BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder where pathophysiological changes begin decades before the onset of clinical symptoms. Analysis of brain atrophy patterns using structural MRI and multivariate data analysis are an effective tool in identifying patients with subjective cognitive decline (SCD) at higher risk of progression to AD dementia. Atrophy patterns obtained from models trained to classify advanced AD versus normal subjects, may not be optimal for subjects at an early stage, like SCD. In this study, we compared the accuracy of the SCD progression prediction using the 'severity index' generated using a standard classification model trained on patients with AD dementia versus a new model trained on β-amyloid (Aβ) positive patients with amnestic mild cognitive impairment (aMCI). METHODS: We used structural MRI data of 504 patients from the Swedish BioFINDER-1 study cohort (cognitively normal (CN), Aβ-negative = 220; SCD, Aβ positive and negative = 139; aMCI, Aβ-positive = 106; AD dementia = 39). We applied multivariate data analysis to create two predictive models trained to discriminate CN individuals from either individuals with Aβ positive aMCI or AD dementia. Models were applied to individuals with SCD to classify their atrophy patterns as either high-risk "disease-like" or low-risk "CN-like". Clinical trajectory and model accuracy were evaluated using 8 years of longitudinal data. RESULTS: In predicting progression from SCD to MCI or dementia, the standard, dementia-based model, reached 100% specificity but only 10.6% sensitivity, while the new, aMCI-based model, reached 72.3% sensitivity and 60.9% specificity. The aMCI-based model was superior in predicting progression from SCD to MCI or dementia, reaching a higher receiver operating characteristic area under curve (AUC = 0.72; P = 0.037) in comparison with the dementia-based model (AUC = 0.57). CONCLUSION: When predicting conversion from SCD to MCI or dementia using structural MRI data, prediction models based on individuals with milder levels of atrophy (i.e. aMCI) may offer superior clinical value compared to standard dementia-based models.
- MeSH
- Alzheimerova nemoc diagnostické zobrazování patologie MeSH
- atrofie * patologie MeSH
- demence * diagnostické zobrazování patologie MeSH
- kognitivní dysfunkce * diagnostické zobrazování patologie diagnóza MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * metody MeSH
- mozek * patologie diagnostické zobrazování MeSH
- neuropsychologické testy MeSH
- progrese nemoci * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
INTRODUCTION: ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments. METHODS: The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test. RESULTS: The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks. CONCLUSIONS: The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04693520 .
- MeSH
- Alzheimerova nemoc * farmakoterapie diagnostické zobrazování MeSH
- amyloidní beta-protein * MeSH
- aplikace orální MeSH
- apolipoprotein E4 * genetika MeSH
- biologické markery * krev MeSH
- heterozygot MeSH
- hipokampus * účinky léků diagnostické zobrazování MeSH
- kognice * účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- peptidové fragmenty krev MeSH
- proteiny tau MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
BACKGROUND: Mild behavioral impairment (MBI) has been commonly reported in early Alzheimer's disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity. METHODS: We included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations. RESULTS: MBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared. CONCLUSIONS: MBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation.
- MeSH
- Alzheimerova nemoc * diagnostické zobrazování epidemiologie genetika MeSH
- apolipoproteiny E genetika MeSH
- genotyp MeSH
- kognitivní dysfunkce * diagnostické zobrazování epidemiologie genetika MeSH
- lidé MeSH
- mozkový neurotrofický faktor genetika MeSH
- neuropsychologické testy MeSH
- polymorfismus genetický genetika MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Objective: Alzheimer's disease (AD) is the most common neurodegenerative disease. The predominantly sporadic form of AD is age-related, but the underlying pathogenic mechanisms remain not fully understood. Current efforts to combat the disease focus on the main pathological hallmarks, in particular beta-amyloid (Aβ) plaque pathology. According to the amyloid cascade hypothesis, Aβ is the critical early initiator of AD pathogenesis. Plaque pathology is very heterogeneous, where a subset of plaques, neuritic plaques (NPs), are considered most neurotoxic rendering their in-depth characterization essential to understand Aβ pathogenicity. Methods: To delineate the chemical traits specific to NP types, we investigated senile Aβ pathology in the postmortem, human sporadic AD brain using advanced correlative biochemical imaging based on immunofluorescence (IF) microscopy and mass spectrometry imaging (MSI). Results: Immunostaining-guided MSI identified distinct Aβ signatures of NPs characterized by increased Aβ1-42(ox) and Aβ2-42. Moreover, correlation with a marker of dystrophy (reticulon 3 [RTN3]) identified key Aβ species that both delineate NPs and display association with neuritic dystrophy. Conclusion: Together, these correlative imaging data shed light on the complex biochemical architecture of NPs and associated dystrophic neurites. These in turn are obvious targets for disease-modifying treatment strategies, as well as novel biomarkers of Aβ pathogenicity.
