BACKGROUND: Spatial navigation deficits are early symptoms of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for AD. This study investigated effects of APOE genotype on spatial navigation in biomarker-defined individuals with amnestic mild cognitive impairment (aMCI) and associations of AD biomarkers and atrophy of AD-related brain regions with spatial navigation. METHODS: 107 participants, cognitively normal older adults (CN, n = 48) and aMCI individuals stratified into AD aMCI (n = 28) and non-AD aMCI (n = 31) groups, underwent cognitive assessment, brain MRI, and spatial navigation assessment using the Virtual Supermarket Test with egocentric and allocentric tasks and a self-report questionnaire. Cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, phosphorylated tau181 and total tau) and amyloid PET imaging were assessed in aMCI participants. RESULTS: AD aMCI participants had the highest prevalence of APOE ε4 carriers and worst allocentric navigation. CSF levels of AD biomarkers and atrophy in AD-related brain regions were associated with worse allocentric navigation. Between-group differences in spatial navigation and associations with AD biomarkers and regional brain atrophy were not influenced by APOE genotype. Self-reported navigation ability was similar across groups and unrelated to spatial navigation performance. CONCLUSIONS: These findings suggest that allocentric navigation deficits in aMCI individuals are predominantly driven by AD pathology, independent of APOE genotype. This highlights the role of AD pathology as measured by biomarkers, rather than genetic status, as a major factor in navigational impairment in aMCI, and emphasizes the assessment of spatial navigation as a valuable tool for early detection of AD.

• Keywords
• Allocentric navigation, Amyloid-β, Egocentric navigation, Entorhinal cortex, Hippocampus, Tau protein,
• MeSH
• Alzheimer Disease * genetics   cerebrospinal fluid   diagnostic imaging   complications   physiopathology   pathology   MeSH
• Amyloid beta-Peptides cerebrospinal fluid   MeSH
• Apolipoprotein E4 * genetics   MeSH
• Apolipoproteins E * genetics   MeSH
• Atrophy MeSH
• Biomarkers cerebrospinal fluid   MeSH
• Genotype MeSH
• Cognitive Dysfunction * genetics   cerebrospinal fluid   diagnostic imaging   physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Brain pathology   diagnostic imaging   MeSH
• Neuropsychological Tests MeSH
• Peptide Fragments cerebrospinal fluid   MeSH
• Positron-Emission Tomography MeSH
• Spatial Navigation * physiology   MeSH
• tau Proteins cerebrospinal fluid   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• amyloid beta-protein (1-42) MeSH Browser
• Amyloid beta-Peptides MeSH
• Apolipoprotein E4 * MeSH
• Apolipoproteins E * MeSH
• Biomarkers MeSH
• Peptide Fragments MeSH
• tau Proteins MeSH

Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.

• Keywords
• Autophagy, Frontotemporal lobar degeneration, MAPT, Neurocognitive impairment, PINK1, TDP-43, TFEB,
• MeSH
• Alzheimer Disease * cerebrospinal fluid   metabolism   pathology   blood   MeSH
• Autophagy * physiology   MeSH
• Biomarkers cerebrospinal fluid   blood   MeSH
• Frontotemporal Lobar Degeneration * cerebrospinal fluid   metabolism   pathology   blood   MeSH
• Autophagy-Related Protein-1 Homolog cerebrospinal fluid   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mitophagy * physiology   MeSH
• Protein Kinases cerebrospinal fluid   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Autophagy-Related Protein-1 Homolog MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Protein Kinases MeSH
• PTEN-induced putative kinase MeSH Browser
• ULK1 protein, human MeSH Browser

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.

