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.

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.

Sex differences in brain atrophy in dementia with Lewy bodies.

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia.

Background: There is a need to better understand the rate of cognitive and motor decline of Dementia with Lewy bodies (DLB) and Parkinson's disease Dementia (PDD). Objectives: To compare the rate of cognitive and motor decline in patients with DLB and PDD from the E-DLB Consortium and the Parkinson's Incidence Cohorts Collaboration (PICC) Cohorts. Methods: The annual change in MMSE and MDS-UPDRS part III was estimated using linear mixed regression models in patients with at least one follow-up (DLB n = 837 and PDD n = 157). Results: When adjusting for confounders, we found no difference in the annual change in MMSE between DLB and PDD (-1.8 [95% CI -2.3, -1.3] vs. -1.9 [95% CI -2.6, -1.2] [P = 0.74]). MDS-UPDRS part III showed nearly identical annual changes (DLB 4.8 [95% CI 2.1, 7.5]) (PDD 4.8 [95% CI 2.7, 6.9], [P = 0.98]). Conclusions: DLB and PDD showed similar rates of cognitive and motor decline. This is relevant for future clinical trial designs.

Reconfiguration of brain network dynamics underlying spatial deficits in subjective cognitive decline.

Brain dynamics and the associations with spatial navigation in individuals with subjective cognitive decline (SCD) remain unknown. In this study, a hidden Markov model (HMM) was inferred from resting-state functional magnetic resonance imaging data in a cohort of 80 SCD and 77 normal control (NC) participants. By HMM, 12 states with distinct brain activity were identified. The SCD group showed increased fractional occupancy in the states with less activated ventral default mode, posterior salience, and visuospatial networks, while decreased fractional occupancy in the state with general network activation. The SCD group also showed decreased probabilities of transition into and out of the state with general network activation, suggesting an inability to dynamically upregulate and downregulate brain network activity. Significant correlations between brain dynamics and spatial navigation were observed. The combined features of spatial navigation and brain dynamics showed an area under the curve of 0.854 in distinguishing between SCD and NC. The findings may provide exploratory evidence of the reconfiguration of brain network dynamics underlying spatial deficits in SCD.

Spatial navigation is associated with subcortical alterations and progression risk in subjective cognitive decline.

BACKGROUND: Subjective cognitive decline (SCD) may serve as a symptomatic indicator for preclinical Alzheimer's disease; however, SCD is a heterogeneous entity regarding clinical progression. We aimed to investigate whether spatial navigation could reveal subcortical structural alterations and the risk of progression to objective cognitive impairment in SCD individuals. METHODS: One hundred and eighty participants were enrolled: those with SCD (n = 80), normal controls (NCs, n = 77), and mild cognitive impairment (MCI, n = 23). SCD participants were further divided into the SCD-good (G-SCD, n = 40) group and the SCD-bad (B-SCD, n = 40) group according to their spatial navigation performance. Volumes of subcortical structures were calculated and compared among the four groups, including basal forebrain, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens. Topological properties of the subcortical structural covariance network were also calculated. With an interval of 1.5 years ± 12 months of follow-up, the progression rate to MCI was compared between the G-SCD and B-SCD groups. RESULTS: Volumes of the basal forebrain, the right hippocampus, and their respective subfields differed significantly among the four groups (p < 0.05, false discovery rate corrected). The B-SCD group showed lower volumes in the basal forebrain than the G-SCD group, especially in the Ch4p and Ch4a-i subfields. Furthermore, the structural covariance network of the basal forebrain and right hippocampal subfields showed that the B-SCD group had a larger Lambda than the G-SCD group, which suggested weakened network integration in the B-SCD group. At follow-up, the B-SCD group had a significantly higher conversion rate to MCI than the G-SCD group. CONCLUSION: Compared to SCD participants with good spatial navigation performance, SCD participants with bad performance showed lower volumes in the basal forebrain, a reorganized structural covariance network of subcortical nuclei, and an increased risk of progression to MCI. Our findings indicated that spatial navigation may have great potential to identify SCD subjects at higher risk of clinical progression, which may contribute to making more precise clinical decisions for SCD individuals who seek medical help.

Sex differences in brain atrophy in dementia with Lewy bodies.

Background and objectives: Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods: We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results: We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions: This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.

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.

MRI data-driven clustering reveals different subtypes of Dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. We used data-driven analysis of magnetic resonance imaging (MRI) data to investigate DLB subtypes. We included 165 DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as ß-amyloid, tau, and cerebrovascular biomarkers at baseline, and cognitive decline over three years. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n = 49, 30%); a subtype with low GM volumes in fronto-occipital regions (n = 76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n = 40, 24%). This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions.