- MeSH
- Alzheimerova nemoc * diagnostické zobrazování patologie MeSH
- amyloidní beta-protein chemie metabolismus MeSH
- amyloidní plaky diagnostické zobrazování patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek patologie MeSH
- myši transgenní MeSH
- myši MeSH
- neurodegenerativní nemoci * patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The volume reduction of the gray matter structures in patients with Alzheimer's disease is often accompanied by an asymmetric increase in the number of white matter fibers located close to these structures. The present study aims to investigate the white matter structure changes in the motor basal ganglia in Alzheimer's disease patients compared to healthy controls using diffusion tensor imaging. The amounts of tracts, tract length, tract volume, quantitative anisotropy, and general fractional anisotropy were measured in ten patients with Alzheimer's disease and ten healthy controls. A significant decrease in the number of tracts and general fractional anisotropy was found in patients with Alzheimer's disease compared to controls in the right caudate nucleus, while an increase was found in the left and the right putamen. Further, a significant decrease in the structural volume of the left and the right putamen was observed. An increase in the white matter diffusion tensor imaging parameters in patients with Alzheimer's disease was observed only in the putamen bilaterally. The right caudate showed a decrease in both the diffusion tensor imaging parameters and the volume in Alzheimer's disease patients. The right pallidum showed an increase in the diffusion tensor imaging parameters but a decrease in volume in Alzheimer's disease patients.
- MeSH
- Alzheimerova nemoc * diagnostické zobrazování MeSH
- bílá hmota * diagnostické zobrazování MeSH
- lidé MeSH
- putamen diagnostické zobrazování MeSH
- šedá hmota diagnostické zobrazování MeSH
- zobrazování difuzních tenzorů metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Úvod: Hodnocení významu vyšetření perfuze mozku pomocí jednofotonové emisní počítačové tomografie (SPECT) v diferenciální diagnostice kognitivních poruch. Metodika: Za období čtyř let byla provedena retrospektivní analýza dat vyšetřených pacientů s cílem porovnat závěry vyšetření SPECT mozku s klinickou diagnózou. 68 nemocných s klinickými diagnózami (33 pacientů s pravděpodobnou Alzheimerovou nemocí (AD – Alzheimer‘s disease), 13 s mírnou kognitivní poruchou (MCI – mild cognitive impairment) a 22 osob s jinými chorobami) bylo podle druhého čtení jejich SPECT obrazů mozku, bez klinických informací, rozděleno do 5 skupin perfuzních vzorců: obraz Alzheimerovy nemoci (AD – 19 pacientů), obraz vaskulární demence (VD – 17), obraz smíšené demence (MIX – 18), ostatní perfuzní vzorce (O – 11) a normální obraz (N – 3). Výsledky: Z 33 pacientů s klinicky pravděpodobnou AD mělo na SPECT mozku v 87 % obraz AD, u poloviny z nich byl přítomen nález MIX. U 13 s MCI byly zjištěny heterogenní vzorce mozkové perfuze odpovídající smíšené populaci jedinců s MCI. Sledováním laterality postižení na SPECT obrazech u 25 praváků byla zjištěna převaha výskytu prvních defektů perfuze temporoparietálně nebo temporálně v dominantní hemisféře u většiny pacientů s MIX nebo klinicky pravděpodobnou AD. Spolehlivost radionuklidové (RN) metody byla posuzována stanovením inter- (89 %) a intrapersonální (87 %) shody závěrů vyšetření perfuze mozku technikou SPECT. Závěr: SPECT mozku přináší, kromě podpory diagnostiky AD, další informaci o možné kombinaci s cévními mechanismy. Heterogenní vzorce odpovídají smíšené populaci jedinců s MCI.
