Missorting of plasma miRNAs in aging and Alzheimer's disease.

The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient.

Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus.

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.

Rapid screening for neglect following stroke: A systematic search and European Academy of Neurology recommendations.

BACKGROUND AND PURPOSE: Unilateral neglect is a common cognitive disorder following stroke. Neglect has a significant impact on functional outcomes, so it is important to detect. However, there is no consensus on which are the best screening tests to administer to detect neglect in time-limited clinical environments. METHODS: Members of the European Academy of Neurology Scientific Panel on Higher Cortical Functions, neuropsychologists, occupational therapists, and researchers produced recommendations for primary and secondary tests for bedside neglect testing based on a rigorous literature review, data extraction, online consensus meeting, and subsequent iterations. RESULTS: A total of 512 articles were screened, and 42 were included. These reported data from 3367 stroke survivors assessed using 62 neglect screens. Tests were grouped into cancellation, line bisection, copying, reading/writing, and behavioral. Cancellation tasks were most frequently used (97.6% of studies), followed by bisection, copying, behavioral, and reading/writing assessments. The panel recommended a cancellation test as the primary screening test if there is time to administer only one test. One of several cancellation tests might be used, depending on availability. If time permits, one or more of line bisection, figure copying, and baking tray task were recommended as secondary tests. Finally, if a functional and ecological test is feasible, the Catherine Bergego Scale was recommended. Overall, the literature suggests that no single test on its own is sufficient to exclude a diagnosis of neglect. Therefore, the panel recommended that multiple neglect tests should be used whenever possible. CONCLUSIONS: This study provides consensus recommendations for rapid bedside detection of neglect in real-world, clinical environments.

Validation of the LUMIPULSE automated immunoassay for the measurement of core AD biomarkers in cerebrospinal fluid.

OBJECTIVES: The core cerebrospinal fluid (CSF) biomarkers; total tau (tTau), phospho-tau (pTau), amyloid ß 1-42 (Aß 1-42), and the Aß 1-42/Aß 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, ß-amyloid 1-42, and with V-PLEX Plus Aß Peptide Panel 1 (6E10) (Meso Scale Discovery) for Aß 1-42/Aß 1-40, as well as with a LC-MS reference method for Aß 1-42. Intra- and inter-laboratory reproducibility was evaluated for all assays. Clinical cutpoints for Aß 1-42, tTau, and pTau was determined by analysis of three cohorts of clinically diagnosed patients, comprising 651 CSF samples. For the Aß 1-42/Aß 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 ß-amyloid 1-40. The reproducibility (inter-laboratory) CVs ranged between 2.1 and 6.5%, with the highest variation observed for ß-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 ß-amyloid 1-42, and 0.072 for the Aß 1-42/Aß 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.

Cognitive Phenotypes of Older Adults with Subjective Cognitive Decline and Amnestic Mild Cognitive Impairment: The Czech Brain Aging Study.

OBJECTIVE: To compare cognitive phenotypes of participants with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI), estimate progression to MCI/dementia by phenotype and assess classification error with machine learning. METHOD: Dataset consisted of 163 participants with SCD and 282 participants with aMCI from the Czech Brain Aging Study. Cognitive assessment included the Uniform Data Set battery and additional tests to ascertain executive function, language, immediate and delayed memory, visuospatial skills, and processing speed. Latent profile analyses were used to develop cognitive profiles, and Cox proportional hazards models were used to estimate risk of progression. Random forest machine learning algorithms reported cognitive phenotype classification error. RESULTS: Latent profile analysis identified three phenotypes for SCD, with one phenotype performing worse across all domains but not progressing more quickly to MCI/dementia after controlling for age, sex, and education. Three aMCI phenotypes were characterized by mild deficits, memory and language impairment (dysnomic aMCI), and severe multi-domain aMCI (i.e., deficits across all domains). A dose-response relationship between baseline level of impairment and subsequent risk of progression to dementia was evident for aMCI profiles after controlling for age, sex, and education. Machine learning more easily classified participants with aMCI in comparison to SCD (8% vs. 21% misclassified). CONCLUSIONS: Cognitive performance follows distinct patterns, especially within aMCI. The patterns map onto risk of progression to dementia.

Interactions of 17ß-Hydroxysteroid Dehydrogenase Type 10 and Cyclophilin D in Alzheimer's Disease.

