Publications by authors named "Zuzana Nedelska"

36 Publications

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

Front Aging Neurosci 2021 3;13:630677. Epub 2021 Jun 3.

Department of Radiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

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 T-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.
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http://dx.doi.org/10.3389/fnagi.2021.630677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210585PMC
June 2021

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

Neurobiol Aging 2021 Sep 14;105:252-261. Epub 2021 May 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.029DOI Listing
September 2021

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

Front Aging Neurosci 2021 24;13:643271. Epub 2021 May 24.

Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.

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 ( = 37) or mild cognitive impairment ( = 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 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 ( = -0.368, < 0.001) and with impulse dyscontrol score ( = -0.284, = 0.002). HV was associated with decreased motivation ( = -0.248, = 0.008) and impulse dyscontrol score ( = -0.240, = 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.
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http://dx.doi.org/10.3389/fnagi.2021.643271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180573PMC
May 2021

The Association Between Homocysteine and Memory in Older Adults.

J Alzheimers Dis 2021 ;81(1):413-426

Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.

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.
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http://dx.doi.org/10.3233/JAD-201558DOI Listing
January 2021

Basal Forebrain Atrophy Is Associated With Allocentric Navigation Deficits in Subjective Cognitive Decline.

Front Aging Neurosci 2021 15;13:596025. Epub 2021 Feb 15.

Department of Radiology, Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China.

Individuals with subjective cognitive decline (SCD) are at higher risk of incipient Alzheimer's disease (AD). Spatial navigation (SN) impairments in AD dementia and mild cognitive impairment patients have been well-documented; however, studies investigating SN deficits in SCD subjects are still lacking. This study aimed to explore whether basal forebrain (BF) and entorhinal cortex (EC) atrophy contribute to spatial disorientation in the SCD stage. In total, 31 SCD subjects and 24 normal controls were enrolled and administered cognitive scales, a 2-dimensional computerized SN test, and structural magnetic resonance imaging (MRI) scanning. We computed the differences in navigation distance errors and volumes of BF subfields, EC, and hippocampus between the SCD and control groups. The correlations between MRI volumetry and navigation distance errors were also calculated. Compared with the controls, the SCD subjects performed worse in both egocentric and allocentric navigation. The SCD group showed volume reductions in the whole BF ( < 0.05, uncorrected) and the Ch4p subfield ( < 0.05, Bonferroni corrected), but comparable EC and hippocampal volumes with the controls. In the SCD cohort, the allocentric errors were negatively correlated with total BF ( = -0.625, < 0.001), Ch4p ( = -0.625, < 0.001), total EC ( = -0.423, = 0.031), and left EC volumes ( = -0.442, = 0.024), adjusting for age, gender, years of education, total intracranial volume, and hippocampal volume. This study demonstrates that SN deficits and BF atrophy may be promising indicators for the early detection of incipient AD patients. The reduced BF volume, especially in the Ch4p subfield, may serve as a structural basis for allocentric disorientation in SCD subjects independent of hippocampal atrophy. Our findings may have further implications for the preclinical diagnosis and intervention for potential AD patients.
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http://dx.doi.org/10.3389/fnagi.2021.596025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917187PMC
February 2021

Ego- and allo-network disconnection underlying spatial disorientation in subjective cognitive decline.

Cortex 2021 04 25;137:35-48. Epub 2021 Jan 25.

Department of Radiology, Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210008, China; Department of Radiology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China; Institute of Brain Science, Nanjing University, Nanjing, 210008, China. Electronic address:

Patients with Alzheimer's disease (AD) related dementia and mild cognitive impairment experience difficulties with spatial navigation (SN). However, SN has rarely been investigated in individuals with subjective cognitive decline (SCD), a preclinical stage with elevated progression rate to symptomatic AD. In this study, 30 SCD subjects and 30 controls underwent cognitive scale (CS) evaluation, a 2D computerized SN test, and resting-state functional magnetic resonance imaging scanning. Two SN brain networks (ego-network and allo-network), each with 10 selected spherical regions, were defined. We calculated the average network functional connectivity (FC) and region-to-region FC within the two networks and evaluated correlations with SN performance. Compared with the controls, the SCD group performed worse in the SN test and showed decreased FC between the right retrosplenial and right prefrontal cortices in the ego-network, and between the right retrosplenial cortex and right hippocampus in the allo-network. The logistic regression model based on SN and FC measures revealed a high area under the curve of .880 in differentiating SCD individuals from controls. These results suggest that SN network disconnection contributes to spatial deficits in SCD, and SN and FC measures could benefit the preclinical detection of subjects with incipient AD dementia.
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http://dx.doi.org/10.1016/j.cortex.2020.12.022DOI Listing
April 2021

The Combined Effect of APOE and BDNF Val66Met Polymorphisms on Spatial Navigation in Older Adults.

J Alzheimers Dis 2020 ;78(4):1473-1492

Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.

Background: The apolipoprotein E (APOE) ɛ4 allele is associated with episodic memory and spatial navigation deficits. The brain-derived neurotrophic factor (BDNF) Met allele may further worsen memory impairment in APOEɛ4 carriers but its role in APOEɛ4-related spatial navigation deficits has not been established.

Objective: We examined influence of APOE and BDNF Val66Met polymorphism combination on spatial navigation and volumes of selected navigation-related brain regions in cognitively unimpaired (CU) older adults and those with amnestic mild cognitive impairment (aMCI).

Methods: 187 participants (aMCI [n = 116] and CU [n = 71]) from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ4-/BDNFVal/Val, ɛ4-/BDNFMet, ɛ4+/BDNFVal/Val, and ɛ4+/BDNFMet. The participants underwent comprehensive neuropsychological examination, brain MRI, and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real-space human analogue of the Morris water maze.

