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Abstract Background There is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer’s disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum. Methods Participants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism. Results Ng levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p

Summary: 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-β positive and negative aMCI. Lower scores were associated with worse navigation performance, greater atrophy in AD-related brain regions, and amyloid-β 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.

Abstract 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.

BackgroundDementia syndrome is one of the most devastating conditions in older adults. As treatments to stop neurodegeneration become available, accurate and timely diagnosis will increase in importance. One issue is that cognitive performance sometimes does not match the corresponding level of neuropathology, affecting diagnostic accuracy. Cognitive reserve (CR), which can preserve cognitive function despite underlying neuropathology, explains at least some variability in cognitive performance. We examined the influence of CR proxies (education and occupational position) on the relationship between hippocampal or total gray matter volume and cognition.MethodsWe used data from the Czech Brain Aging Study. Participants were clinically confirmed to be without dementia (n = 457, including subjective cognitive decline and amnestic mild cognitive impairment) or with dementia syndrome (n = 113).ResultsFor participants without dementia, higher education magnified the associations between (a) hippocampal volume and executive control (b = 0.09, p = 0.033), (b) total gray matter volume and language (b = 0.12, p < 0.001), and (c) total gray matter volume and memory (b = 0.08, p = 0.018). Similarly, higher occupational position magnified the association between total gray matter volume and (a) attention/working memory (b = 0.09, p = 0.009), (b) language (b = 0.13, p = 0.002), and (c) memory (b = 0.10, p = 0.013). For participants with dementia, the associations between hippocampal (b = –0.26, p = 0.024) and total gray matter (b = –0.28, p = 0.024) volume and visuospatial skills decreased in magnitude with higher education.ConclusionWe found that the association between brain volume and cognitive performance varies based on CR, with greater CR related to a stronger link between brain volume and cognition before, and a weaker link after, dementia diagnosis.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

BackgroundSpatial navigation impairment is a promising cognitive marker of Alzheimer’s disease (AD) that can reflect the underlying pathology.ObjectivesWe assessed spatial navigation performance in AD biomarker positive older adults with amnestic mild cognitive impairment (AD aMCI) vs. those AD biomarker negative (non-AD aMCI), and examined associations between navigation performance, MRI measures of brain atrophy, and cerebrospinal fluid (CSF) biomarkers.MethodsA total of 122 participants with AD aMCI (n = 33), non-AD aMCI (n = 31), mild AD dementia (n = 28), and 30 cognitively normal older adults (CN) underwent cognitive assessment, brain MRI (n = 100 had high-quality images for volumetric analysis) and three virtual navigation tasks focused on route learning (body-centered navigation), wayfinding (world-centered navigation) and perspective taking/wayfinding. Cognitively impaired participants underwent CSF biomarker assessment [amyloid-β1–42, total tau, and phosphorylated tau181 (p-tau181)] and amyloid PET imaging (n = 47 and n = 45, respectively), with a subset having both (n = 19).ResultsIn route learning, AD aMCI performed worse than non-AD aMCI (p < 0.001), who performed similarly to CN. In wayfinding, aMCI participants performed worse than CN (both p ≤ 0.009) and AD aMCI performed worse than non-AD aMCI in the second task session (p = 0.032). In perspective taking/wayfinding, aMCI participants performed worse than CN (both p ≤ 0.001). AD aMCI and non-AD aMCI did not differ in conventional cognitive tests. Route learning was associated with parietal thickness and amyloid-β1–42, wayfinding was associated with posterior medial temporal lobe (MTL) volume and p-tau181 and perspective taking/wayfinding was correlated with MRI measures of several brain regions and all CSF biomarkers.ConclusionAD biomarker positive and negative older adults with aMCI had different profiles of spatial navigation deficits that were associated with posterior MTL and parietal atrophy and reflected AD pathology.

Alzheimer’s disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular ‘garbage’ clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.