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.

Moderating effect of cognitive reserve on brain integrity and cognitive performance.

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.

Different Profiles of Spatial Navigation Deficits In Alzheimer's Disease Biomarker-Positive Versus Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment.

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-ß1-42, 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-ß1-42, 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.

Corrigendum: Mild Behavioral Impairment Is Associated With Atrophy of Entorhinal Cortex and Hippocampus in a Memory Clinic Cohort.

[This corrects the article DOI: 10.3389/fnagi.2021.643271.].

Emotional prosody recognition is impaired in Alzheimer's disease.

BACKGROUND: The ability to understand emotions is often disturbed in patients with cognitive impairments. Right temporal lobe structures play a crucial role in emotional processing, especially the amygdala, temporal pole (TP), superior temporal sulcus (STS), and anterior cingulate (AC). Those regions are affected in early stages of Alzheimer´s disease (AD). The aim of our study was to evaluate emotional prosody recognition (EPR) in participants with amnestic mild cognitive impairment (aMCI) due to AD, AD dementia patients, and cognitively healthy controls and to measure volumes or thickness of the brain structures involved in this process. In addition, we correlated EPR score to cognitive impairment as measured by MMSE. The receiver operating characteristic (ROC) analysis was used to assess the ability of EPR tests to differentiate the control group from the aMCI and dementia groups. METHODS: Eighty-nine participants from the Czech Brain Aging Study: 43 aMCI due to AD, 36 AD dementia, and 23 controls, underwent Prosody Emotional Recognition Test. This experimental test included the playback of 25 sentences with neutral meaning each recorded with different emotional prosody (happiness, sadness, fear, disgust, anger). Volume of the amygdala and thickness of the TP, STS, and rostral and caudal parts of AC (RAC and CAC) were measured using FreeSurfer algorithm software. ANCOVA was used to evaluate EPR score differences. ROC analysis was used to assess the ability of EPR test to differentiate the control group from the aMCI and dementia groups. The Pearson's correlation coefficients were calculated to explore relationships between EPR scores, structural brain measures, and MMSE. RESULTS: EPR was lower in the dementia and aMCI groups compared with controls. EPR total score had high sensitivity in distinguishing between not only controls and patients, but also controls and aMCI, controls and dementia, and aMCI and dementia. EPR decreased with disease severity as it correlated with MMSE. There was a significant positive correlation of EPR and thickness of the right TP, STS, and bilateral RAC. CONCLUSIONS: EPR is impaired in AD dementia and aMCI due to AD. These data suggest that the broad range of AD symptoms may include specific deficits in the emotional sphere which further complicate the patient's quality of life.

Longitudinal atrophy in prodromal dementia with Lewy bodies points to cholinergic degeneration.

Mild cognitive impairment with the core clinical features of dementia with Lewy bodies is recognized as a prodromal stage of dementia with Lewy bodies. Although grey matter atrophy has been demonstrated in prodromal dementia with Lewy bodies, longitudinal rates of atrophy during progression to probable dementia with Lewy bodies are unknown. We investigated the regional patterns of cross-sectional and longitudinal rates of grey matter atrophy in prodromal dementia with Lewy bodies, including those who progressed to probable dementia with Lewy bodies. Patients with mild cognitive impairment with at least one core clinical feature of dementia with Lewy bodies (mean age = 70.5; 95% male), who were enrolled in the Mayo Clinic Alzheimer's Disease Research Center and followed for at least two clinical evaluations and MRI examinations, were included (n = 56). A cognitively unimpaired control group (n = 112) was matched 2:1 to the patients with mild cognitive impairment by age and sex. Patients either remained stable (n = 28) or progressed to probable dementia with Lewy bodies (n = 28) during a similar follow-up period and pathologic confirmation was available in a subset of cases (n = 18). Cross-sectional and longitudinal rates of grey matter atrophy were assessed using voxel-based and atlas-based region of interest analyses. At baseline, prodromal dementia with Lewy bodies was characterized by atrophy in the nucleus basalis of Meynert both in those who remained stable and those who progressed to probable dementia with Lewy bodies (P < 0.05 false discovery rate corrected). Increase in longitudinal grey matter atrophy rates were widespread, with greatest rates of atrophy observed in the enthorhinal and parahippocampal cortices, temporoparietal association cortices, thalamus and the basal ganglia, in mild cognitive impairment patients who progressed to probable dementia with Lewy bodies at follow-up (P < 0.05 false discovery rate corrected). Rates of inferior temporal atrophy were associated with greater rates of worsening on the clinical dementia rating-sum of boxes. Seventeen of the 18 (94%) autopsied cases had Lewy body disease. Results show that atrophy in the nucleus basalis of Meynert is a feature of prodromal dementia with Lewy bodies regardless of proximity to progression to probable dementia with Lewy bodies. Longitudinally, grey matter atrophy progresses in regions with significant cholinergic innervation, in alignment with clinical disease progression, with widespread and accelerated rates of atrophy in patients who progress to probable dementia with Lewy bodies. Given the prominent neurodegeneration in the cholinergic system, patients with prodromal dementia with Lewy bodies may be candidates for cholinesterase inhibitor treatment.