Results: Among the aMCI participants, the ɛ4+/BDNFMet group had the least accurate egocentric navigation performance (p < 0.05) and lower verbal memory performance than the ɛ4-/BDNFVal/Val group (p = 0.007). The ɛ4+/BDNFMet group had smaller hippocampal and entorhinal cortical volumes than the ɛ4-/BDNFVal/Val (p≤0.019) and ɛ4-/BDNFMet (p≤0.020) groups. Among the CU participants, the ɛ4+/BDNFMet group had less accurate allocentric and allocentric delayed navigation performance than the ɛ4-/BDNFVal/Val group (p < 0.05).

Conclusion: The combination of APOEɛ4 and BDNF Met polymorphisms is associated with more pronounced egocentric navigation impairment and atrophy of the medial temporal lobe regions in individuals with aMCI and less accurate allocentric navigation in CU older adults.
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http://dx.doi.org/10.3233/JAD-200615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836052PMC
January 2020

Thalamic Atrophy Plays a Crucial Role in the Effect of Asymptomatic Carotid Stenosis on Cognitive Impairment.

Clin Interv Aging 2020 6;15:2083-2094. Epub 2020 Nov 6.

Department of Radiology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.

Purpose: Our objectives were to assess the abnormalities of subcortical nuclei by combining volume and shape analyses and potential association with cognitive impairment.

Patients And Methods: Twenty-nine patients with severe ACS of the unilateral internal carotid artery and 31 controls were enrolled between January 2017 to August 2018. All participants underwent a comprehensive neuropsychological evaluation, blood lipid biochemical measurements, and structural magnetic resonance imaging (MRI) to measure subcortical volumes and sub-regional shape deformations. Basic statistics, correction for multiple comparisons. Seventeen ACS patients underwent carotid endarterectomy (CEA) within one week after baseline measurements, cognitive assessments and MRI scans were repeated 6 months after CEA.

Results: The ACS patients had higher apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio and worse performance in all cognitive domains than controls. Moreover, the ACS patients showed more profound thalamic atrophy assessed by shape and volume analysis, especially in the medial dorsal thalamus. No significant differences were found in other subcortical nuclei after multiple comparisons correction. At baseline, thalamic atrophy correlated with cognitive impairment and ApoB/ApoA1 ratio. Furthermore, mediation analysis at baseline showed that the association of carotid intima-media thickness with executive functioning was mediated by thalamic volume. After CEA, cognitive improvement and increase in the bilateral medial dorsal thalamic volume were observed.

Conclusion: Our study identified the distinct atrophy of subcortical nuclei and their association with cognition in patients with ACS. Assessments of the thalamus by volumetric and shape analysis may provide an early marker for cerebral ischemia and reperfusion after CEA.
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http://dx.doi.org/10.2147/CIA.S273185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654547PMC
March 2021

β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies.

Neurology 2020 12 28;95(24):e3257-e3268. Epub 2020 Sep 28.

From the Division of Clinical Geriatrics (D.F., S.G.-P., E.W.), Center for Alzheimer's Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden; Departments of Radiology (D.F., Z.N., C.G.S., M.L.S., V.J.L., C.R.J., K.K.), Health Sciences (S.A.P., T.G.L.), Neurology (J.G.-R., D.S.K., R.S., R.C.P., B.F.B.), Information Technology (M.L.S.), and Psychiatry and Psychology (J.A.F.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center (A.W.L.), VU University Medical Center, Amsterdam, the Netherlands; Clinical Memory Research Unit (E.L.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Day Hospital of Geriatrics (F.B.), Memory Resource and Research Centre (CM2R) of Strasbourg; Department of Geriatrics (F.B.), Hopitaux Universitaires de Strasbourg; University of Strasbourg and French National Centre for Scientific Research (CNRS) (F.B.), ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg (FMTS), Team Imagerie Multimodale Integrative en Sante (IMIS)/ICONE, Strasbourg, France; Department of Neurology (Z.N., J.H.), Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic; Departments of Psychiatry and Psychology (T.J.F.) and Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Paracelsus-Elena-Klinik (B.M.), Kassel; and University Medical Center (B.M.), Department of Neurosurgery and Institute of Neuropathology, Göttingen, Germany; Fundació ACE (C.A.), Alzheimer Research Center and Memory Clinic, Institut Català de Neurociències Aplicades, Barcelona, Spain; International Clinical Research Center (J.H.), St. Anne's University Hospital Brno, Czech Republic; Department of Neuroscience Imaging and Clinical Sciences and CESI (L.B.), University G d'Annunzio of Chieti-Pescara, Chieti, Italy; Centre for Age-Related Medicine (K.O., D.A.), Stavanger University Hospital; Stavanger Medical Imaging Laboratory (SMIL) (K.O.), Department of Radiology, Stavanger University Hospital; Department of Electrical Engineering and Computer Science (K.O.), University of Stavanger, Norway; Department of Neurology (M.G.K.), University Medical Centre Ljubljana, Medical Faculty, University of Ljubljana, Slovenia; Institute of Psychiatry, Psychology and Neuroscience (D.A.) and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Objective: In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.

Methods: We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+.

Results: A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.

Conclusions: Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Classification Of Evidence: This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.
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http://dx.doi.org/10.1212/WNL.0000000000010943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836666PMC
December 2020

The combined effect of amyloid-β and tau biomarkers on brain atrophy in dementia with Lewy bodies.

Neuroimage Clin 2020 2;27:102333. Epub 2020 Jul 2.

Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Alzheimer's disease (AD)-related pathology is frequently found in patients with dementia with Lewy bodies (DLB). However, it is unknown how amyloid-β and tau-related pathologies influence neurodegeneration in DLB. Understanding the mechanisms underlying brain atrophy in DLB can improve our knowledge about disease progression, differential diagnosis, drug development and testing of anti-amyloid and anti-tau therapies in DLB.

Objectives: We aimed at investigating the combined effect of CSF amyloid-β42, phosphorylated tau and total tau on regional brain atrophy in DLB in the European DLB (E-DLB) cohort.