Background: The hippocampus, entorhinal cortex (EC), and basal forebrain (BF) are among the earliest regions affected by Alzheimer’s disease (AD) pathology. They play an essential role in spatial pattern separation, a process critical for accurate discrimination between similar locations.Objective: We examined differences in spatial pattern separation performance between older adults with amnestic mild cognitive impairment (aMCI) with AD versus those with non-Alzheimer’s pathologic change (non-AD) and interrelations between volumes of the hippocampal, EC subregions and BF nuclei projecting to these subregions (medial septal nuclei and vertical limb of the diagonal band of Broca – Ch1-2 nuclei) with respect to performance.Methods: Hundred and eighteen older adults were recruited from the Czech Brain Aging Study. Participants with AD aMCI (n = 37), non-AD aMCI (n = 26), mild AD dementia (n = 26), and cognitively normal older adults (CN; n = 29) underwent spatial pattern separation testing, cognitive assessment and brain magnetic resonance imaging.Results: The AD aMCI group had less accurate spatial pattern separation performance than the non-AD aMCI (p = 0.039) and CN (p < 0.001) groups. The AD aMCI and non-AD groups did not differ in other cognitive tests. Decreased BF Ch1-2 volume was indirectly associated with worse performance through reduced hippocampal tail volume and reduced posteromedial EC and hippocampal tail or body volumes operating in serial.Conclusion: The study demonstrates that spatial pattern separation testing differentiates AD biomarker positive and negative older adults with aMCI and provides evidence that BF Ch1-2 nuclei influence spatial pattern separation through the posteromedial EC and the posterior hippocampus.

Alzheimer’s disease (AD) is a central nervous system (CNS) disease characterized by loss of memory, cognitive functions, and neurodegeneration. Plasmin is an enzyme degrading many plasma proteins. In the CNS, plasmin may reduce the accumulation of beta amyloid (Aβ) and have other actions relevant to AD pathophysiology. Brain plasmin synthesis is regulated by two enzymes: one activating, the tissue plasminogen activator (tPA), and the other inhibiting, the plasminogen activator inhibitor-1 (PAI-1). We investigated the levels of tPA and PAI-1 in serum from 40 AD and 40 amnestic mild cognitively impaired (aMCI) patients compared to 10 cognitively healthy controls. Moreover, we also examined the PAI-1/tPA ratio in these patient groups. Venous blood was collected and the PAI-1 and tPA serum concentrations were quantified using sandwich ELISAs. The results showed that PAI-1 levels increased in AD and aMCI patients. This increase negatively correlated with cognitive performance measured using the Mini-Mental Status Exam (MMSE). Similarly, the ratio between tPA and PAI-1 gradually increases in aMCI and AD patients. This study demonstrates that AD and aMCI patients have altered PAI-1 serum levels and PAI-1/tPA ratio. Since these enzymes are CNS regulators of plasmin, PAI-1 serum levels could be a marker reflecting cognitive decline in AD.

ObjectivesMild behavioral impairment (MBI) is a syndrome describing late-onset persistent neuropsychiatric symptoms (NPS) in non-demented older adults. Few studies to date have investigated the associations of MBI with structural brain changes. Our aim was to explore structural correlates of NPS in a non-demented memory clinic sample using the Mild Behavioral Impairment Checklist (MBI-C) that has been developed to measure MBI.MethodsOne hundred sixteen non-demented older adults from the Czech Brain Aging Study with subjective cognitive concerns were classified as subjective cognitive decline (n = 37) or mild cognitive impairment (n = 79). Participants underwent neurological and neuropsychological examinations and brain magnetic resonance imaging (MRI) (1.5 T). The Czech version of the MBI-C was administered to participants’ informants. Five a priori selected brain regions were measured, namely, thicknesses of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and entorhinal cortex (ERC) and volume of the hippocampus (HV), and correlated with MBI-C total and domain scores.ResultsEntorhinal cortex was associated with MBI-C total score (rS = −0.368, p < 0.001) and with impulse dyscontrol score (rS = −0.284, p = 0.002). HV was associated with decreased motivation (rS = −0.248, p = 0.008) and impulse dyscontrol score (rS = −0.240, p = 0.011).ConclusionNeuropsychiatric symptoms, particularly in the MBI impulse dyscontrol and motivation domains, are associated with medial temporal lobe atrophy in a clinical cohort of non-demented older adults. This study supports earlier involvement of temporal rather than frontal regions in NPS manifestation. Since these regions are typically affected early in the course of Alzheimer’s disease (AD), the MBI-C may potentially help further identify individuals at-risk of developing AD dementia.

