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Background: Memory tests using controlled encoding and cued recall paradigm (CECR) have been shown to identify prodromal Alzheimer’s disease (AD), but information about the effectiveness of CECR compared to other memory tests in predicting clinical progression is missing. Objective: The aim was to examine the predictive ability of a memory test based on the CECR paradigm in comparison to other memory/non-memory tests for conversion to dementia in patients with amnestic mild cognitive impairment (aMCI). Methods: 270 aMCI patients from the clinical-based Czech Brain Aging Study underwent a comprehensive neuropsycholog- ical assessment including the Enhanced Cued Recall test (ECR), a memory test with CECR, two verbal memory tests without controlled encoding: the Auditory Verbal Learning Test (AVLT) and Logical memory test (LM), a visuospatial memory test: the Rey-Osterrieth Complex Figure test, and cognitive testing based on the Uniform Data Set battery. The patients were followed prospectively. Conversion to dementia as a function of cognitive performance was examined using Cox proportional hazard models. Results: 144 (53%) patients converted to dementia. Most converters (89%) developed dementia due to AD or mixed (AD and vascular) dementia. Comparing the four memory tests, the delayed recall scores on AVLT and LM best predicted conversion to dementia. Adjusted hazard ratios (HR) of immediate recall scores on ECR, AVLT, and LM were similar to the HR of categorical verbal fluency. Conclusion: Using the CECR memory paradigm in assessment of aMCI patients has no superiority over verbal and non-verbal memory tests without cued recall in predicting conversion to dementia. &nbsp

Background: Older adults with subjective cognitive decline (SCD) are at an increased risk of progression to mild cognitive impairment (MCI) or dementia. However, few have examined the specific cognitive tests that are associated with progression. Objective: This study examined performance on 18 neuropsychological tests among participants with SCD who later progressed to MCI or dementia. Methods: We included 131 participants from the Czech Brain Aging Study that had SCD at baseline. They completed a comprehensive neuropsychological battery including cognitive tests from the Uniform Data Set 2.0 enriched by the verbal memory test Rey Auditory Verbal Learning Test (RAVLT) and Rey-Osterrieth Complex Figure Test (ROCFT). Results: Fifty-five participants progressed: 53% to non-amnestic MCI (naMCI), 44% to amnestic MCI (aMCI), and 4% to dementia. Scoring one SD below the mean at baseline on the RAVLT 1 and RAVLT 1–5 was associated with 133% (RAVLT 1; HR: 2.33 [1.50, 3.62]) and 122% (RAVLT 1–5; HR: 2.22 [1.55, 3.16]) greater risk of progression to MCI or dementia over 3.84 years on average. Worse performance on the RAVLT 5, RAVLT 1–5, RAVLT 30, and ROCFT–Recall was associated with progression to aMCI whereas worse performance on the RAVLT 1, TMT B, and Boston Naming Test was associated with progression to naMCI. Conclusion: At baseline, lower verbal memory performance was most strongly associated with progression to aMCI whereas lower executive or language performance was most strongly associated with progression to naMCI.

Objectives The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid β 1-42 (Aβ 1-42), and the Aβ 1-42/Aβ 1-40 ratio have transformed Alzheimer’s disease (AD) research and are today increasingly used in clinical routine laboratories as diagnostic tools. Fully automated immunoassay instruments with ready-to-use assay kits and calibrators has simplified their analysis and improved reproducibility of measurements. We evaluated the analytical performance of the fully automated immunoassay instrument LUMIPULSE G (Fujirebio) for measurement of the four core AD CSF biomarkers and determined cutpoints for AD diagnosis. Methods Comparison of the LUMIPULSE G assays was performed with the established INNOTEST ELISAs (Fujirebio) for hTau Ag, pTau 181, β-amyloid 1-42, and with V-PLEX Plus Aβ Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aβ 1-42/Aβ 1-40, as well as with a LC-MS reference method for Aβ 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aβ 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aβ 1-42/Aβ 1-40 ratio, the cutpoint was determined by mixture model analysis of 2,782 CSF samples. Results The LUMIPULSE G assays showed strong correlation to all other immunoassays (r>0.93 for all assays). The repeatability (intra-laboratory) CVs ranged between 2.0 and 5.6%, with the highest variation observed for β-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for β-amyloid 1-42. The clinical cutpoints for AD were determined to be 409 ng/L for total tau, 50.2 ng/L for pTau 181, 526 ng/L for β-amyloid 1-42, and 0.072 for the Aβ 1-42/Aβ 1-40 ratio. Conclusions Our results suggest that the LUMIPULSE G assays for the CSF AD biomarkers are fit for purpose in clinical laboratory practice. Further, they corroborate earlier presented reference limits for the biomarkers.