Methods: 86 probable DLB patients from the E-DLB cohort with CSF and MRI data were included. Random forest was used to analyze the association of CSF biomarkers (predictors) with visual rating scales for medial temporal lobe atrophy (MTA), posterior atrophy (PA) and global cortical atrophy scale-frontal subscale (GCA-F) (outcomes), including age, sex, education and disease duration as extra predictors.

Results: DLB patients with abnormal MTA scores had abnormal CSF Aβ42, shorter disease duration and older age. DLB patients with abnormal PA scores had abnormal levels of CSF Aβ42 and p-tau, older age, lower education and shorter disease duration. Abnormal GCA-F scores were associated with lower education, male sex, and older age, but not with any AD-related CSF biomarker.

Conclusions: This study shows preliminary data on the potential combined effect of amyloid-β and tau-related pathologies on the integrity of posterior brain cortices in DLB patients, whereas only amyloid-β seems to be related to MTA. Future availability of α-synuclein biomarkers will help us to understand the effect of α-synuclein and AD-related pathologies on brain integrity in DLB.
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http://dx.doi.org/10.1016/j.nicl.2020.102333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363702PMC
June 2021

Cholinergic white matter pathways make a stronger contribution to attention and memory in normal aging than cerebrovascular health and nucleus basalis of Meynert.

Neuroimage 2020 05 6;211:116607. Epub 2020 Feb 6.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Faculty of Psychology, University of La Laguna, La Laguna, Tenerife, Spain. Electronic address:

The integrity of the cholinergic system plays a central role in cognitive decline both in normal aging and neurological disorders including Alzheimer's disease and vascular cognitive impairment. Most of the previous neuroimaging research has focused on the integrity of the cholinergic basal forebrain, or its sub-region the nucleus basalis of Meynert (NBM). Tractography using diffusion tensor imaging data may enable modelling of the NBM white matter projections. We investigated the contribution of NBM volume, NBM white matter projections, small vessel disease (SVD), and age to performance in attention and memory in 262 cognitively normal individuals (39-77 years of age, 53% female). We developed a multimodal MRI pipeline for NBM segmentation and diffusion-based tracking of NBM white matter projections, and computed white matter hypointensities (WM-hypo) as a marker of SVD. We successfully tracked pathways that closely resemble the spatial layout of the cholinergic system as seen in previous post-mortem and DTI tractography studies. We found that high WM-hypo load was associated with older age, male sex, and lower performance in attention and memory. A high WM-hypo load was also associated with lower integrity of the cholinergic system above and beyond the effect of age. In a multivariate model, age and integrity of NBM white matter projections were stronger contributors than WM-hypo load and NBM volume to performance in attention and memory. We conclude that the integrity of NBM white matter projections plays a fundamental role in cognitive aging. This and other modern neuroimaging methods offer new opportunities to re-evaluate the cholinergic hypothesis of cognitive aging.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116607DOI Listing
May 2020

Czech Brain Aging Study (CBAS): prospective multicentre cohort study on risk and protective factors for dementia in the Czech Republic.

BMJ Open 2019 12 18;9(12):e030379. Epub 2019 Dec 18.

International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.

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).
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http://dx.doi.org/10.1136/bmjopen-2019-030379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937049PMC
December 2019

The Impact of Spatial Normalization Strategies on the Temporal Features of the Resting-State Functional MRI: Spatial Normalization Before rs-fMRI Features Calculation May Reduce the Reliability.

Front Neurosci 2019 26;13:1249. Epub 2019 Nov 26.

Department of Radiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies frequently applied the spatial normalization on fMRI time series before the calculation of temporal features (here referred to as "Prenorm"). We hypothesized that calculating the rs-fMRI features, for example, functional connectivity (FC), regional homogeneity (ReHo), or amplitude of low-frequency fluctuation (ALFF) in individual space, before the spatial normalization (referred to as "Postnorm") can be an improvement to avoid artifacts and increase the results' reliability. We utilized two datasets: (1) simulated images where temporal signal-to-noise ratio (tSNR) is kept a constant and (2) an empirical fMRI dataset with 50 healthy young subjects. For simulated images, the tSNR is constant as generated in individual space but increased after Prenorm and intersubject variability of tSNR was induced. In contrast, tSNR was kept constant after Postnorm. Consistently, for empirical images, higher tSNR, ReHo, and FC (default mode network, seed in precuneus) and lower ALFF were found after Prenorm compared to those of Postnorm. Coefficient of variability of tSNR and ALFF was higher after Prenorm compared to those of Postnorm. Moreover, the significant correlation was found between simulated tSNR after Prenorm and empirical tSNR, ALFF, and ReHo after Prenorm, indicating algorithmic variation in empirical rs-fMRI features. Furthermore, comparing to Prenorm, ALFF and ReHo showed higher intraclass correlation coefficients between two serial scans after Postnorm. Our results indicated that Prenorm may induce algorithmic intersubject variability on tSNR and reduce its reliability, which also significantly affected ALFF and ReHo. We suggest using Postnorm instead of Prenorm for future rs-fMRI studies using ALFF/ReHo.
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http://dx.doi.org/10.3389/fnins.2019.01249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902012PMC
November 2019

Association of Longitudinal β-Amyloid Accumulation Determined by Positron Emission Tomography With Clinical and Cognitive Decline in Adults With Probable Lewy Body Dementia.

JAMA Netw Open 2019 12 2;2(12):e1916439. Epub 2019 Dec 2.

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Importance: In patients with probable dementia with Lewy bodies (DLB), overlapping Alzheimer disease pathology is frequent and is associated with faster decline and shorter survival. More than half of patients with DLB have elevated β-amyloid levels on carbon-11 labeled Pittsburgh compound B (PiB) positron emission tomography, but the trajectory of longitudinal β-amyloid accumulation and its associations with clinical and cognitive decline in DLB are not known.