Introduction: The importance of brain perfusion examination using single photon emission computed tomography (SPECT) in the differential diagnosis of cognitive disorders is evaluated in this study. Methods: For a period of four years a retrospective analysis of the examined patient´s data was performed in order to compare the conclusions of the brain SPECT examination with the clinical diagnosis. 68 patients with clinical diagnoses (33 patients with probable Alzheimer‘s disease (AD), 13 with mild cognitive impairment (MCI) and 22 with other diseases) were divided into 5 groups of perfusion patterns according to the second reading of their brain SPECT images without clinical information: Alzheimer‘s disease (AD – 19 patients), vascular dementia picture (VD – 17), mixed dementia picture (MIX – 18), other perfusion patterns (O – 11) and normal picture (N – 3). Results: Thirty-three patients with probable Alzheimer’s disease were studied. 87 % of them showed typical image of AD on SPECT scan and half of them showed an image of mixed type dementia. In 13 patients with MCI was found heterogeneous blood perfusion corresponding with miscellaneous population of patients with MCI. In 25 right-handed patients with the SPECT pattern suggestive of AD or MIX, temporoparietal or temporal hypoperfusion was detected in the first examination of these patients on the left in 60 %, on the right in 8 % and bilaterally in 32 % of AD patients. The reliability of the radionuclide (RN) method was assessed by determining the inter (89%) and intrapersonal (87%) agreement of the conclusions of the brain perfusion examination using the SPECT technique. Conclusion: In addition to supporting of the AD diagnosis, brain SPECT perfusion provides additional information about a possible combination with vascular mechanisms. Heterogeneous patterns correspond to a mixed population of individuals with MCI.
BACKGROUND AND OBJECTIVES: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. METHODS: The contribution of amyloid and tau pathology was assessed through CSF levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest. RESULTS: We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123). DISCUSSION: In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.
- MeSH
- Alzheimerova nemoc * diagnostické zobrazování genetika metabolismus MeSH
- amyloid metabolismus MeSH
- amyloidní beta-protein metabolismus MeSH
- amyloidogenní proteiny metabolismus MeSH
- amyloidóza * MeSH
- apolipoprotein E4 genetika MeSH
- bílá hmota * patologie MeSH
- biologické markery MeSH
- cholinergní látky MeSH
- lidé MeSH
- proteiny tau metabolismus MeSH
- senioři MeSH
- zobrazování difuzních tenzorů MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- alely MeSH
- Alzheimerova nemoc * diagnostické zobrazování genetika MeSH
- atrofie MeSH
- cholinergní látky MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- pars basalis telencephali * diagnostické zobrazování MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
White Matter Lesions (WML) are a radiological finding common in aged subjects. We explored the impact of WML on underlying neurodegenerative processes. We focused on the impact of WML on two neurodegenerative diseases with different pathology. In this cross-sectional study of 137 subjects (78 female, 59 men, mean age 67.2; 43-87 years), we compared WML in healthy controls (HC; n = 55), patients with Alzheimer's disease and amnestic Mild Cognitive Impairment (aMCI), and Parkinson's disease patients with normal cognition and with MCI. Subjects with AD and aMCI were treated as one group (n = 40), subjects with PD and PDMCI were another group (n = 42). MRI T2_FLAIR sequences were analyzed. WML were divided into periventricular (pWML) or subcortical (sWML) depending on their distance from the ventricles. Subjects from the AD + aMCI group, had a significantly greater volume of WML than both HC and the PD + PDMCI group. The volume of WML was greater in the PD + PDMCI than in HC but the difference was not significant. In AD + aMCI subjects, sWML and not pWML were related to a decrease in global cognitive functioning despite greater volume of pWML. In PD + PDMCI, pWML correlate with decline in executive functions and working memory. In HC, pWML correlated with the multidomain decrease corresponding with the aging. This points to a difference between normal aging and pathological aging due to AD and PD brain pathology. The WML location together with underlying disease related neurodegeneration may play a role in determining the effect of WML on cognition. Our results suggest that the impact of WML is not uniform in all patients; rather, their volume, location and cognitive effect may be disease-specific.
- MeSH
- Alzheimerova nemoc * komplikace diagnostické zobrazování patologie MeSH
- bílá hmota * diagnostické zobrazování patologie MeSH
- kognice MeSH
- kognitivní dysfunkce * komplikace etiologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- nemoci nervového systému * MeSH
- neuropsychologické testy MeSH
- Parkinsonova nemoc * komplikace diagnostické zobrazování patologie MeSH
- progrese nemoci MeSH
- průřezové studie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field's spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer's disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer's disease, thus holding great promise in the DBS treatment of the disease.
- MeSH
- Alzheimerova nemoc * diagnostické zobrazování terapie MeSH
- cortex entorhinalis diagnostické zobrazování fyziologie MeSH
- hluboká mozková stimulace * metody MeSH
- kognice MeSH
- krysa rodu rattus MeSH
- magnetická rezonanční tomografie metody MeSH
- mozek MeSH
- septální jádra * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