Deterioration of dynamic visual acuity (DVA) as a result of impaired vestibulo-ocular reflex (VOR) has been well described in peripheral vestibulopathies, however, changes in DVA in patients with degenerative cerebellar ataxias (CA) and its relation to VOR impairment in these patients has not yet been evaluated. Our aim was to assess the alterations of DVA in CA and to evaluate its relation to vestibular function. 32 patients with CA and 3 control groups: 13 patients with unilateral and 13 with bilateral vestibulopathy and 21 age matched healthy volunteers were examined by clinical DVA test, VOR was assessed by video Head Impulse Test and caloric irrigation. The severity of ataxia in CA was assessed by Scale for the assessment and rating of ataxia (SARA). Relationship between DVA and vestibular function in CA patients was examined by linear regressions. DVA impairment was highly prevalent in CA patients (84%) and its severity did not differ between CA and bilateral vestibulopathy patients. The severity of DVA impairment in CA was linked mainly to VOR impairment and only marginally to the degree of ataxia. However, DVA impairment was present also in CA patients without significant vestibular lesion showing that central mechanisms such as impairment of central adaptation of VOR are involved. We suggest that the evaluation of DVA should be a standard part of clinical evaluation in patients with progressive CA, as this information can help to target vestibular and oculomotor rehabilitation.

Age-related spatial navigation decline is more pronounced in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. We used a realistic-looking virtual navigation test suite to analyze different aspects of visuospatial processing in typical and atypical aging. A total of 219 older adults were recruited from the Czech Brain Aging Study cohort. Cognitively normal older adults (CN; n = 78), patients with amnestic MCI (n = 75), and those with mild AD dementia (n = 66) underwent three navigational tasks, cognitive assessment, and brain MRI. Route learning and wayfinding/perspective-taking tasks distinguished the groups as performance and learning declined and specific visuospatial strategies were less utilized with increasing cognitive impairment. Increased perspective shift and utilization of non-specific strategies were associated with worse task performance across the groups. Primacy and recency effects were observed across the groups in the route learning and the wayfinding/perspective-taking task, respectively. In addition, a primacy effect was present in the wayfinding/perspective-taking task in the CN older adults. More effective spatial navigation was associated with better memory and executive functions. The results demonstrate that a realistic and ecologically valid spatial navigation test suite can reveal different aspects of visuospatial processing in typical and atypical aging.

Aerospace technologies are crucial for modern civilization; space-based infrastructure underpins weather forecasting, communications, terrestrial navigation and logistics, planetary observations, solar monitoring, and other indispensable capabilities. Extraplanetary exploration—including orbital surveys and (more recently) roving, flying, or submersible unmanned vehicles—is also a key scientific and technological frontier, believed by many to be paramount to the long-term survival and prosperity of humanity. All of these aerospace applications require reliable control of the craft and the ability to record high-precision measurements of physical quantities. Magnetometers deliver on both of these aspects and have been vital to the success of numerous missions. In this review paper, we provide an introduction to the relevant instruments and their applications. We consider past and present magnetometers, their proven aerospace applications, and emerging uses. We then look to the future, reviewing recent progress in magnetometer technology. We particularly focus on magnetometers that use optical readout, including atomic magnetometers, magnetometers based on quantum defects in diamond, and optomechanical magnetometers. These optical magnetometers offer a combination of field sensitivity, size, weight, and power consumption that allows them to reach performance regimes that are inaccessible with existing techniques. This promises to enable new applications in areas ranging from unmanned vehicles to navigation and exploration.