Objectives: To determine the trajectory of β-amyloid accumulation in patients with probable DLB and to investigate the associations of β-amyloid accumulation with measures of clinical and cognitive decline over time in DLB.

Design, Setting, And Participants: This cohort study included 35 consecutive patients with probable DLB from the Mayo Clinic Alzheimer Disease Research Center and matched them by age, sex, and apolipoprotein e4 status with 140 cognitively unimpaired participants from the population-based Mayo Clinic Study of Aging. Participants were observed from April 2010 to September 2017. Data analysis was conducted from January 2018 to January 2019.

Exposure: Baseline and follow-up PiB positron emission tomography and comprehensive clinical evaluations.

Main Outcomes And Measures: Rate of change in PiB standardized uptake value ratios (SUVRs) by PiB SUVR and time in years; the associations between baseline PiB SUVR, change in PiB SUVR, and change in several measures of clinical and cognitive decline.

Results: A total of 175 participants were evaluated (35 [20.0%] with probable DLB; mean [SD] age, 69.6 [7.3] years; 16 [45.7%] apolipoprotein e4 carriers; 31 [88.6%] men; and 140 [80.0%] cognitively unimpaired adults; mean [SD] age, 69.7 [7.2] years; 64 [45.7%] apolipoprotein e4 carriers; 124 [88.6%] men). In both groups, the rates of change in PiB SUVR showed an initial acceleration at lower baseline PiB SUVR followed by a deceleration at higher baseline PiB SUVR, thus forming an inverted-U shape. The trajectories of the rates of change in PiB SUVR did not differ between participants with probable DLB and cognitively unimpaired participants in terms of shape (P = .59) or vertical shift (coefficient [SE] 0.007 [0.006]; P = .22). The integral association of cumulative PiB SUVR with time in years showed a sigmoid-shaped functional form in both groups. In participants with probable DLB, higher baseline PiB SUVR and change in PiB SUVR were associated with more rapid clinical decline, as measured by the Clinical Dementia Rating, sum of boxes (baseline PiB SUVR: regression coefficient [SE], 1.90 [0.63]; P = .005; R2 = 0.215; change in PiB SUVR, regression coefficient [SE], 16.17 [7.47]; P = .04; R2 = 0.124) and the Auditory Verbal Learning Test, delayed recall (baseline PiB SUVR, regression coefficient [SE], -2.09 [0.95]; P = .04; R2 = 0.182; change in PiB SUVR, regression coefficient [SE], -25.05 [10.04]; P = .02; R2 = 0.221).

Conclusions And Relevance: In this study, the rate of change in PiB SUVR among participants with probable DLB increased, peaked, and then decreased, which was similar to the trajectory in cognitively unimpaired participants and the Alzheimer disease dementia continuum. Higher baseline PiB SUVR and change in PiB SUVR were associated with more rapid clinical and cognitive decline over time. Measuring the change in PiB SUVR has implications for designing anti-β-amyloid randomized clinical trials for individuals with probable DLB.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.16439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902746PMC
December 2019

Impact of APOE and BDNF Val66Met Gene Polymorphisms on Cognitive Functions in Patients with Amnestic Mild Cognitive Impairment.

J Alzheimers Dis 2020 ;73(1):247-257

Department of Neurology, Memory Clinic, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.

Apolipoprotein (APOE) ɛ4 is a well-known risk factor for late-onset Alzheimer's disease (AD), but other AD-related gene polymorphisms might also be important, such as the polymorphism within the brain-derived neurotrophic factor (BDNF) gene. Carriage of BDNF Val66Met has been associated with faster cognitive decline and greater hippocampal atrophy in cognitively normal elderly. Thus, we examined the effects of the concurrent presence of APOE and BDNF polymorphisms on cognitive functions and brain morphometry in amnestic mild cognitive impairment (aMCI) patients. 107 aMCI patients (mean age = 72.2) were recruited from the Czech Brain Aging Study and, based on APOE and BDNF genes polymorphisms, were divided into four groups: ɛ4-BDNFVal/Val (n = 37), ɛ4-BDNFMet (n = 19), ɛ4+BDNFVal/Val (n = 35), and ɛ4+BDNFMet (n = 16). All patients underwent clinical examination, magnetic resonance imaging, and complex neuropsychological battery. The combination of APOEɛ4+ and BDNF Met was associated with significantly worse memory performance in immediate and delayed recall compared to other polymorphism groups. We did not observe increased atrophy in areas related to memory function in the ɛ4+BDNFMet group. Our findings suggest that carriage of ɛ4+BDNFMet is associated with more pronounced memory dysfunction, a typical feature of early AD, but not with structural brain changes in aMCI patients. These findings suggest that in APOEɛ4/BDNF Met carriers, synaptic dysfunction affecting memory may precede pronounced structural changes.
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http://dx.doi.org/10.3233/JAD-190464DOI Listing
April 2021

Characterization of white matter changes along fibers by automated fiber quantification in the early stages of Alzheimer's disease.

Neuroimage Clin 2019 18;22:101723. Epub 2019 Feb 18.