Contains fulltext : 231797.pdf (Publisher’s version ) (Closed access) 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.

ObjectiveAlthough the link between microbial infections and Alzheimer’s disease (AD) has been demonstrated in multiple studies, the involvement of pathogens in the development of AD remains unclear. Therefore, this theory beckons further systematic investigation. In this study, we have examined the association between the 10 most widely discussed viral and bacterial pathogens found in serum and cerebrospinal fluid (CSF) from patients with AD.MethodsWe have used an in-house developed multiplex PCR kit for simultaneous detection of five bacterial and five viral pathogens in serum and CSF from 50 AD patients and 53 healthy controls. Data analysis was performed with multiple statistical methods: Fisher’s exact test, chisquare goodness of fit test, and one-sample proportion test.ResultsWe observed an increased frequency of AD patients tested positive for Treponema spp. (AD: 62.2%; CTRL: 30.3%; p-value = 0.007). Furthermore, we confirmed a significantly higher prevalence of cases with two and more simultaneous infections in AD patients compared to controls (AD: 24%; CTRL 7.5%; p-value = 0.029). The studied pathogens were widespread equally in serum and CSF. Borrelia burgdorferi, human herpesvirus 7, and human cytomegalovirus were not detected in any of the studied samples.DiscussionAn increased prevalence of Treponema spp. and double-species infections in AD patients compared to the healthy controls provides further evidence of the association between microbial infections and AD. Paralleled analysis of multiple sample specimens provides complementary information and is advisable for future studies.

There is evidence indicating that a vegan diet could be beneficial in the prevention of neurodegenerative disorders, including Alzheimer’s disease (AD). The purpose of this review is to summarize the current knowledge on the positive and negative aspects of a vegan diet regarding the risk of AD. Regarding AD prevention, a vegan diet includes low levels of saturated fats and cholesterol, contributing to a healthy blood lipid profile. Furthermore, it is rich in phytonutrients, such as vitamins, antioxidants, and dietary fiber, that may help prevent cognitive decline. Moreover, a vegan diet contributes to the assumption of quercetin, a natural inhibitor of monoamine oxidase (MAO), which can contribute to maintaining mental health and reducing AD risk. Nonetheless, the data available do not allow an assessment of whether strict veganism is beneficial for AD prevention compared with vegetarianism or other diets. A vegan diet lacks specific vitamins and micronutrients and may result in nutritional deficiencies. Vegans not supplementing micronutrients are more prone to vitamin B12, vitamin D, and DHA deficiencies, which have been linked to AD. Thus, an evaluation of the net effect of a vegan diet on AD prevention and/or progression should be ascertained by taking into account all the positive and negative effects described here.