BACKGROUND:Neuropsychiatric symptoms and reduced health-related quality of life (HRQoL) are frequent in multiple sclerosis, where are associated with structural brain changes, but have been less studied in clinically isolated syndrome (CIS). OBJECTIVE:To characterize HRQoL, neuropsychiatric symptoms (depressive symptoms, anxiety, apathy and fatigue), their interrelations and associations with structural brain changes in CIS. METHODS:Patients with CIS (n = 67) and demographically matched healthy controls (n = 46) underwent neurological and psychological examinations including assessment of HRQoL, neuropsychiatric symptoms and cognitive functioning, and MRI brain scan with global, regional and lesion load volume measurement. RESULTS:The CIS group had more, mostly mild, depressive symptoms and anxiety, and lower HRQoL physical and social subscores (p≤0.037). Neuropsychiatric symptoms were associated with most HRQoL subscores (β≤-0.34, p≤0.005). Cognitive functioning unlike clinical disability was associated with depressive symptoms and lower HRQoL emotional subscores (β≤-0.29, p≤0.019). Depressive symptoms and apathy were associated with right temporal, left insular and right occipital lesion load (ß≥0.29, p≤0.032). Anxiety was associated with lower white matter volume (ß = -0.25, p = 0.045). CONCLUSION:Mild depressive symptoms and anxiety with decreased HRQoL are present in patients with CIS. Neuropsychiatric symptoms contributing to decreased HRQoL are the result of structural brain changes and require complex therapeutic approach in patients with CIS.

Background: Spatial navigation deficits including egocentric (body‐centered) and allocentric (world‐centered) navigation impairment are present early in Alzheimer´s disease (AD). We evaluated a potential of a realistic‐looking spatial navigation task to differentiate older adults with amnestic mild cognitive impairment (aMCI) who have positive AD biomarkers (AD aMCI) from those with negative AD biomarkers (non‐AD aMCI). Method: Participants with AD aMCI (n = 24), non‐AD aMCI (n = 25), mild AD dementia (n = 14) and cognitively normal (CN) older adults (n = 35) underwent spatial navigation assessment in the virtual Supermarket task. Participants passively travelled through the supermarket and followed different routes to reach specific locations. In the final location, the participants had to indicate their starting location (egocentric heading) and their current location and final heading orientation on an aerial spatial map of the supermarket (distance from the correct location and allocentric heading, respectively, both measures of allocentric navigation). Result: In the egocentric heading, the AD aMCI and mild AD dementia groups indicated their original starting location less accurately than the CN group (p<0.001) and with similar accuracy as the non‐AD aMCI group (p> = 0.219). The non‐AD aMCI group did not significantly differ from the CN group (p = 0.055). In the first allocentric task (distance from the correct location), the AD aMCI group and mild AD dementia groups indicated their positions on a paper aerial map of the supermarket with greater distance errors compared to the non‐AD aMCI group (p< = 0.013) and CN (p<0.001) groups. The non‐AD aMCI group had comparable performance to the CN group (p = 0.172). In the second allocentric task (allocentric heading), both the AD aMCI and mild AD dementia groups made more errors indicating final heading orientation than the non‐AD aMCI (p< = 0.040) and the CN (p<0.001) groups. The non‐AD aMCI group had worse performance than the CN group (p = 0.004). The sensitivity and specificity for discriminating AD aMCI and non‐AD aMCI was 72% and 71%, respectively. Conclusion: Both, egocentric and allocentric spatial navigation tasks detected spatial navigation impairment in older adults with AD aMCI. However, only the allocentric tasks differentiated AD aMCI from non‐AD aMCI. The virtual Supermarket task has a potential to become a screening tool for early AD‐related spatial navigation deficits. [ABSTRACT FROM AUTHOR]

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 diseaseParadoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltratesIn Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance [ABSTRACT FROM AUTHOR]

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

Background: Cognitive screening by pharmacists may help to identify seniors with metabolic syndrome (MetS)-related cognitive impairment. We aimed to evaluate the implementation of an easy-to-use cognitive screening into the pharmaceutical care of seniors and to test whether cognitive decline is associated with suspected MetS (sMetS). Methods: Questionnaires were completed by 323 randomly selected elderly patients receiving pharmaceutical care in community pharmacies or in senior care centres in Slovakia. The presence of sMetS was estimated according to criteria of the International Diabetes Federation. Cognitive performance was evaluated by the Montreal Cognitive Assessment (MoCA) test and its short form (s-MoCA). In these tests, the cut-offs for impaired cognitive status were ± 24, and ± 12, respectively. Results: 56% of participants scored below the screening cut-off MoCA threshold. Cognitive impairment was significantly more frequent in sMetS+ subjects (71%) vs. sMetS-(52%; p < 0.05). MoCA scores were significantly lower in sMetS+ (mean ± SD = 20.0 ± 5.9 points) vs. sMetS- (22.2 ± 5.4 points; p < 0.05). sMetS components type 2 diabetes mellitus, hypertension and obesity, but not dyslipidaemia, had an influence on lower cognitive performance. Conclusions:We unveiled a significant relationship of cognitive dysfunction to sMetS in elderly patients. A quick and simple cognitive assessment could be a helpful extension of pharmaceutical care. [ABSTRACT FROM AUTHOR]

SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel. [ABSTRACT FROM AUTHOR]

Background: The Memory Binding Test (MBT) and Face‐Name Associative Memory Exam (FNAME‐12) are challenging tests based on relational memory binding paradigm. Recent studies support their sensitivity to subtle memory changes; however, their specificity to Alzheimer´s disease (AD) related memory deficit has not been studied. This study aimed to explore differences in MBT and FNAME‐12 scores between patients with amnestic mild cognitive impairment (aMCI) due to AD (aMCI‐AD), those with aMCI with non‐Alzheimer´s etiology (aMCI‐nonAD), and cognitively normal older adults (CN) as a control group, and to compare the potential of the challenging tests and the standard Rey Auditory Verbal Learning Test (RAVLT) to discriminate between the aMCI groups. Method: Sixty‐seven Czech Brain Aging Study participants (aMCI, n = 37; CN, n = 30) underwent neuropsychological assessment (including the MBT and FNAME‐12), laboratory evaluation, and brain magnetic resonance imaging, and were further classified as aMCI‐AD (n = 18) or aMCI‐nonAD (n = 19) based on the results of amyloid positron emission tomography or AD cerebrospinal fluid biomarkers. The groups were compared using the multivariate analysis of covariance controlling for sex, age, education, and global cognition. Result: In MBT, aMCI‐AD patients scored the lowest on the paired cued recall scores (CR) (aMCI‐AD

Background: Mild behavioral impairment (MBI) describes de novo emergent and persistent neuropsychiatric symptoms in older individuals. MBI is common in individuals with mild cognitive impairment (MCI), but self‐endorsed symptoms may not align with reports from informants. In this study, we explore the consistency between self‐ and informant‐rated versions of the Mild behavioral impairment checklist (MBI‐C), which is used to assess MBI. Method: We included 68 individuals with MCI (MMSE 26.59±2.55) who underwent neurological, extensive neuropsychological examination and brain MRI within the Czech Brain Aging Study and had no history of prior psychiatric disorder. Both participants and their close informants completed The Czech version of the MBI‐C (MBI‐C self and MBI‐C informant, respectively). The consistency and differences between the MBI‐C self and informant total and domain scores (i.e. motivation, affect, impulse dyscontrol, social inappropriateness and psychotic symptoms), and the presence of MBI based on a cut‐off of ≥7, were examined using Wilcoxon signed‐rank test, the binomial test and Spearman´s rank correlation. Further, we explored the association between the informant‐self score difference with the MMSE as a measure of global cognition. Result: There was no difference between MBI‐C self and informant total score (both median ratings were 5.0). Among the domain scores, we observed a difference between self and informant ratings in the impulse dyscontrol (Z = ‐2.97, p = 0.003), but not in any other score. Disagreements on the presence of MBI were observed in 19 participants (28%), but both patients and informants were equally likely to disagree on the MBI presence vs. absence. We observed weak to modest correlations between MBI‐C self and informant total and domain scores (rS = 0.34‐0.53, ps<0.01). The informant‐self score difference in MBI‐C impulse dyscontrol was negatively associated with the MMSE (rS = ‐0.39, p = 0.001). Conclusion: Patients with MCI and their informants were not consistent regarding the presence of MBI, but among those who disagreed, neither informants nor patients were more likely to report MBI. The informants reported more severe impulse dyscontrol symptoms compared to the patients with MCI themselves and this difference was negatively associated with lower MMSE. The observed inconsistencies provide implications for clinical and research settings. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive complaints (SCC) in the elderly may represent an early cognitive marker of Alzheimer's disease (AD). Currently, there is no recommended gold standard for evaluating SCC. In addition, available questionnaires were originally developed to identify individuals at later stages of AD. Based on previous research, we constructed the Subjective Cognitive Changes Questionnaire (SCC‐Q), which includes items potentially sensitive to early cognitive decline. The study aimed to analyse reliability of the individual items and construct and convergent validity of the SCC‐Q. Method: A total of 211 non‐demented participants over the age of 55 from the Czech Brain Aging Study (CBAS) underwent a comprehensive neuropsychological examination, based on which they were classified into two groups: patients with amnestic mild cognitive impairment (n = 88) and those with subjective cognitive decline (SCD) (n = 88). Further, we included cognitively healthy volunteers without SCC (n = 35). All participants completed the novel 26‐item SCC‐Q in which they evaluated change in specific cognitive abilities during the last 5 years on a 5‐point Likert scale. The structure of the SCC‐Q was explored using the principal component analysis (PCA) with varimax rotation. To analyse associations between the components and cognitive performance (convergent validity), non‐parametric partial rank correlations controlled for sex, age and education were performed. Cognitive performance was expressed as composite z‐scores representing memory, attention and working memory, language, executive, and visuospatial function. Result: Item analysis showed that all included items were highly reliable (McDonald's Ω > 0.9, Cronbach's α > 0.9). Using the PCA, four components explaining 57.6% of the variance were identified. Two of them were significantly associated with memory, attention and working memory, and executive or visuospatial function, respectively (all ps ≤ 0.048). The component more closely associated with cognitive domains includes items related to spatial orientation changes. Conclusion: The SCC‐Q has the potential to become a valuable method for clinical practice in identifying individuals at risk of developing cognitive deficits. Further analyses are needed to confirm its validity. [ABSTRACT FROM AUTHOR]

