Influence of Adenine-Nucleotid-Translocase-1-overexpression on the creatine- kinase-system

Einleitung: Die ANT1 spielt eine wichtige Rolle im Metabolismus eukaryontischer Zellen einerseits als Bindeglied von mitochondrialem Energieaufbau und zytosolischem –abbau, andererseits als konstitutiver Bestandteil einer die Apoptose modulierenden mitochondrialen Membranpore. In beiden Funktionen besteht eine enge Verbindung zum Enzymsystem der Kreatinkinase, das aus einer zytosolischen und einer mitochondrialen Form besteht. Die ANT1 beliefert das Kreatinkinasesystem mit den gemeinsamen Substraten Adenosin-Di- und –Tri-Phosphat (ADP und ATP). Aufgrund der engen Beziehung zwischen ANT1 und CK soll der Einfluss einer kardialen ANT1-Überexpression auf das Kreatinkinasesystem unter physiologischen und pathologischen Bedingungen analysiert werden. Methoden: Um den Einfluss der ANT1-Überexpression auf die myokardialen CKAktivitäten und ihre Isoformverteilung in der Herzmuskelzelle unter physiologischen und pathologischen Bedingungen zu bestimmen, wurden die genannten Parameter an ANT1-, REN- und doppelt-transgenen, d. h. ANT1 und Renin parallel überexprimierenden Tieren (ANT/REN) sowie an Wildtyp-Tieren gemessen und analysiert. Die Enzymaktivitäten wurden photometrisch, die Expressionsmuster elektrophoretisch bestimmt und densitometrisch ausgewertet. Für die Analysen wurden parametrische und nicht-parametrische Tests verwendet. Bei normalverteilten Standardfehlern wurde nach dem t-Test, bei nicht normalverteilten nach dem Mann-Whitney-U-Test gerechnet. Ergebnisse: Bei Vergleich der ANT1-transgenen Tiere mit der Kontrollgruppe zeigt sich kein signifikanter Unterschied in der Aktivität des Kreatinkinasesystems, die Enzymaktivitäten der REN-Tiere sind dagegen signifikant erniedrigt. Die doppelttransgenen Tiere zeigen dagegen dem Wildtyp angeglichene CK- Aktivitäten, ein signifikanter Unterschied besteht nicht. Schlussfolgerung: Eine erhöhte Expression der ANT1, die in Energiestoffwechsel und Apoptose eine zentrale Rolle spielt, beeinflusst die Aktivität des CK-Systems unter pathologischen Bedingungen günstig. Erniedrigte CK-Aktivitäten an einfach transgenen REN-Tieren konnten durch gleichzeitige Überexpression der ANT1 in doppelt-transgenen ANT/REN-Tieren soweit ausgeglichen werden, dass kein signifikanter Unterschied in der CK-Aktivität gegenüber dem Wildtyp beobachtet werden konnte. Diese Ergebnisse sprechen für eine kardioprotektive Wirkung der ANT1-Überexpression.The ANT1 plays a key role in eucaryontic metabolism on the one hand as a link between mitochondrial energy-production and cytosolic –consumption, on the other hand as a constitutive part of a pore, located in the inner mitochondrial membrane, modulating apoptosis. In either function the ANT1 is tightly connected to the enzymatic system of the Creatine-Kinase, that consists of a cytosolic and a mitochondrial form. The ANT1 delivers ATP to the mitochondrial form and accepts ADP from the cytosolic form. Due to the apparently close relationship the influence of a cardiac ANT1-overexpression on the CK-system shall be investigated under physiological and pathological conditions. Methods: To investigate the influence of a cardiac ANT1-overexpression on the CK-system under physiological and pathological conditions, the activities of the enzymes were measured on ANT1-, REN-, and double-transgenic (ANT/REN) rats and compared to those of genetically unaltered controls. The enzymatic activities were assessed photometrically, the patterns of expression densitometrically. Tests used are parametric and non-parametric, if Gaussian distribution of standard error was given t-test, if not Mann-Whitney-U-test. Results: Compared to that of controls, the activity of the CK-system was significantly lower in the REN-group, no significant difference could be seen in the ANT/REN-group. Conclusion: Overexpression of ANT1 has an advantageous influence on the activity of the CK-system under pathological conditions. Lowered enzymatic activities in the REN-group were compensated under simultaneous overexpression of ANT1 in the ANT/REN-group, so that no significant difference could be seen compared to controls. These results hint to a cardioprotective effect of ANT1-overexpression

Impact of myocardial inflammation on cytosolic and mitochondrial creatine kinase activity and expression.