Department of Radiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. Electronic address:

Brain white matter fiber bundles in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have abnormalities not usually seen in unaffected subjects. Ideal algorithm of the localization-specific properties in white matter integrity might reveal the changes of tissue properties varying along each tract, while previous studies only detected the mean DTI parameters of each fiber. The aim of this study was to investigate whether these abnormalities of nerve fiber tracts are localized to specific regions of the tracts or spread throughout and to analyze which of the examined fiber tracts are involved in the early stages of Alzheimer's disease. In this study, we utilized VBA, TBSS as well as AFQ together to comprehensively investigate the white matter fiber impairment on 25 CE patients, 29 MCI patients and 34 normal control (NC) subjects. Two tract profiles, fractional anisotropy (FA) and mean diffusivity (MD), were extracted to evaluate the white matter integrity at 100 locations along each of 20 fiber tracts and then we validated the results with 27 CE patients, 21 MCI patients and 22 NC from the ADNI cohort. Also, we compare the AFQ with VBA and TBSS in our cohort. In comparison with NC, AD patients showed widespread FA reduction in 25% (5 /20) and MD increase in 65%(13/20) of the examined fiber tracts. The MCI patients showed a regional FA reduction in 5% (1/20) of the examined fiber tracts (right cingulum cingulate) and MD increase in 5%(1/20) of the examined fiber tracts (left arcuate fasciculus). Among these changed tracts, only the right cingulum cingulate showed widespread disruption of myelin or/and fiber axons in MCI and aggravated deterioration in AD, findings supported by FA/MD changes both by the mean and FA changes by point wise methods and TBSS. And the AFQ findings from ADNI cohort showed some similarity with our cohort, especially in the pointwise comparison of MD profiles between AD vs NC. Furthermore, the pattern of white matter abnormalities was different across neuronal fiber tracts; for example, the MCI and AD patients showed similar FA reduction in the middle part of the right cingulum cingulate, and the anterior part were not damaged. However, the left arcuate fasciculus showed MD elevation located at the temporal part of the fibers in the MCI patients and expanding to the temporal and middle part of the fibers in AD patients. So, the AFQ may be an alternative complementary method of VBA and TBSS, and may provide new insights into white matter degeneration in MCI and its association with AD.
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http://dx.doi.org/10.1016/j.nicl.2019.101723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384328PMC
December 2019

F-AV-1451 uptake differs between dementia with lewy bodies and posterior cortical atrophy.

Mov Disord 2019 03 7;34(3):344-352. Epub 2019 Jan 7.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Posterior cortical atrophy and dementia with Lewy bodies are 2 distinct clinical syndromes, yet they can overlap in symptoms and occipital hypometabolism. Patients with dementia with Lewy bodies often have overlapping Alzheimer's disease pathology. Similarly, Lewy bodies can be found in patients with posterior cortical atrophy. We investigated differences in the distribution and magnitude of F18-AV-1451 uptake in patients with these 2 syndromes.

Methods: Consecutive patients with probable dementia with Lewy bodies (n = 33), posterior cortical atrophy (n = 18), and cognitively unimpaired controls (n = 100) underwent F-AV-1451 positron emission tomography. Regional differences in AV-1451 uptake were assessed using voxel-wise and an atlas-based approach. The greatest differences in AV-1451 uptake between patient groups were identified using area under receiver operating curve statistics, and a composite region was derived.

Results: AV-1451 uptake in both patient groups was predominantly localized to the lateral occipital regions, but the magnitude of uptake was markedly greater in posterior cortical atrophy compared with dementia with Lewy bodies. The posterior cortical atrophy group showed the greatest AV-1451 uptake throughout all the gray matter compared with that in other groups. The occipital composite region, consisting of superior, middle, and inferior occipital cortices, distinguished posterior cortical atrophy from dementia with Lewy bodies (area under the curve >0.97; P < 0.001, Bonferroni-corrected) with excellent sensitivity (88%) and specificity (100%).

Conclusions: Posterior cortical atrophy and dementia with Lewy bodies can share clinical features, and although the pattern of AV-1451 uptake in occipital cortices overlaps between these 2 syndromes, its magnitude is significantly higher in posterior cortical atrophy. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420367PMC
March 2019

Regional cortical perfusion on arterial spin labeling MRI in dementia with Lewy bodies: Associations with clinical severity, glucose metabolism and tau PET.

Neuroimage Clin 2018 19;19:939-947. Epub 2018 Jun 19.

Department of Radiology, Mayo Clinic, Rochester, MN, United States. Electronic address:

Visually preserved metabolism in posterior cingulate cortex relative to hypometabolism in precuneus and cuneus, the , is a feature of dementia with Lewy bodies (DLB) on FDG-PET. Lower (posterior cingulate cortex/cuneus+precuneus; FDG-CISr) values have been associated with a higher Braak neurofibrillary tangle stage in autopsied DLB. Using voxel-wise analysis, we assessed the patterns of regional cortical perfusion and metabolism, and using an atlas-based approach, we measured perfusion cingulate island sign ratio on arterial spin labeling MRI (ASL-CISr), and its associations with FDG-CISr, uptake on tau-PET and clinical severity in DLB. Our study sample ( = 114) included clinically probable DLB patients ( = 19), age-matched patients with probable Alzheimer's disease dementia (AD;  = 19) and matched controls ( = 76) who underwent MRI with 3-dimensional pseudo-continuous arterial spin labeling, 18F-FDG-PET and 18F-AV-1451 tau PET. Patterns of cortical perfusion and metabolism were derived from quantitative maps using Statistical Parametric Mapping. DLB patients showed hypoperfusion on ASL-MRI in precuneus, cuneus and posterior parieto-occipital cortices, compared to controls, and relatively spared posterior cingulate gyrus, similar to pattern of hypometabolism on FDG-PET. DLB patients had higher ASL-CISr and FDG-CISr than AD patients ( <0.001). ASL-CISr correlated with FDG-CISr in DLB patients ( = 0.67;  =0.002). Accuracy of distinguishing DLB from AD patients was 0.80 for ASL-CISr and 0.91 for FDG-CISr. Lower ASL-CISr was moderately associated with a higher composite medial temporal AV-1451 uptake ( = -0.50;  =0.03) in DLB. Lower perfusion in precuneus and cuneus was associated with worse global clinical scores. In summary, the pattern of cortical hypoperfusion on ASL-MRI is similar to hypometabolism on FDG-PET, and respective cingulate island sign ratios correlate with each other in DLB. Non-invasive and radiotracer-free ASL-MRI may be further developed as a tool for the screening and diagnostic evaluation of DLB patients in a variety of clinical settings where FDG-PET is not accessible.
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http://dx.doi.org/10.1016/j.nicl.2018.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039836PMC
January 2019

The effect of Alzheimer's disease on spatial navigation strategies.