Background: Autophagy is a cellular self "garbage clearance "system through which cells eliminate and recycle dysfunctional cytoplasmatic components, such as defective organelles and misfolded protein aggregates. Mitophagy is the sub‐type of autophagy that recognizes and degrades damaged or superfluous mitochondria to maintain cellular homeostasis. Emerging evidence demonstrates that autophagy and mitophagy are impaired in Alzheimer's disease (AD); its upregulation ameliorates Aß pathology and slows down the cognitive decline in animal models of AD, thus representing a potentially treatable target. The change in the mitophagy biomarkers in individuals with AD needs to be clarified. We aimed to explore the changes of mitophagy biomarkers in biomarkers‐defined individuals in various stages of AD and compare them to cognitively unimpaired individuals (CU). Method: We included 228 biomarker‐defined individuals from the Czech Brain Aging Study:98 AD dementia (ADD), 88 mild cognitive impairment due to AD (MCI‐AD), and 42 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), a biomarker of neurodegeneration (neurofilament light chain – NfL), synaptic dysfunction (neurogranin, Ng), and mitophagy biomarkers in CSF (PINK1‐ mitochondrial kinase crucial for mitophagy) and in serum (BNIP3L‐ mitophagy receptor, TFEB‐ transcription factor critical for lysosomal degradation). Result: We found a significant increase in PINK1 CSF and BNIP3L serum levels in ADD compared to MCI‐AD and CU (ps<.001). TFEB serum levels were decreased in ADD compared to MCI‐AD and CU (ps<.05). Additionally, in ADD, PINK1 correlated with NfL (r = 0.27) and Ng (r = 0.47). In MCI‐AD, there was a correlation between PINK1 and Ng (r = 0.51), but not with NfL. There was no correlation in CU individuals with NfL or Ng. Conclusion: We identified candidate proteins of mitophagy that are changed in various cognitive stages of AD. In the ADD stage, there is an upregulation of the mitophagy inducers, PINK1 and BNIP3L, together with decreased levels of TFEB, a master regulator of lysosomal biogenesis. One of the possible explanations is that these findings reflect impairment in the final stage of autophagy–lysosomal degradation. Further research is needed to clarify its pathophysiological importance in the AD cascade. [ABSTRACT FROM AUTHOR]