Although the link between microbial infections and Alzheimer's disease (AD) has been demonstrated in multiple studies, the involvement of pathogens in the development of AD remains unclear. Here, we investigated the frequency of the 10 most commonly cited viral (HSV-1, EBV, HHV-6, HHV-7, and CMV) and bacterial (Chlamydia pneumoniae, Helicobacter pylori, Borrelia burgdorferi, Porphyromonas gingivalis, and Treponema spp.) pathogens in serum, cerebrospinal fluid (CSF) and brain tissues of AD patients. We have used an in-house multiplex PCR kit for simultaneous detection of five bacterial and five viral pathogens in serum and CSF samples from 50 AD patients and 53 healthy controls (CTRL). We observed a significantly higher frequency rate of AD patients who tested positive for Treponema spp. compared to controls (AD: 62.2 %; CTRL: 30.3 %; p-value = 0.007). Furthermore, we confirmed a significantly higher occurrence of cases with two or more simultaneous infections in AD patients compared to controls (AD: 24 %; CTRL 7.5 %; p-value = 0.029). The studied pathogens were detected with comparable frequency in serum and CSF. In contrast, Borrelia burgdorferi, human herpesvirus 7, and human cytomegalovirus were not detected in any of the studied samples. This study provides further evidence of the association between microbial infections and AD and shows that paralleled analysis of multiple sample specimens provides complementary information and is advisable for future studies.

Background Subjective cognitive complaints (SCCs) may represent an early cognitive marker of Alzheimer's disease (AD). There is a need to identify specific SCCs associated with an increased likelihood of underlying AD. Objective Using the Questionnaire of Cognitive Complaints (QPC), we evaluated the pattern of SCCs in a clinical sample of non-demented older adults in comparison to cognitively healthy community-dwelling volunteers (HV). Methods In total, 142 non-demented older adults from the Czech Brain Aging Study referred to two memory clinics for their SCCs were classified as having subjective cognitive decline (SCD, n = 85) or amnestic mild cognitive impairment (aMCI, n = 57) based on a neuropsychological evaluation. Furthermore, 82 age-, education-, and gender-matched HV were recruited. All subjects completed the QPC assessing the presence of specific SCCs in the last six months. Results Both SCD and aMCI groups reported almost two times more SCCs than HV, but they did not differ from each other in the total QPC score. Impression of memory change and Impression of worse memory in comparison to peers were significantly more prevalent in both SCD and aMCI groups in comparison to HV; however, only the latter one was associated with lower cognitive performance. Conclusion The pattern of QPC-SCCs reported by SCD individuals was more similar to aMCI individuals than to HV. A complaint about memory change seems unspecific to pathological aging whereas a complaint about worse memory in comparison to peers might be one of the promising items from QPC questionnaire potentially reflecting subtle cognitive changes.

Human induced pluripotent stem cell (iPSC) lines were generated from patients with spontaneous late-onset Alzheimer’s disease (AD) and three healthy control individuals. Peripheral blood mononuclear cells were reprogrammed with Yamanaka factors (OSKM) using a commercially available Epi5 Reprogramming Kit. The pluripotency of iPSCs was confirmed by the expression of pluripotency factors and by their ability to differentiate to all three germ layers in vitro. Newly derived cell lines can be used to model Alzheimer’s disease in vitro.

PurposeIdentification of demographic, physical/physiological, lifestyle and genetic factors contributing to the onset of dementia, specifically Alzheimer disease (AD), and implementation of novel methods for early diagnosis are important to alleviate prevalence of dementia globally. The Czech Brain Aging Study (CBAS) is the first large, prospective study to address these issues in Central/Eastern Europe by enrolling non-demented adults aged 55+ years, collecting a variety of personal and biological measures and tracking cognitive function over time.ParticipantsThe CBAS recruitment was initiated in 2011 from memory clinics at Brno and Prague University Hospitals, and by the end of 2018, the study included 1228 participants. Annual follow-ups include collection of socioeconomic, lifestyle and personal history information, neurology, neuropsychology, laboratory, vital sign and brain MRI data. In a subset, biomarker assessment (cerebrospinal fluid (CSF) and amyloid positron emission tomography) and spatial navigation were performed. Participants were 69.7±8.1 years old and had 14.6±3.3 years of education at baseline, and 59% were women. By the end of 2018, 31% finished three and more years of follow-up; 9% converted to dementia. Apolipoprotein E status is available from 95% of the participants. The biological sample bank linked to CBAS database contained CSF, serum and DNA.Findings to dateOverall, the findings, mainly from cross-sectional analyses, indicate that spatial navigation is a promising marker of early AD and that it can be distinguished from other cognitive functions. Specificity of several standard memory tests for early AD pathology was assessed with implications for clinical practice. The relationship of various lifestyle factors to cognition and brain atrophy was reported.Future plansRecruitment is ongoing with secured funding. Longitudinal data analyses are currently being conducted. Proposals for collaboration on specific data from the database or biospecimen, as well as collaborations with similar cohort studies to increase sample size, are welcome. Study details are available online (www.cbas.cz).