Neurobiol Aging 2018 04 29;64:107-115. Epub 2017 Dec 29.

Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic. Electronic address:

Hippocampal and basal forebrain (BF) atrophy is associated with allocentric navigation impairment in Alzheimer's disease (AD) and may lead to recruitment of compensatory navigation strategies. We examined navigation strategy preference, its association with allocentric navigation, and the role of hippocampal and BF volumes in this association in early clinical stages of AD. Sixty nine participants-amnestic mild cognitive impairment (aMCI) due to AD (n = 28), AD dementia (n = 21), and cognitively normal (CN) older adults (n = 20)-underwent virtual Y-maze strategy assessment, real-space navigation testing, cognitive assessment, and hippocampal and BF volumetry. Preference for egocentric over allocentric strategy increased with AD severity (aMCI: 67% vs. 33%; dementia: 94% vs. 6%), which contrasted with preference in the CN group (39% vs. 61%). Those with aMCI who preferred egocentric strategy had worse allocentric navigation. Among those with aMCI, hippocampal and BF atrophy explained up to 25% of the association between strategy preference and allocentric navigation. The preference for egocentric strategy in AD may reflect recruitment of compensatory extrahippocampal navigation strategies as adaptation to hippocampal and BF neurodegeneration.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.12.019DOI Listing
April 2018

Subjective Spatial Navigation Complaints - A Frequent Symptom Reported by Patients with Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease.

Curr Alzheimer Res 2018 ;15(3):219-228

Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.

Background: Great effort has been put into developing simple and feasible tools capable to detect Alzheimer's disease (AD) in its early clinical stage. Spatial navigation impairment occurs very early in AD and is detectable even in the stage of mild cognitive impairment (MCI).

Objective: The aim was to describe the frequency of self-reported spatial navigation complaints in patients with subjective cognitive decline (SCD), amnestic and non-amnestic MCI (aMCI, naMCI) and AD dementia and to assess whether a simple questionnaire based on these complaints may be used to detect early AD.

Method: In total 184 subjects: patients with aMCI (n=61), naMCI (n=27), SCD (n=63), dementia due to AD (n=20) and normal controls (n=13) were recruited. The subjects underwent neuropsychological examination and were administered a questionnaire addressing spatial navigation complaints. Responses to the 15 items questionnaire were scaled into four categories (no, minor, moderate and major complaints).

Results: 55% of patients with aMCI, 64% with naMCI, 68% with SCD and 72% with AD complained about their spatial navigation. 38-61% of these complaints were moderate or major. Only 33% normal controls expressed complaints and none was ranked as moderate or major. The SCD, aMCI and AD dementia patients were more likely to express complaints than normal controls (p's<0.050) after adjusting for age, education, sex, depressive symptoms (OR for SCD=4.00, aMCI=3.90, AD dementia=7.02) or anxiety (OR for SCD=3.59, aMCI=3.64, AD dementia=6.41).

Conclusion: Spatial navigation complaints are a frequent symptom not only in AD, but also in SCD and aMCI and can potentially be detected by a simple and inexpensive questionnaire.
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http://dx.doi.org/10.2174/1567205014666171120145349DOI Listing
March 2019

Spatial Navigation Impairment Is Associated with Alterations in Subcortical Intrinsic Activity in Mild Cognitive Impairment: A Resting-State fMRI Study.

Behav Neurol 2017 20;2017:6364314. Epub 2017 Sep 20.

Department of Radiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Impairment of spatial navigation (SN) skills is one of the features of the Alzheimer's disease (AD) already at the stage of mild cognitive impairment (MCI). We used a computer-based battery of spatial navigation tests to measure the SN performance in 22 MCI patients as well as 21 normal controls (NC). In order to evaluate intrinsic activity in the subcortical regions that may play a role in SN, we measured ALFF, fALFF, and ReHo derived within 14 subcortical regions. We observed reductions of intrinsic activity in MCI patients. We also demonstrated that the MCI versus NC group difference can modulate activity-behavior relationship, that is, the correlation slopes between ReHo and allocentric SN task total errors were significantly different between NC and MCI groups in the right hippocampus (interaction = 4.44, = 0.05), pallidum ( = 8.97, = 0.005), and thalamus ( = 5.95, = 0.02), which were negative in NC (right hippocampus, = -0.49; right pallidum, = -0.50; right thalamus, = -0.45; all < 0.05) but absent in MCI (right hippocampus, = 0.21; right pallidum, = 0.32; right thalamus = 0.28; all > 0.2). These findings may provide a novel insight of the brain mechanism associated with SN impairment in MCI and indicated a stage specificity of brain-behavior correlation in dementia. This trial is registered with ChiCTR-BRC-17011316.
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http://dx.doi.org/10.1155/2017/6364314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632470PMC
January 2018

Subregional Structural Alterations in Hippocampus and Nucleus Accumbens Correlate with the Clinical Impairment in Patients with Alzheimer's Disease Clinical Spectrum: Parallel Combining Volume and Vertex-Based Approach.

Front Neurol 2017 15;8:399. Epub 2017 Aug 15.

