AIMS: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. METHODS: We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). RESULTS: We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. CONCLUSIONS: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.

• MeSH
• alfa-synuklein * metabolismus   MeSH
• biologické markery metabolismus   MeSH
• chaperon endoplazmatického retikula BiP * metabolismus   MeSH
• demence s Lewyho tělísky * patologie   metabolismus   MeSH
• eukaryotický iniciační faktor 2 * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek metabolismus   patologie   MeSH
• neurotrofní faktory metabolismus   MeSH
• proteiny tepelného šoku * metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální dráha UPR * fyziologie   MeSH
• stres endoplazmatického retikula fyziologie   MeSH
• upregulace * 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

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 APOE 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-amyloid1-42 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 APOE 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.

• MeSH
• amyloidní beta-protein mozkomíšní mok   metabolismus   MeSH
• apolipoprotein E4 genetika   MeSH
• biologické markery metabolismus   MeSH
• demence s Lewyho tělísky klasifikace   komplikace   metabolismus   patofyziologie   MeSH
• fenotyp MeSH
• kognitivní dysfunkce etiologie   patofyziologie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidové fragmenty mozkomíšní mok   MeSH
• pozitronová emisní tomografie MeSH
• proteiny tau mozkomíšní mok   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory 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
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Neuropathological diagnostic criteria of neurodegenerative disorders are based on the presence of specific inclusions in a specific area of brain tissue that correlate with clinical manifestations. Concomitant neurodegenerative disorders correspond to a combination of two (or more) different fully developed diseases in the same patient. Concomitant neurodegenerative pathology represents the presence of definite neurodegeneration and deposits of pathological proteins specific for another disease, which is not, however, fully developed. Very frequent overlaps include Alzheimer's disease and alpha-synuclein inclusions. Nevertheless, careful neuropathological investigations reveal an increasing frequency of different co-pathologies in examined brains. In Alzheimer's disease, protein TDP-43 may co-aggregate, but it is not clear whether this is atypical isolated Alzheimer's disease or overlap of Alzheimer's disease with early frontotemporal lobar degeneration. Comorbidities of Alzheimer's disease and tauopathies are relatively rare. A combination of vascular pathology with primary neurodegeneration (mostly Alzheimer's disease or dementia with Lewy bodies) is historically called mixed dementia. Overlap of different neuropathologically confirmed neurodegenerations could lead to atypical and unusual clinical presentations and may be responsible for faster disease progression. Several CSF biomarkers have been evaluated for their utility in diagnostic processes in different neurodegenerative dementias; however, evidence regarding their role in neurodegenerative overlaps is still limited.

• MeSH
• alfa-synuklein metabolismus   MeSH
• Alzheimerova nemoc metabolismus   patologie   MeSH
• biologické markery metabolismus   MeSH
• demence s Lewyho tělísky metabolismus   patologie   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• lidé MeSH
• patologická konformace proteinů metabolismus   patologie   MeSH
• proteiny tau metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Visually preserved metabolism in posterior cingulate cortex relative to hypometabolism in precuneus and cuneus, the cingulate island sign, is a feature of dementia with Lewy bodies (DLB) on FDG-PET. Lower cingulate island sign ratio (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 (n = 114) included clinically probable DLB patients (n = 19), age-matched patients with probable Alzheimer's disease dementia (AD; n = 19) and matched controls (n = 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 (p <0.001). ASL-CISr correlated with FDG-CISr in DLB patients (r = 0.67; p =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 (r = -0.50; p =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.

• MeSH
• demence s Lewyho tělísky diagnostické zobrazování   metabolismus   patofyziologie   MeSH
• glukosa metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mozková kůra diagnostické zobrazování   metabolismus   patofyziologie   MeSH
• mozkový krevní oběh fyziologie   MeSH
• pozitronová emisní tomografie MeSH
• proteiny tau metabolismus   MeSH
• senioři MeSH
• spinové značení MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

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.

• MeSH
• amyloidní beta-protein metabolismus   MeSH
• anizotropie MeSH
• bílá hmota patologie   MeSH
• demence s Lewyho tělísky metabolismus   patologie   MeSH
• glukosa metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pozitronová emisní tomografie MeSH
• senioři MeSH
• týlní lalok metabolismus   MeSH
• zobrazování difuzních tenzorů metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• antiparkinsonika farmakokinetika   farmakologie   metabolismus   MeSH
• cholinesterasové inhibitory farmakokinetika   metabolismus   terapeutické užití   MeSH
• demence s Lewyho tělísky farmakoterapie   metabolismus   MeSH
• demence farmakoterapie   klasifikace   metabolismus   MeSH
• dopaminové látky farmakokinetika   metabolismus   toxicita   MeSH
• kognitivní poruchy farmakoterapie   psychologie   MeSH
• lidé MeSH
• Parkinsonova nemoc farmakoterapie   metabolismus   MeSH
• Check Tag
• lidé MeSH