Background: In a previous study, we demonstrated that the enzyme plasminogen activator inhibitor‐1 (PAI‐1), which inhibits plasmin synthesis in the central nervous system (CNS), is increased in the serum of patients with Alzheimer's disease (AD). In addition to reducing the accumulation of Ab, plasmin in the CNS regulates the synthesis of the trophic factor brain‐derived neurotrophic factor (BDNF) which appears to be altered in the brain of patients with AD. We investigated whether BDNF serum levels in AD and amnestic mild cognitive impairment (aMCI) patients are altered compared to cognitively healthy controls. Moreover, we examined the PAI‐1/BDNF ratio in these patient groups and correlated with cognitive scores as measured by Mini‐Mental State Examination (MMSE). Method: 40 AD, 40 aMCI and 10 healthy controls were recruited. Venous blood was collected and BDNF serum concentration were quantified by sandwich ELISAs. Comparisons among the experimental groups (AD dementia, aMCI patients, and cognitively healthy controls) on BDNF serum levels were performed using univariate analyses of variance (ANOVA). Pearson correlation coefficients were calculated to explore relationships between biochemical and clinical data. The level of statistical significance was set at p<0.05. Result: The results showed that BDNF serum levels are decreased in AD as compared to aMCI patients (p <.05). In addition, there was a positive correlation between PAI‐1 and BDNF serum levels (r =.190, p <.05). Furthermore, PAI‐1/BDNF ratio was significantly increased in AD patients as compared to aMCI (p <.001) and controls (p <.001). Lastly, PAI‐1/BDNF ratio negatively correlated with MMSE score (r = ‐.508, p <.001). Conclusion: These data suggest that in AD a reduction of plasmin caused by PAI‐1 may negatively affect the production of BDNF and promote disease progression. Our results also demonstrate that the PAI‐1/BDNF ratio is increased in AD patients compared with aMCI and controls. They also suggest that this ratio could be used as a marker of AD in a state of overt cognitive impairment, as supported by the strong negative correlation between PAI‐1/BDNF ratio and MMSE. [ABSTRACT FROM AUTHOR]

Background: Reduced removal of dysfunctional mitochondria has been implicated in the pathogenesis of many neurodegenerative diseases, including Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD). Mitophagy is the main cellular pathway through which aberrant and aged mitochondria are removed. Impaired neuronal mitophagy triggers the accumulation of damaged mitochondria, leading to cell death and neurodegeneration. While recent evidence suggests that levels of various mitophagy‐associated proteins are altered in AD, whether and in which direction mitophagy biomarkers are altered in non‐AD pathologies remains unclear. Therefore, we aimed to compare the levels of mitophagy markers between biomarker‐defined patients in various stages of AD and FTLD and cognitively unimpaired individuals (CU). Method: We included 253 biomarker‐defined individuals from Czech Brain Aging Study: 86 AD dementia (ADD), 86 mild cognitive impairment due to AD (AD‐MCI) 21 FTLD dementia (FTLDD), 21 MCI due to FTLD (FTLD‐MCI), and 39 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), and mitophagy biomarkers in CSF (ULK1‐ autophagy factor essential for mitophagy initiation) and in serum (TFEB‐ transcription factor critical for mitophagic flux). Result: We found a significant increase in ULK1 CSF levels in MCI‐FTLD compared to MCI‐AD (p<.01), ADD (p<.001), and CU (p<.01). There was also a significant increase in TFEB serum levels in FTLDD compared to MCI‐AD (p<.01) and CU (p<.01). Similarly, TFEB serum levels were elevated in FTLD‐MCI compared to ADD (p<.001), but were not elevated compared to CU. Conclusion: There is an upregulation in the key mitophagy activator (ULK1) and in the mitochondrial quality control protein (TFEB) in FTLD compared to AD in various stages of disease (MCI vs dementia). Our data suggest that mitophagy plays different roles in the sub‐types of neurocognitive disorders, with a significant increase in the levels of mitophagy markers in patients with FTLD compared to healthy controls and patients with AD. Further research is needed to elucidate the role of mitophagy in the pathophysiology of different sub‐types of neurocognitive disorders. [ABSTRACT FROM AUTHOR]