Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer's Disease or Depressive Disorder.

BACKGROUND Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer's disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. MATERIAL AND METHODS A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. RESULTS Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ε4 allele of APOE. CONCLUSIONS Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ε4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ε4 allele.

[Psychological problems of patients who survived cardiac arrest out of hospital]. / Psychologická problematika pacientu prezivsích mimonemocnicní srdecní zástavu.

Out-of-hospital circulatory arrest is a major challenge of current medicine. Circulatory arrest survivors bear increased risk of developing anxiety disorders and depressions both during hospitalization and after discharging to the home care. Circulatory arrest survivors are not provided routinely with psychological care. Patients included in our pilot research were identified in the register of surviving circulatory arrest. The survey was carried out using a non-standardized questionnaire. A total of 28 patients surviving the circulatory arrest were included in the pilot research. The average age of respondents was 54 years. There were 20 men and 8 women. The project showed that 18 (64.3 %) people, since they went through the critical status, have suffered from negative and bothering symptoms, such as: fear of a repeated cardiac arrest, sleeping disorders, persistent tiredness etc. Despite the fact that our group of patients was relatively small and larger studies addressing the issue are needed, our finding is alarming - the patients after the cardiac arrest suffer from many anxious and depressive symptoms as well as from cognitive deficit. In the situation when the common psychological intervention by a specialist is not provided, it seems that an early psychological invention is highly desirable and may have a beneficial effect on return of the patients to their everyday life.

Plasma homocysteine in Alzheimer's disease with or without co-morbid depressive symptoms.

OBJECTIVE: Elevated homocysteine is associated with a variety of diseases, including Alzheimer's disease (AD) and depressive disorder. This study was designed to detect an association between plasma homocysteine and AD with or without co-morbid depressive symptoms. METHODS: Plasma homocysteine concentrations were measured in 85 AD patients (36 of them with depressive symptoms), 33 non-AD patients with a depression diagnosis and 44 healthy controls, all aged above 50 years. RESULTS: Positive correlation between age and homocysteine was confirmed. Significantly higher mean plasma homocysteine was found in AD patients, but not in depressive patients, when compared with controls. We confirmed significant correlation between homocysteine concentration and the degree of cognitive impairment in AD patients. There was no incremental effect of concurrent depressive symptoms on homocysteine concentration in AD patients. CONCLUSION: The association of high homocysteine with degree of cognitive impairment or stage of dementia in AD indicate potential role of high plasma homocysteine as a biomarker of the disease and/or indicator of brain damage during the progression of AD dementia.

Plasma cortisol in Alzheimer's disease with or without depressive symptoms.

BACKGROUND: Cortisol is presumed to be a risk factor for stress- and age-related disorders, such as depressive disorder and Alzheimer's disease (AD). The aim of this study was to investigate the association of plasma cortisol concentration with AD in presence or absence of comorbid depressive symptoms. MATERIAL AND METHODS: Plasma cortisol concentration was measured in 80 AD patients (35 of them with depressive symptoms), 27 elderly depressive patients without AD, and 37 elderly controls. RESULTS: Compared to controls, a significant increase of mean plasma cortisol was found in AD patients but not in depressive patients. Plasma cortisol was positively correlated with cognitive impairment in AD patients. We confirmed a U-shaped association between plasma cortisol and major depression and a linear association between plasma cortisol and AD without depressive symptoms. Significantly increased relative risk of disease in people with high plasma cortisol was found for AD with depressive symptoms and for AD with mild dementia. CONCLUSIONS: Plasma cortisol reflects the degree of cognitive impairment in AD rather than the severity of comorbid depression. We confirmed that both hypercortisolemia and hypocortisolemia are associated with depressive disorder. Significant association between high plasma cortisol and AD was found, supporting the use of high plasma cortisol as a component of a panel of biochemical markers for AD with depressive symptoms as well as AD in the early stage of dementia development.

Age-Dependent Alterations in Platelet Mitochondrial Respiration.

Mitochondrial dysfunction is an important cellular hallmark of aging and neurodegeneration. Platelets are a useful model to study the systemic manifestations of mitochondrial dysfunction. To evaluate the age dependence of mitochondrial parameters, citrate synthase activity, respiratory chain complex activity, and oxygen consumption kinetics were assessed. The effect of cognitive impairment was examined by comparing the age dependence of mitochondrial parameters in healthy individuals and those with neuropsychiatric disease. The study found a significant negative slope of age-dependence for both the activity of individual mitochondrial enzymes (citrate synthase and complex II) and parameters of mitochondrial respiration in intact platelets (routine respiration, maximum capacity of electron transport system, and respiratory rate after complex I inhibition). However, there was no significant difference in the age-related changes of mitochondrial parameters between individuals with and without cognitive impairment. These findings highlight the potential of measuring mitochondrial respiration in intact platelets as a means to assess age-related mitochondrial dysfunction. The results indicate that drugs and interventions targeting mitochondrial respiration may have the potential to slow down or eliminate certain aging and neurodegenerative processes. Mitochondrial respiration in platelets holds promise as a biomarker of aging, irrespective of the degree of cognitive impairment.