International audienceThe disturbance of myocardial energy metabolism has been discussed as contributing to the progression of heart failure. Little however is known about the cardiac mitochondrial/cytosolic energy transfer in murine and human inflammatory heart disease. We examined the myocardial creatine kinase (CK) system, which connects mitochondrial ATP-producing and cytosolic ATP-consuming processes and is thus of central importance to the cellular energy homeostasis. The time course of expression and enzymatic activity of mitochondrial (mtCK) and cytosolic CK (cytCK) was investigated in Coxsackievirus B3 (CVB3)-infected SWR mice, which are susceptible to the development of chronic myocarditis. In addition, cytCK activity and isoform expression were analyzed in biopsies from patients with chronic inflammatory heart disease (n = 22). Cardiac CVB3 titer in CVB3-infected mice reached its maximum at 4 days post-infection (pi) and became undetectable at 28 days pi; cardiac inflammation cumulated 14 days pi but persisted through the 28-day survey. MtCK enzymatic activity was reduced by 40% without a concurrent decrease in mtCK protein during early and acute MC. Impaired mtCK activity was correlated with virus replication and increased level of interleukine 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and elevated catalase expression, a marker for intracellular oxidative stress. A reduction in cytCK activity of 48% was observed at day 14 pi and persisted to day 28 pi. This restriction was caused by a decrease in cytCK subunit expression but also by direct inhibition of specific cytCK activity. CytCK activity and expression were also reduced in myocardial biopsies from enterovirus genome-negative patients with inflammatory heart disease. The decrease in cytCK activity correlated with the number of infiltrating macrophages. Thus, viral infection and myocardial inflammation significantly influence the myocardial CK system via restriction of specific CK activity and down-regulation of cytCK protein. These changes may contribute to the progression of chronic inflammatory heart disease and malfunction of the heart

Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as “predementia AD with depression”

Brain Morphometric Correlates of Depressive Symptoms among Patients with and without Dementia

Introduction: Findings regarding brain morphometry among patients with dementia and concomitant depressive symptoms have been inconsistent. Thus, the aim of the present study was to test the hypothesis that dementia and concomitant depressive symptoms are associated with structural brain changes in the temporal lobe measured with structural magnetic resonance imaging (MRI). Methods: A sample of 492 patients from Norwegian memory clinics (n = 363) and Old Age Psychiatry services (n = 129) was studied. The assessment included the Cornell Scale for Depression in Dementia (CSDD), Instrumental Activities of Daily Living Scale, Mini Mental State Examination, and MRI of the brain, processed with FreeSurfer to derive ROI measures of cortical thickness, volume, and area using the Desikan-Killiany parcellation, as well as subcortical volumes. Dementia was diagnosed according to ICD-10 research criteria. Correlates of brain morphometry using multiple linear regression were examined. Results: Higher scores on the CSDD were associated with larger cortical volume (β = 0.125; p value = 0.003) and area of the left isthmus of the cingulate gyrus (β = 0.151; p value = &#x3c;0.001) across all patients. Inclusion of an interaction term (dementia × CSDD) revealed a smaller area in the left temporal pole (β = −0.345; p value = 0.001) and right-transverse temporal cortex (β = −0.321; p value = 0.001) in patients with dementia and depressive symptoms. Discussion/Conclusion: We confirm the previous findings of structural brain changes in temporal regions among patients with dementia and concomitant depressive symptoms. This may contribute to a better understanding of the mechanisms underlying depression in dementia. To the best of our knowledge, this is the largest study conducted on this topic to date

Brain Morphometric Correlates of Depressive Symptoms among Patients with and without Dementia