The nucleus-encoded 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) regulates cyclophilin D (cypD) in the mitochondrial matrix. CypD regulates opening of mitochondrial permeability transition pores. Both mechanisms may be affected by amyloid ß peptides accumulated in mitochondria in Alzheimer's disease (AD). In order to clarify changes occurring in brain mitochondria, we evaluated interactions of both mitochondrial proteins in vitro (by surface plasmon resonance biosensor) and detected levels of various complexes of 17ß-HSD10 formed in vivo (by sandwich ELISA) in brain mitochondria isolated from the transgenic animal model of AD (homozygous McGill-R-Thy1-APP rats) and in cerebrospinal fluid samples of AD patients. By surface plasmon resonance biosensor, we observed the interaction of 17ß-HSD10 and cypD in a direct real-time manner and determined, for the first time, the kinetic parameters of the interaction (ka 2.0 × 105 M1s-1, kd 5.8 × 104 s-1, and KD 3.5 × 10-10 M). In McGill-R-Thy1-APP rats compared to controls, levels of 17ß-HSD10-cypD complexes were decreased and those of total amyloid ß increased. Moreover, the levels of 17ß-HSD10-cypD complexes were decreased in cerebrospinal fluid of individuals with AD (in mild cognitive impairment as well as dementia stages) or with Frontotemporal lobar degeneration (FTLD) compared to cognitively normal controls (the sensitivity of the complexes to AD dementia was 92.9%, that to FTLD 73.8%, the specificity to AD dementia equaled 91.7% in a comparison with the controls but only 26.2% with FTLD). Our results demonstrate the weakened ability of 17ß-HSD10 to regulate cypD in the mitochondrial matrix probably via direct effects of amyloid ß. Levels of 17ß-HSD10-cypD complexes in cerebrospinal fluid seem to be the very sensitive indicator of mitochondrial dysfunction observed in neurodegeneration but unfortunately not specific to AD pathology. We do not recommend it as the new biomarker of AD.

Clock drawing test in screening for Alzheimer's dementia and mild cognitive impairment in clinical practice.

OBJECTIVES: The clock drawing test (CDT) is a commonly used brief cognitive measure. We evaluated diagnostic accuracy of subjective ratings of CDT by physicians (with/without specialty in cognitive neurology) and neuropsychologists in discriminating amnestic mild cognitive impairment (aMCI), Alzheimer's dementia (AD) and cognitively healthy older adults. We further compared the diagnostic accuracy of subjective categorical ratings with complex scoring of CDT. METHODS: Three cognitive neurologists, three neuropsychologists and six neurology residents without experience in cognitive neurology blinded to the diagnosis rated 187 CDTs (50 mild AD, 49 aMCI and 88 cognitively healthy older adults) using a "yes" (abnormal) versus "suspected" versus "no" (normal) classification. The rating suspected was combined with yes or no to obtain two sets of sensitivity estimates. We also used a 17-point CDT rating system. RESULTS: When using the categorical rating, neuropsychologists had highest sensitivity (89%) in differentiating patients with mild AD (yes/suspected versus no), followed by neurologic residents (80%) and cognitive neurologists (79%). When differentiating patients with aMCI (yes/suspected versus no), the sensitivity was 84% for neuropsychologists, 64% for cognitive neurologists and 62% for residents. The sensitivity using the complex scoring system was 92% in patients with mild AD and 69% in patients with aMCI. CONCLUSIONS: A categorical rating of CDT shows high sensitivity for mild AD even in non-experienced raters. Neuropsychologists outperformed physicians in differentiating patients with aMCI from cognitively healthy older adults (specificity), which was counterbalanced by the lower specificity of their ratings. The diagnostic accuracy was not substantially improved by using complex scoring system. Copyright © 2016 John Wiley & Sons, Ltd.

Analysis of lipophilic fluorescent products in blood of Alzheimer's disease patients.

Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by cognitive decline. Prodromal stage of AD, also called mild cognitive impairment (MCI), especially its amnestic type (aMCI), precedes dementia stage of AD. There are currently no reliable diagnostic biomarkers of AD in the blood. Alzheimer's disease is accompanied by increased oxidative stress in brain, which leads to oxidative damage and accumulation of free radical reaction end-products. In our study, specific products of lipid peroxidation in the blood of AD patients were studied. Lipophilic extracts of erythrocytes (AD dementia = 19, aMCI = 27, controls = 16) and plasma (AD dementia = 11, aMCI = 17, controls = 16) were analysed by fluorescence spectroscopy. The level of these products is significantly increased in erythrocytes and plasma of AD dementia and aMCI patients versus controls. We concluded that oxidative stress end-products are promising new biomarkers of AD, but further detailed characterisation of these products is needed.

Cholesterol and cognitive performance among community volunteers from the Czech Republic.