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.

Disrupted Network Topology Contributed to Spatial Navigation Impairment in Patients With Mild Cognitive Impairment.

Impairment in spatial navigation (SN) and structural network topology is not limited to patients with Alzheimer's disease (AD) dementia and can be detected earlier in patients with mild cognitive impairment (MCI). We recruited 32 MCI patients (65.91 ± 11.33 years old) and 28 normal cognition patients (NC; 69.68 ± 10.79 years old), all of whom underwent a computer-based battery of SN tests evaluating egocentric, allocentric, and mixed SN strategies and diffusion-weighted and T1-weighted Magnetic Resonance Imaging (MRI). To evaluate the topological features of the structural connectivity network, we calculated its measures such as the global efficiency, local efficiency, clustering coefficient, and shortest path length with GRETNA. We determined the correlation between SN accuracy and network topological properties. Compared to NC, MCI subjects demonstrated a lower egocentric navigation accuracy. Compared with NC, MCI subjects showed significantly decreased clustering coefficients in the left middle frontal gyrus, right rectus, right superior parietal gyrus, and right inferior parietal gyrus and decreased shortest path length in the left paracentral lobule. We observed significant positive correlations of the shortest path length in the left paracentral lobule with both the mixed allocentric-egocentric and the allocentric accuracy measured by the average total errors. A decreased clustering coefficient in the right inferior parietal gyrus was associated with a larger allocentric navigation error. White matter hyperintensities (WMH) did not affect the correlation between network properties and SN accuracy. This study demonstrated that structural connectivity network abnormalities, especially in the frontal and parietal gyri, are associated with a lower SN accuracy, independently of WMH, providing a new insight into the brain mechanisms associated with SN impairment in MCI.

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.

Mild Behavioral Impairment Is Associated With Atrophy of Entorhinal Cortex and Hippocampus in a Memory Clinic Cohort.

OBJECTIVES: Mild 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. METHODS: One 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. RESULTS: Entorhinal 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). CONCLUSION: Neuropsychiatric 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.

The Association Between Homocysteine and Memory in Older Adults.

BACKGROUND: Identifying modifiable risk factors for cognitive decline can reduce burden of dementia. OBJECTIVE: We examined whether homocysteine was associated with memory performance, mediated by entorhinal volume, hippocampal volume, total gray matter volume, or white matter lesions, and moderated by APOE ɛ4 allele, B vitamins, creatinine, total cholesterol, or triglycerides. METHODS: All 204 members of the Czech Brain Aging Study with subjective cognitive decline (SCD; n = 60) or amnestic mild cognitive impairment (aMCI; n = 144) who had valid data were included. Linear regression was used, followed by conditional process modeling to examine mediation and moderation. RESULTS: Controlling for age, sex, and education, higher homocysteine was related to poorer memory performance overall (b = -0.03, SE = 0.01, p = 0.017) and in participants with SCD (b = -0.06, SE = 0.03, p = 0.029), but less so in aMCI (b = -0.03, SE = 0.02, p = 0.074); though sensitivity analyses revealed a significant association when sample was reduced to aMCI patients with more complete cognitive data (who were also better functioning; b = -0.04, SE = 0.02, p = 0.022). Results were unchanged in fully adjusted models. Neither mediation by markers of brain integrity nor moderation by APOE ɛ4, B vitamins, creatinine, and cardiovascular factors were significant. Memory sub-analyses revealed that results for SCD were likely driven by non-verbal memory. The homocysteine-memory relationship was significant when hippocampal volume was below the median (b = -0.04, SE = 0.02, p = 0.046), but not at/above the median (p = 0.247). CONCLUSION: Higher homocysteine levels may adversely influence memory performance, which appears particularly apparent in those without cognitive impairment. Results appear to be independent of brain health, suggesting that homocysteine may represent a good target for intervention.