Introduction: Findings regarding brain morphometry among patients with dementia and concomitant depressive symptoms have been inconsistent. Thus, the aim of the present study was to test the hypothesis that dementia and concomitant depressive symptoms are associated with structural brain changes in the temporal lobe measured with structural magnetic resonance imaging (MRI). Methods: A sample of 492 patients from Norwegian memory clinics (n = 363) and Old Age Psychiatry services (n = 129) was studied. The assessment included the Cornell Scale for Depression in Dementia (CSDD), Instrumental Activities of Daily Living Scale, Mini Mental State Examination, and MRI of the brain, processed with FreeSurfer to derive ROI measures of cortical thickness, volume, and area using the Desikan-Killiany parcellation, as well as subcortical volumes. Dementia was diagnosed according to ICD-10 research criteria. Correlates of brain morphometry using multiple linear regression were examined. Results: Higher scores on the CSDD were associated with larger cortical volume (β = 0.125; p value = 0.003) and area of the left isthmus of the cingulate gyrus (β = 0.151; p value = <0.001) across all patients. Inclusion of an interaction term (dementia × CSDD) revealed a smaller area in the left temporal pole (β = −0.345; p value = 0.001) and right-transverse temporal cortex (β = −0.321; p value = 0.001) in patients with dementia and depressive symptoms. Discussion/Conclusion: We confirm the previous findings of structural brain changes in temporal regions among patients with dementia and concomitant depressive symptoms. This may contribute to a better understanding of the mechanisms underlying depression in dementia. To the best of our knowledge, this is the largest study conducted on this topic to date

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment and Alzheimer's disease with dementia

We present associations between neuropsychiatric symptoms (NPS) and brain morphology in a large sample of patients with mild cognitive impairment (MCI) and Alzheimer's disease with dementia (AD dementia). Several studies assessed NPS factor structure in MCI and AD dementia, but we know of no study that tested for associations between NPS factors and brain morphology. The use of factor scores increases parsimony and power. For transparency, we performed an additional analysis with selected Neuropsychiatric Inventory - Questionnaire (NPI-Q) items. Including regional cortical thickness, cortical and subcortical volumes, we examined associations between NPS and brain morphology across the whole brain in an unbiased fashion. We reported both statistical significance and effect sizes, using linear models adjusted for multiple comparisons by false discovery rate (FDR). Moreover, we included an interaction term for diagnosis and could thereby compare associations of NPS and brain morphology between MCI and AD dementia. We found an association between the factor elation and thicker right anterior cingulate cortex across MCI and AD dementia. Associations between the factors depression to thickness of the banks of the left superior temporal sulcus and psychosis to the left post-central volume depended on diagnosis: in MCI these associations were positive, in AD dementia negative. Our findings indicate that NPS in MCI and AD dementia are not exclusively associated with atrophy and support previous findings of associations between NPS and mainly frontotemporal brain structures.Objectives: Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and Alzheimer's disease with dementia (AD dementia), but their brain structural correlates are unknown. We tested for associations between NPS and MRI-based cortical and subcortical morphometry in patients with MCI and AD dementia. Design: Cross-sectional. Settings: Conducted in Norway. Participants: Patients with MCI (n = 102) and AD dementia (n = 133) from the Memory Clinic and the Geriatric Psychiatry Unit at Oslo University Hospital. Measurements: Neuropsychiatric Inventory - Questionnaire (NPI-Q) severity indices were reduced using principal component analysis (PCA) and tested for associations with 170 MRI features using linear models and false discovery rate (FDR) adjustment. We also tested for differences between groups. For transparency, we added analyses with selected NPI-Q items. Results: PCA revealed four factors: elation, psychosis, depression, and motor behavior. FDR adjustment revealed a significant positive association (B = 0.20, p(FDR) < 0.005) between elation and thickness of the right caudal anterior cingulate cortex (ACC) across groups, and significant interactions between diagnosis and psychosis (B = -0.48, p(FDR) < 0.0010) on the left post-central volume and between diagnosis and depression (B = -0.40, p(FDR) < 0.005) on the thickness of the banks of the left superior temporal sulcus. Associations of apathy, anxiety, and nighttime behavior to the left temporal lobe were replicated. Conclusions: The positive association between elation and ACC thickness suggests that mechanisms other than atrophy underly elation. Interactions between diagnosis and NPS on MRI features suggest different mechanisms of NPS in our MCI and AD dementia samples. The results contribute to a better understanding of NPS brain mechanisms in MCI and AD dementia