentially relevant articles. After screening the full text, eight articles were included in the qualitative analysis and six were included in the quantitative analysis. Almost all indexes showed a negative ES for all types of dementia and mild cognitive impairment. The most common frequency band of the power spectrum density function was the high frequency, which was reported by six studies. The meta-analysis of high frequency power in Alzheimer's disease group showed high heterogeneity and inconsistent results. Conclusion: The negative effect size suggests an autonomic dysfunction in all types of dementia as well as mild cognitive impairment. However, further analysis is necessary to support these results.

Background: Ginkgo biloba extract EGb761 has shown the neuroprotective effects on Alzheimer's disease (AD) through the protection against the Aβ-induced neurotoxicity. However, it is not completedly clear whether EGb761 attenuates tau hyperphosphorylation, another of the most prominent mechanisms underlying the pathology of AD. Methods: we employed hyperhomocysteinemia (HHcy) to mimic AD like pathological alterations and memory deficits in rats as model, and injected EGb761 with or after HHcy injection as prevention and treatment, injected saline as control. We measured the status of oxidative damage and spatial and learning memory in rats. Then we detected the level of memory-related proteins, tau phosphorylation and the level and activity of tau kinase (GSK-3β) and phosphatase (PP2A) by Western blotting and Immunohistochemistry. Results: We found that EGb761 could significantly antagonize HHcy-induced oxidative damage, recover PP2Ac and GSK3β activities deregulated by HHcy. Furthermore, tau was hyperphosphorylated at Thr231, Ser262, Ser396, and Ser404, most common PP2Ac and GSK3β targeted sites in the hippocampus and prefrontal cortex of HHcy rats, whereas EGb761 recovered the tau phosphorylation at those sites. Behavioral tests revealed that EGb761 rescued HHcy-induced spatial reference memory deficit and upregulated the expression of synapse-associated protein PSD95 and synapsin-1. Conclusion: EGb761 might be a promising drug to treat AD through its anti-oxidative activity and decreasing tau hyperphosphorylation besides the protection against the Aβ-induced neurotoxicity.