Department of Radiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Deep gray matter structures are associated with memory and other important functions that are impaired in Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, systematic characterization of the subregional atrophy and deformations in these structures in AD and MCI still need more investigations. In this article, we combined complex volumetry- and vertex-based analysis to investigate the pattern of subregional structural alterations in deep gray matter structures and its association with global clinical scores in AD ( = 30) and MCI patients ( = 30), compared to normal controls (NCs,  = 30). Among all seven pairs of structures, the bilateral hippocampi and nucleus accumbens showed significant atrophy in AD compared with NCs ( < 0.05). But only the subregional atrophy in the dorsal-medial part of the left hippocampus, the ventral part of right hippocampus, and the left nucleus accumbens, the posterior part of the right nucleus accumbens correlated with the worse clinical scores of MMSE and MOCA ( < 0.05). Furthermore, the medial-ventral part of right thalamus significantly shrank and correlated with clinical scores without decreasing in its whole volume ( > 0.05). In conclusion, the atrophy of these four subregions in bilateral hippocampi and nucleus accumbens was associated with cognitive impairment of patients, which might be potential target regions of treatment in AD. The surface analysis could provide additional information to volume comparison in finding the early pathological progress in deep gray matter structures.
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http://dx.doi.org/10.3389/fneur.2017.00399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559429PMC
August 2017

H-MRS metabolites and rate of β-amyloid accumulation on serial PET in clinically normal adults.

Neurology 2017 Sep 25;89(13):1391-1399. Epub 2017 Aug 25.

From the Departments of Radiology (Z.N., C.G.S., V.J.L., C.R.J., K.K.), Health Sciences Research (S.A.P., T.G.L., W.K.K., M.M.M., R.O.R.), Psychiatry and Psychology (M.M.M.), and Neurology (M.M.M., R.O.R., B.F.B., D.S.K., R.C.P.), Mayo Clinic, Rochester, MN; and Department of Neurology (Z.N.), Charles University, Second Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.

Objective: To assess whether noninvasive proton magnetic resonance spectroscopy (H-MRS) tissue metabolite measurements at baseline can predict an increase in the rate of β-amyloid (Aβ) accumulation on serial PET in clinically normal (CN) older adults.

Methods: Consecutive participants aged 60 years and older (n = 594) from the Mayo Clinic Study of Aging who were CN at baseline and who underwent H-MRS from the posterior cingulate voxel and longitudinal C-Pittsburgh compound B (PiB)-PET were included. The rate of Aβ accumulation by serial cortical PiB standardized uptake value ratios was estimated as a function of baseline H-MRS metabolite ratios and time using mixed-effect models adjusted for age, sex, and ε4. Effect of ε4 on the relationship between baseline MRS and an increased rate of Aβ accumulation was also assessed.

Results: Among all participants, a higher myo-inositol (mI)/creatine ( = 0.011) and a lower -acetylaspartate/mI ( = 0.006) at baseline were associated with an increased Aβ accumulation over time after adjusting for age, sex, and ε4. ε4 did not modify the association of baseline H-MRS metabolite ratios and rate of Aβ accumulation. However, ε4 carriers accumulated Aβ faster than noncarriers regardless of the baseline Aβ load ( = 0.001).

Conclusion: Among CN older adults, early metabolic alterations on H-MRS and ε4 status are independently associated with an increased rate of Aβ accumulation. Our findings could have important implications for early diagnosis and identification of individuals for secondary prevention trials, because an increased rate of Aβ accumulation in CN older adults may confer a higher risk for cognitive decline and mild cognitive impairment.
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http://dx.doi.org/10.1212/WNL.0000000000004421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649764PMC
September 2017

Exploring the contribution of spatial navigation to cognitive functioning in older adults.

Neurobiol Aging 2017 03 14;51:67-70. Epub 2016 Dec 14.

Department of Neurology, Memory Clinic, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.

Spatial navigation (SN) impairment is present early in Alzheimer's disease (AD). We tested whether SN performance, self-centered (egocentric) and world-centered (allocentric), was distinguishable from performance on established cognitive functions-verbal and nonverbal memory, executive and visuospatial function, attention/working memory, and language function. 108 older adults (53 cognitively normal [CN] and 55 with amnestic mild cognitive impairment [aMCI]) underwent neuropsychological examination and real-space navigation testing. Subset (n = 63) had automated hippocampal volumetry. In a factor analysis, allocentric and egocentric navigation tasks loaded highly onto the same factor with low loadings on other factors comprising other cognitive functions. In linear regression, performance on other cognitive functions was not, or was only marginally, associated with spatial navigation performance in CN or aMCI groups. After adjustment for age, gender, and education, right hippocampal volume explained 26% of the variance in allocentric navigation in aMCI group. In conclusion, spatial navigation, a known cognitive marker of early AD, may be distinguished from other cognitive functions. Therefore, its assessment along with other major cognitive functions may be highly beneficial in terms of obtaining a comprehensive neuropsychological profile.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.12.003DOI Listing
March 2017

Presence of lacunar infarctions is associated with the spatial navigation impairment in patients with mild cognitive impairment: a DTI study.

Oncotarget 2016 Nov;7(48):78310-78319

Department of Neurology, The Affiliated Drum Tower Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China.

Lacunar cerebral infarction (LI) is one of risk factors of vascular dementia and correlates with progression of cognitive impairment including the executive functions. However, little is known on spatial navigation impairment and its underlying microstructural alteration of white matter in patients with LI and with or without mild cognitive impairment (MCI). Our aim was to investigate whether the spatial navigation impairment correlated with the white matter integrity in LI patients with MCI (LI-MCI). Thirty patients with LI were included in the study and were divided into LI-MCI (n=17) and non MCI (LI-Non MCI) groups (n=13) according neuropsychological tests.The microstructural integrity of white matter was assessed by calculating a fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI) scans. The spatial navigation accuracy, separately evaluated as egocentric and allocentric, was assessed by a computerized human analogue of the Morris Water Maze tests Amunet. LI-MCI performed worse than the CN and LI-NonMCI groups on egocentric and delayed spatial navigation subtests. LI-MCI patients have spatial navigation deficits. The microstructural abnormalities in diffuse brain regions, including hippocampus, uncinate fasciculus and other brain regions may contribute to the spatial navigation impairment in LI-MCI patients at follow-up.
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http://dx.doi.org/10.18632/oncotarget.13409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346640PMC
November 2016

Aberrant Spontaneous Brain Activity in Patients with Mild Cognitive Impairment and concomitant Lacunar Infarction: A Resting-State Functional MRI Study.