• Keywords
• Alzheimer’s disease, Assessment, Mild cognitive impairment,
• MeSH
• Alzheimer Disease * diagnosis   cerebrospinal fluid   MeSH
• Amyloid beta-Peptides cerebrospinal fluid   MeSH
• Biomarkers * cerebrospinal fluid   MeSH
• Diagnosis, Differential MeSH
• Cognitive Dysfunction * diagnosis   etiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neuropsychological Tests * standards   statistics & numerical data   MeSH
• tau Proteins cerebrospinal fluid   MeSH
• Cross-Sectional Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH
• Biomarkers * MeSH
• tau Proteins MeSH

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 < .001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p = .029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p = .034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p = .001) and AD-dementia (F[1, 100] = 20.90, p < .001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p = .491) or FTLD-dementia (F[1, 62]= 2.27, p = .051). The main effect of diagnosis across the diagnostic subgroups on Aβ1-42/Ng ratio was significant too (F[4, 263]=, p < .001). We found a non-significant association between Ng levels and memory scores overall (β=-0.25, p = .154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (β=-0.32, p = .358). CONCLUSIONS: In this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aβ1-42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits.

• Keywords
• APOE, Alzheimer’s disease, Frontotemporal lobar degeneration, Memory, Neurogranin,
• MeSH
• Alzheimer Disease * cerebrospinal fluid   diagnosis   MeSH
• Amyloid beta-Peptides cerebrospinal fluid   MeSH
• Apolipoproteins E genetics   cerebrospinal fluid   MeSH
• Biomarkers * cerebrospinal fluid   MeSH
• Frontotemporal Lobar Degeneration * cerebrospinal fluid   diagnosis   MeSH
• Cognitive Dysfunction * cerebrospinal fluid   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neurogranin * cerebrospinal fluid   MeSH
• Neuropsychological Tests MeSH
• Cross-Sectional Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH
• Apolipoproteins E MeSH
• Biomarkers * MeSH
• Neurogranin * MeSH
• NRGN protein, human MeSH Browser

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: Aβ: 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.

• Keywords
• Autophagy, BNIP3L, PINK1, TFEB, mild cognitive impairment, mitophagy,
• MeSH
• Alzheimer Disease * cerebrospinal fluid   blood   diagnosis   MeSH
• Biomarkers * cerebrospinal fluid   blood   metabolism   MeSH
• Cognitive Dysfunction cerebrospinal fluid   blood   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Proteins cerebrospinal fluid   metabolism   blood   MeSH
• Mitophagy * MeSH
• Brain metabolism   pathology   MeSH
• Tumor Suppressor Proteins MeSH
• Protein Kinases metabolism   MeSH
• tau Proteins cerebrospinal fluid   metabolism   MeSH
• Proto-Oncogene Proteins cerebrospinal fluid   blood   metabolism   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers * MeSH
• BNIP3L protein, human MeSH Browser
• Membrane Proteins MeSH
• Tumor Suppressor Proteins MeSH
• Protein Kinases MeSH
• tau Proteins MeSH
• Proto-Oncogene Proteins MeSH
• PTEN-induced putative kinase MeSH Browser
• TFEB protein, human MeSH Browser
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors MeSH

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.

• Keywords
• Clinical neuroscience, Disease, Neuroscience,
• Publication type
• Journal Article MeSH

BACKGROUND: Dementia 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. METHODS: We 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). RESULTS: For 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. CONCLUSION: We 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.

• Keywords
• MRI, attention/working memory, executive control, language, visuospatial skills,
• Publication type
• Journal Article MeSH

BACKGROUND: Spatial navigation impairment is a promising cognitive marker of Alzheimer's disease (AD) that can reflect the underlying pathology. OBJECTIVES: We 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. METHODS: A 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). RESULTS: In 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. CONCLUSION: AD 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.

• Keywords
• allocentric navigation, egocentric navigation, entorhinal cortex, hippocampus, neurodegeneration, precuneus, retrosplenial cortex, tauopathies,
• Publication type
• Journal Article MeSH

PURPOSE: Identification 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. PARTICIPANTS: The 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 DATE: Overall, 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 PLANS: Recruitment 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).

• Keywords
• dementia, epidemiology, mental health,
• MeSH
• Alzheimer Disease epidemiology   MeSH
• Dementia epidemiology   MeSH
• Risk Assessment MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Protective Factors MeSH
• Prospective Studies MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic epidemiology   MeSH