BACKGROUND: Research shows that lipid levels may be associated with cognitive function, particularly among women. We aimed to examine total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein (HDL), and HDL/LDL ratio in relation to cognitive performance, measured with six well-established cognitive domains and a composite cognitive score (CCS). METHODS: In this cross-sectional study, biomarkers and neuropsychological assessment were available for 141 adults with MMSE scores ≥ 24 (mean age = 69 years, 47% female, mean education = 14.4 years) attending a neuropsychological evaluation. Ordinary least squares regressions were adjusted for age, gender, education, and depressive symptoms in Model 1 and also for apolipoprotein E4 (APOE4) status in Model 2. RESULTS: High-density lipoprotein cholesterol (HDL-C) was associated with better CCS (ß = 0.24; p = 0.014). This association was significant among women (ß = 0.30; p = 0.026) and not among men (ß = 0.20; p = 0.124). HDL-C was also related to attention/working memory (ß = 0.24; p = 0.021), again only among women (ß = 0.37; p = 0.012) and not men (ß = 0.15; p = 0.271). Adjusting for APOE4 yielded significance for high HDL-C and CCS (ß = 0.24; p = 0.022). CONCLUSIONS: HDL-C was the main lipoprotein affecting cognitive function, with results somewhat more pronounced among women. Research should investigate the possibility of finding ways to boost HDL-C levels to potentially promote cognitive function.

Spatial navigation impairment is proportional to 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 (ß = -0.62, P < 0.001) and virtual (ß = -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.

Diagnosis of Alzheimer's Disease in Clinical Practice: Time to Incorporate Biomarkers?

Hippocampal dysfunction is associated with early clinical signs of Alzheimer's disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities.

Evaluation of Differential Diagnostics Potential of Uniform Data Set 2 Neuropsychology Battery Using Alzheimer's Disease Biomarkers.

OBJECTIVE: This study aims to evaluate the efficacy of the Uniform Data Set (UDS) 2 battery in distinguishing between individuals with mild cognitive impairment (MCI) attributable to Alzheimer's disease (MCI-AD) and those with MCI due to other causes (MCI-nonAD), based on contemporary AT(N) biomarker criteria. Despite the implementation of the novel UDS 3 battery, the UDS 2 battery is still used in several non-English-speaking countries. METHODS: We employed a cross-sectional design. A total of 113 Czech participants with MCI underwent a comprehensive diagnostic assessment, including cerebrospinal fluid biomarker evaluation, resulting in two groups: 45 individuals with prodromal AD (A+T+) and 68 participants with non-Alzheimer's pathological changes or normal AD biomarkers (A-). Multivariable logistic regression analyses were employed with neuropsychological test scores and demographic variables as predictors and AD status as an outcome. Model 1 included UDS 2 scores that differed between AD and non-AD groups (Logical Memory delayed recall), Model 2 employed also Letter Fluency and Rey's Auditory Verbal Learning Test (RAVLT). The two models were compared using area under the receiver operating characteristic curves. We also created separate logistic regression models for each of the UDS 2 scores. RESULTS: Worse performance in delayed recall of Logical Memory significantly predicted the presence of positive AD biomarkers. In addition, the inclusion of Letter Fluency RAVLT into the model significantly enhanced its discriminative capacity. CONCLUSION: Our findings demonstrate that using Letter Fluency and RAVLT alongside the UDS 2 battery can enhance its potential for differential diagnostics.

Spatial navigation questionnaires as a supportive diagnostic tool in early Alzheimer's disease.

Impaired spatial navigation is early marker of Alzheimer's disease (AD). We examined ability of self- and informant-reported navigation questionnaires to discriminate between clinically and biomarker-defined participants, and associations of questionnaires with navigation performance, regional brain atrophy, AD biomarkers, and biomarker status. 262 participants (cognitively normal, with subjective cognitive decline, amnestic mild cognitive impairment [aMCI], and mild dementia) and their informants completed three navigation questionnaires. Navigation performance, magnetic resonance imaging volume/thickness of AD-related brain regions, and AD biomarkers were measured. Informant-reported questionnaires distinguished between cognitively normal and impaired participants, and amyloid-ß positive and negative aMCI. Lower scores were associated with worse navigation performance, greater atrophy in AD-related brain regions, and amyloid-ß status. Self-reported questionnaire scores did not distinguish between the groups and were weakly associated with navigation performance. Other associations were not significant. Informant-reported navigation questionnaires may be a screening tool for early AD reflecting atrophy of AD-related brain regions and AD pathology.

Mild behavioral impairment in early Alzheimer's disease and its association with APOE and BDNF risk genetic polymorphisms.

BACKGROUND: Mild behavioral impairment (MBI) has been commonly reported in early Alzheimer's disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity. METHODS: We included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations. RESULTS: MBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared. CONCLUSIONS: MBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation.

Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease.

Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aß: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

Risk factors for spatial memory impairment in patients with temporal lobe epilepsy.