J Alzheimers Dis 2016 ;50(4):1243-54

Department of Radiology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Background: Lacunar infarctions (LI) have been associated with a cognitive decline and an increased risk of dementia. Whether and how the pattern of spontaneous brain activity in patients with mild cognitive impairment (MCI) differs in subjects with and without concomitant LI remains unclear.

Objective: To compare the pattern of spontaneous brain activity in MCI patients with versus those without LI using resting-state functional magnetic resonance imaging (rs-fMRI).

Methods: Forty-eight MCI patients, including 22 with LI [MCI-LI] and 26 without LI [MCI-no LI], and 28 cognitive normal subjects underwent rs-fMRI post-processed using regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF) methods.

Results: Compared with cognitively normal subjects, the MCI-LI patients had decreased ReHo in the precuneus/cuneus (Pcu/CU) and insula; decreased ALFF in the Pcu/CU and frontal lobe; and increased ALFF and ReHo in the temporal lobe. While the MCI-no LI group had increased ReHo and ALFF in the bilateral hippocampus and parahippocampal gyrus, frontal lobe, and decreased ALFF and ReHo in the temporal lobe. Compared with the MCI-no LI patients, those with MCI-LI had decreased ALFF in the frontal lobe; decreased ReHo in the Pcu/CU and insula; and increased ALFF and ReHo in the temporal lobe (p <  0.05, AlphaSim corrected). In MCI-LI patients, the MOCA scores showed a relatively weak correlation with ALFF values in the medial frontal gyrus (r = 0.432, p = 0.045) (of borderline significance after Bonferroni correction).

Conclusions: The spontaneous brain activities in MCI-LI were distinct from MCI-no LI. The probable compensatory mechanism observed in MCI-no LI might be disrupted in MCI with LI due to vascular damage.
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http://dx.doi.org/10.3233/JAD-150622DOI Listing
December 2016

Basal Forebrain Atrophy Contributes to Allocentric Navigation Impairment in Alzheimer's Disease Patients.

Front Aging Neurosci 2015 28;7:185. Epub 2015 Sep 28.

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland , Brisbane, QLD , Australia.

The basal forebrain degenerates in Alzheimer's disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants' ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy.
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http://dx.doi.org/10.3389/fnagi.2015.00185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585346PMC
October 2015

White matter integrity in dementia with Lewy bodies: a voxel-based analysis of diffusion tensor imaging.

Neurobiol Aging 2015 Jun 14;36(6):2010-7. Epub 2015 Mar 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Many patients with dementia with Lewy bodies (DLB) have overlapping Alzheimer's disease (AD)-related pathology, which may contribute to white matter (WM) diffusivity alterations on diffusion tensor imaging (DTI). Consecutive patients with DLB (n = 30), age- and sex-matched AD patients (n = 30), and cognitively normal controls (n = 60) were recruited. All subjects underwent DTI, 18F 2-fluoro-deoxy-d-glucose, and (11)C Pittsburgh compound B positron emission tomography scans. DLB patients had reduced fractional anisotropy (FA) in the parietooccipital WM but not elsewhere compared with cognitively normal controls, and elevated FA in parahippocampal WM compared with AD patients, which persisted after controlling for β-amyloid load in DLB. The pattern of WM FA alterations on DTI was consistent with the more diffuse posterior parietal and occipital glucose hypometabolism of 2-fluoro-deoxy-d-glucose positron emission tomography in the cortex. DLB is characterized by a loss of parietooccipital WM integrity, independent of concomitant AD-related β-amyloid load. Cortical glucose hypometabolism accompanies WM FA alterations with a concordant pattern of gray and WM involvement in the parietooccipital lobes in DLB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433563PMC
June 2015

The effect of TOMM40 on spatial navigation in amnestic mild cognitive impairment.

Neurobiol Aging 2015 Jun 16;36(6):2024-33. Epub 2015 Mar 16.

Memory Clinic, Department of Neurology, Charles University in Prague, Second Faculty of Medicine and Motol University Hospital, Prague, The Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Brno, The Czech Republic.

The very long (VL) poly-T variant at rs10524523 ("523") of the TOMM40 gene may hasten the onset of late-onset Alzheimer's disease (LOAD) and induce more profound cognitive impairment compared with the short (S) poly-T variant. We examined the influence of TOMM40 "523" polymorphism on spatial navigation and its brain structural correlates. Participants were apolipoprotein E (APOE) ε3/ε3 homozygotes with amnestic mild cognitive impairment (aMCI). The homozygotes were chosen because APOE ε3/ε3 variant is considered "neutral" with respect to LOAD risk. The participants were stratified according to poly-T length polymorphisms at "523" into homozygous for S (S/S; n = 16), homozygous for VL (VL/VL; n = 15) TOMM40 poly-T variant, and heterozygous (S/VL; n = 28) groups. Neuropsychological examination and testing in real-space human analog of the Morris Water Maze were administered. Both self-centered (egocentric) and world-centered (allocentric) spatial navigation was assessed. Brain magnetic resonance imaging scans were analyzed using FreeSurfer software. The S/S group, although similar to S/VL and VL/VL groups in demographic and neuropsychological profiles, performed better on allocentric navigation (p ≤ 0.004) and allocentric delayed recall (p ≤ 0.014), but not on egocentric navigation. Both S/VL and VL/VL groups had thinner right entorhinal cortex (p ≤ 0.043) than the S/S group, whereas only the VL/VL group had thinner left entorhinal cortex (p = 0.043) and left posterior cingulate cortex (p = 0.024) than the S/S group. In conclusion, TOMM40 "523" VL variants are related to impairment in allocentric spatial navigation and reduced cortical thickness of specific brain regions among aMCI individuals with (LOAD neutral) APOE ε3/ε3 genotype. This may reflect a specific role of TOMM40 "523" in the pathogenesis of LOAD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.03.004DOI Listing
June 2015
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