Background: Great effort has been put into developing simple and feasible tools capable to detect Alzheimer's disease (AD) in its early clinical stage. Spatial navigation impairment occurs very early in AD and is detectable even in the stage of mild cognitive impairment (MCI). Objective: The aim was to describe the frequency of self-reported spatial navigation complaints in patients with subjective cognitive decline (SCD), amnestic and non-amnestic MCI (aMCI, naMCI) and AD dementia and to assess whether a simple questionnaire based on these complaints may be used to detect early AD. Method: In total 184 subjects: patients with aMCI (n=61), naMCI (n=27), SCD (n=63), dementia due to AD (n=20) and normal controls (n=13) were recruited. The subjects underwent neuropsychological examination and were administered a questionnaire addressing spatial navigation complaints. Responses to the 15 items questionnaire were scaled into four categories (no, minor, moderate and major complaints). Results: 55% of patients with aMCI, 64% with naMCI, 68% with SCD and 72% with AD complained about their spatial navigation. 38-61% of these complaints were moderate or major. Only 33% normal controls expressed complaints and none was ranked as moderate or major. The SCD, aMCI and AD dementia patients were more likely to express complaints than normal controls (p's Conclusion: Spatial navigation complaints are a frequent symptom not only in AD, but also in SCD and aMCI and can potentially be detected by a simple and inexpensive questionnaire.

Background and Objective: Cognitive deficits in older adults attributable to Alzheimer’s disease (AD) pathology are featured early on by hippocampal impairment. Among tests used to evaluate memory, verbal memory tests with controlled encoding and cued recall are believed to be specific for hippocampal impairment. The objective of this study was to assess the relation between left and right hippocampal volumes and several frequently used memory tests. 14 15 16 17 Methods: Fifty six nondemented older adults (30 with amnestic mild cognitive impairment and 26 cognitively healthy older adults) underwent neuropsychological testing including: 1) The Enhanced Cued Recall test (ECR), a memory test with controlled encoding and recall; 2) the Auditory Verbal Learning Test (AVLT), a verbal memory test without controlled encoding and with delayed recall; and 3) The Rey-Osterrieth Complex Figure test (ROCF), a visuospatial memory test–recall condition. 1.5T brain MRI scans were used to measure estimated total intracranial volume (eTIV) along with hippocampal right and left volumes, which were measured with quantitative volumetry using FreeSurfer package (version 4.4.0). Spearman partial correlation controlled for age was used to correct for non-normal score distribution and effect of age. 18 19 20 21 22 23 24 Results: We found moderate correlations of hippocampal volumes with AVLT 1–5 scores, AVLT delayed recall, ECR free and total recall, and ROCF reproduction. Total recall in ECR using cued recall was not superior to any of the free recall tests. No correlation in any memory test was achieved with eTIV. 25 26 27 Conclusion: Verbal memory tests, either with controlled encoding and cued delayed recall (ECR), or without it (AVLT), as well as nonverbal memory test with delayed recall (ROCF), equally reflect hippocampal atrophy in nondemented older adults. 28 29