At present, the risk factors for world-centered (allocentric) navigation impairment in patients with temporal lobe epilepsy (TLE) are not known. There is some evidence on the importance of the right hippocampus but other clinical features have not been investigated yet. In this study, we used an experimental human equivalent to the Morris water maze to examine spatial navigation performance in patients with drug-refractory unilateral TLE. We included 47 left-hemisphere speech dominant patients (25 right sided; 22 left sided). The aim of our study was to identify clinical and demographic characteristics of TLE patients who performed poorly in allocentric spatial memory tests. Our results demonstrate that poor spatial navigation is significantly associated with younger age at epilepsy onset, longer disease duration, and lower intelligence level. Allocentric navigation in TLE patients was impaired irrespective of epilepsy lateralization. Good and poor navigators did not differ in their age, gender, or preoperative/postoperative status. This study provides evidence on risk factors that increase the likelihood of allocentric navigation impairment in TLE patients. The results indicate that not only temporal lobe dysfunction itself but also low general cognitive abilities may contribute to the navigation impairment.

Memory Binding Test and Its Associations With Hippocampal Volume Across the Cognitive Continuum Preceding Dementia.

Innovative memory paradigms have been introduced to capture subtle memory changes in early Alzheimer's disease (AD). We aimed to examine the associations between different indexes of the challenging Memory Binding Test (MBT) and hippocampal volume (HV) in a sample of individuals with subjective cognitive decline (SCD; n = 50), amnestic mild cognitive impairment (aMCI) due to AD (n = 31), and cognitively normal (CN) older adults (n = 29) recruited from the Czech Brain Aging Study, in contrast to traditional verbal memory tests. Both MBT free and cued recall scores in immediate and delayed recall conditions were associated with lower HV in both SCD and aMCI due to AD, whereas in traditional verbal memory tests only delayed recall scores were associated with lower HV. In SCD, the associations with lower HV in the immediate recall covered specific cued recall indexes only. In conclusion, the MBT is a promising test for detecting subtle hippocampal-associated memory decline during the predementia continuum.

Diffusion tensor imaging in Alzheimer disease and mild cognitive impairment.

A wide range of imaging studies provides growing support for the potential role of diffusion tensor imaging (DTI) in evaluating microstructural white matter integrity in Alzheimer disease (AD) and mild cognitive impairment (MCI). Our review aims to present DTI principles, post-processing and analysis frameworks and to report the results of particular studies. The distribution of AD-related white matter abnormalities is widely discussed in the light of deteriorated connectivity within certain tracts due to secondary white matter degeneration; primary alterations are also assumed to contribute to the pattern. The question whether it is more effective to assess the whole-brain diffusion or to directly concentrate on specific regions remains an interesting issue. Assessing white matter microstructure alterations, as evaluated by group-level differences of tensor-derived parameters, may be a promising neuroimaging tool for differential diagnosis between AD, MCI and other cognitive disorders, as well as being particularly helpful in the interpretation of underlying pathological processes.

APOEɛ4 Allele Moderates the Association Between Basal Forebrain Nuclei Volumes and Allocentric Navigation in Older Adults Without Dementia.

BACKGROUND: Cholinergic deficit and medial temporal lobe (MTL) atrophy are hallmarks of Alzheimer's disease (AD) leading to early allocentric spatial navigation (aSN) impairment. APOEɛ4 allele (E4) is a major genetic risk factor for late-onset AD and contributes to cholinergic dysfunction. Basal forebrain (BF) nuclei, the major source of acetylcholine, project into multiple brain regions and, along with MTL and prefrontal cortex (PFC), are involved in aSN processing. OBJECTIVE: We aimed to determine different contributions of individual BF nuclei atrophy to aSN in E4 positive and E4 negative older adults without dementia and assess whether they operate on aSN through MTL and PFC or independently from these structures. METHODS: 120 participants (60 E4 positive, 60 E4 negative) from the Czech Brain Aging Study underwent structural MRI and aSN testing in real-space arena setting. Hippocampal and BF nuclei volumes and entorhinal cortex and PFC thickness were obtained. Associations between brain regions involved in aSN were assessed using MANOVA and complex model of mutual relationships was built using structural equation modelling (SEM). RESULTS: Path analysis based on SEM modeling revealed that BF Ch1-2, Ch4p, and Ch4ai nuclei volumes were indirectly associated with aSN performance through MTL (pch1 - 2 = 0.039; pch4p = 0.042) and PFC (pch4ai = 0.044). In the E4 negative group, aSN was indirectly associated with Ch1-2 nuclei volumes (p = 0.015), while in the E4 positive group, there was indirect effect of Ch4p nucleus (p = 0.035). CONCLUSION: Our findings suggest that in older adults without dementia, BF nuclei affect aSN processing indirectly, through MTL and PFC, and that APOE E4 moderates these associations.

Progression from Subjective Cognitive Decline to Mild Cognitive Impairment or Dementia: The Role of Baseline Cognitive Performance.

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.