Objective: Memory complaints in non-demented elderly are reported frequently and are often associated with depression/anxiety. The relationship between depression/anxiety, memory complaints and risk of dementia is unclear. Spatial disorientation is a common problem reported by patients with early Alzheimer´s disease (AD). Objective testing of spatial navigation (SN) in human analogue of Morris water maze showed that subject with mild cognitive impairment (MCI) present with identical SN impairment as AD patients. There is not much known about how subjective perception of spatial navigation skills reflects the real SN performance and whether depression/anxiety plays a role in this association. We investigated whether subjects with MCI reported more subjective spatial navigation complaints (SSNC) than individuals with subjective cognitive decline (SCD) with no cognitive deficit and whether SSNC reporting depends on anxiety or/and depression regardless of real SN performance. Methods: A total of 123 non-demented participants, including 52 with SCD and 71 with MCI underwent spatial navigation (SN) testing, neuropsychological examination and completed SSNC questionnaire, Geriatric Depression Scale (GDS), and Beck Anxiety Inventory (BAI). Results: There were no differences in GDS and BAI scores between MCI and SMC groups. The MCI group did not report more SSNC than SMC group regardless of worse real-SN performance in the MCI group (p

memory (MOD-MEM) included 43% of patients. On visual inspection these patients had more severe MTA and were more often APOE e4 positive. Memory-spared clusters mild-executive (MILD-EXE), mild-visuoperception-language (MILD-VILA) and moderate-visuospatial (MOD-VISP) included 30% of patients. Using MILD-MEM as reference cluster, younger age was associated with higher likelihood for membership of MOD-VISP (Odds Ratio [OR] 6.21, 95% confidence interval [CI] 3.56-10.83) and MILD-EXE (OR 2.06, CI 1.32-3.23). Membership of MOD-VISP was more likely when APOE e4 was absent (OR 1.82, CI 1.04-3.20) and PA and GCAwere more severe (resp. OR 2.17, CI 1.15-4.10 and OR 2.64, CI 1.44-4.84). On visual inspection, MTA was less severe in memory-spared clusters than in other clusters. Finally, mild-diffuse (MILD-DIFF), moderate-language (MOD-LAN) and severe-diffuse (SEV-DIFF) were characterized by a memory-indifferent profile and included 28% of patients. Using MILD-MEM as reference, membership of SEV-DIFF was more likely when patients were younger (OR 2.77, CI 1.65-4.63), had longer duration of complaints (OR 2.18, CI 1.04-4.57) and had more severe PA and GCA (resp. OR 2.10, CI 1.07-3.76 and OR 2.28, CI 1.29-4.03). Conclusions: We demonstrated that LCA is an eligible method to identify cognitive subtypes in AD dementia using an extensive neuropsychological test battery. The cluster characteristics we found corresponded with earlier findings regarding the association between neurobiological characteristics and cognition.

We investigated the association between APOE ε4 status and spatial navigation in patients with amnestic mild cognitive impairment (aMCI) and assessed the role of hippocampal volume in this association.Participants were 74 patients with clinically confirmed aMCI (33 APOE ε4 noncarriers, 26 heterozygous, and 15 homozygous ε4 carriers). Body-centered (egocentric) and world-centered (allocentric) spatial navigation in a computerized human analogue of the Morris Water Maze was assessed. Brain MRI with subsequent automated hippocampal volumetry was included.Groups were similar in neuropsychological profile. Controlling for age, sex, education, and free memory recall, the APOE ε4 carriers performed more poorly on all spatial navigation subtasks (ps.05). APOE ε4 homozygotes performed worse than heterozygotes (p = .021). Right hippocampal volume accounted for the differences in allocentric and delayed subtasks (ps.05), but not in the egocentric subtask (p.001).Using an easy-to-use, computer-based tool to assess spatial navigation, we found spatial navigation deficits to worsen in a dose-dependent manner as a function of APOE ε4 status. This was at least partially due to differences in right hippocampal volume.

Cognitive deficits in older adults attributable to Alzheimer's disease (AD) pathology are featured early on by hippocampal impairment. Among these individuals, deterioration in spatial navigation, manifested by poor hippocampus-dependent allocentric navigation, may occur well before the clinical onset of dementia. Our aim was to determine whether allocentric spatial navigation impairment would be proportional to right hippocampal volume loss irrespective of general brain atrophy. We also contrasted the respective spatial navigation scores of the real-space human Morris water maze with its corresponding 2D computer version. We included 42 cognitively impaired patients with either amnestic mild cognitive impairment ( n = 23) or mild and moderate AD ( n = 19), and 14 cognitively intact older controls. All participants underwent 1.5T MRI brain scanning with subsequent automatic measurement of the total brain and hippocampal (right and left) volumes. Allocentric spatial navigation was tested in the real-space version of the human Morris water maze and in its corresponding computer version. Participants used two navigational cues to locate an invisible goal independent of the start position. We found that smaller right hippocampal volume was associated with poorer navigation performance in both the real-space (β = −0.62, P < 0.001) and virtual (β = −0.43, P = 0.026) versions, controlling for demographic variables, total brain and left hippocampal volumes. In subsequent analyses, the results were significant in cognitively impaired ( P ≤ 0.05) but not in cognitively healthy ( P > 0.59) subjects. The respective real-space and virtual scores strongly correlated with each other. Our findings indicate that the right hippocampus plays a critical role in allocentric navigation, particularly when cognitive impairment is present.

Background: Spatial navigation performance in the Hidden Goal Task (HGT), a real-space human analogue of the Morris Water Maze, can identify amnestic mild cognitive impairment (aMCI) patients with memory impairment of the hippocampal type, a known indicator of incipient Alzheimer’s disease (AD). Objective: Contrast results from computer versus real-space versions of the HGT. Methods: A total of 42 aMCI patients were clinically and neuropsychologically classified into: (1) memory impairment of the hippocampal type – the hippocampal aMCI (HaMCI; n = 10) and (2) isolated retrieval impairment – the nonhippocampal aMCI (NHaMCI; n = 32). Results were compared to the control (n = 28) and AD (n = 21) groups. Results: The HaMCI group, although similar to the NHaMCI group with respect to overall cognitive impairment, performed poorer on the computer version of the HGT and yielded parallel results to the real-space version. The two versions were strongly correlated. Conclusions: Both versions of the HGT can reliably identify aMCI with pronounced memory impairment of the hippocampal type. The computer version of the HGT may be a useful, relatively inexpensive screening tool for early detection of individuals at a high risk of AD.

Amyotrophic lateral sclerosis (ALS) may be accompanied by cognitive impairment; when present, it is mainly in the form of frontotemporal impairment. We report on two cases with clinically defined ALS that subsequently developed dementia. Neuropathological examination showed not only the typical neuropathological hallmarks characteristic of ALS but, surprisingly, also showed neurofibrillary tangles and neuritic plaques in sufficient numbers to fulfill the diagnostic criteria of definite Alzheimer's disease.

Background Identification of famous landmarks (FLI), famous faces (FFI) and recognition of facial emotions (FER) is affected early in the course of Alzheimer's disease (AD). FFI, FER and FLI may represent domain specific tasks relying on activation of distinct regions of the medial temporal lobe, which are affected successively during the course of AD. However, the data on FFI and FER in MCI are controversial and FLI domain remains almost unexplored. Objectives To determine whether and how are these three specific domains impaired in head to head comparison of patients with amnestic MCI (aMCI) single domain (SD-aMCI) and multiple domain (MD-aMCI). We propose that FLI might be most reliable in differentiating SD-aMCI, which is considered to be an earlier stage of AD pathology spread out, from the controls. Patients and Methods A total of 114 patients, 13 with single domain (SD–aMCI) and 30 with multiple domains (MD–aMCI), 29 with mild AD and 42 controls underwent standard neurological and neuropsychological evaluations as well as tests of FLI, FER and FFI. Results Compared to the control group, AD subjects performed worse on FFI (p = 0.020), FER (p