Transient psychosis due to caregiver burden in a patient caring for severely demented spouses.

OBJECTIVES: Caring for demented people has been associated with negative effect on caregiver health. One or more severe stress factors can precipitate brief reactive psychosis. METHODS: A 59-year-old Caucasian married woman with no prior psychosis has been caring for her severely demented husband for more than 3 years. She was treated for anxiety disorder and reaction to severe stress in our clinic for 1 year. RESULTS: Five days after husband's nursing home placement our patient developed the abnormal thought, that someone might tell her neighbours of her laziness and failures. She believed that she was under constant surveillance. These ideas grew rapidly into delusions and hallucinations. She was diagnosed as having transient psychosis with associated acute stress and was treated with risperidone. The psychosis lasted for two months. CONCLUSION: Careful differential diagnosis is necessary in the cases of transient psychosis. Psychotic symptoms in overloaded individuals may be more common than was previously thought.

Frequency of some psychosomatic symptoms in informal caregivers of Alzheimer's disease individuals. Prague's experience.

BACKGROUND: This study was motivated by the growth in the number of elderly with dementia and consequent need to help family caregivers who face the daily stress for long periods of time. The aim was to describe the frequency of some common psychosomatic symptoms in self-assessed health status and to determine whether there are gender differences in these symptoms and the perception of one´s own health in family caregivers. METHODS: The first results of cross-sectional survey design as the first phase of a longitudinal cohort study are presented. The participants in this investigation (n=73) were family caregivers of outpatients suffering from moderate (59 cases = 80.8%) or mild (14 cases = 19.2%) stage of Alzheimer´ s disease (AD). RESULTS: The group of caregivers consisting of 61 (83.6%) women and 12 men (16.4%). Participants of this study were recruited from the Department of Psychiatry, Prague, Czech Republic. Data from caregivers were collected by using a self-administered questionnaire containing various items to measure self-perceived health including some common psychosomatic symptoms in relationship with their caregiving role. CONCLUSIONS: The following symptoms appeared the most frequent among family caregivers: chronic fatigue and sleeping disturbances. Most caregivers of patients with moderate stage of AD evaluated their own health as poor and experienced more symptoms in comparison with caregivers of patients with mild stage of Alzheimer´s disease, who scored their own health as good or very good. A follow-up of the survey population seems to be necessary.

Clinical aspects of Alzheimer's disease.

Alzheimer's disease is a progressive, irreversible, incurable, neurodegenerative illness and the most common of the dementing disorders. It starts usually after 60 years of age and may span 8 to 12 years. The continuous and slow decline caused by this disease, is characterized by cognitive deterioration, loss of functional independence, changes in behaviour, and expanding needs for care. In the last three decades, the proteins predominating neuritic plaques and neurofibrillary tangles have been detected and researched: amyloid-beta protein in the plaques and hyperphosphorylated tau in the tangles. Alzheimer's disease is now considered a long-term process with a slow progress and with a prolonged development of pathological changes that precedes symptoms by years. AD is becoming one of the most problematic and expensive illness for the civilization, also known as "silent threat".

Activities of mitochondrial respiratory chain complexes in platelets of patients with Alzheimer's disease and depressive disorder.

We analyzed activities of complex I, II, III, and IV, and citrate synthase (CS) in patients with major depressive disorder (MDD) or Alzheimer's disease (AD) presenting with or without depression. Associations of these parameters with disease or disease severity were observed in both AD and MDD; however, mean values of mitochondrial parameters were significantly altered in AD but not in MDD. Potential mitochondrial dysfunction in MDD seems not to be caused by disturbed activity of CS or respiratory complexes. In AD, a decrease in the activity of CS and complex IV may cause mitochondrial dysfunction, whereas an increase in activities of other mitochondrial complexes or their ratios to CS may be an adaptive response. The data indicate that comorbid depression in AD is associated with increased complex II activity. The mitochondrial parameters measured can be included in the panel of biomarkers of AD.

Plasma amyloid beta levels and platelet mitochondrial respiration in patients with Alzheimer's disease.

OBJECTIVES: Altered amyloid metabolism and mitochondrial dysfunction play key roles in the development of Alzheimer's disease (AD). We asked whether an association exists between disturbed platelet mitochondrial respiration and the plasma concentrations of Aß40 and Aß42 in patients with AD. DESIGN AND METHODS: Plasma Aß40 and Aß42 concentrations and mitochondrial respiration in intact and permeabilized platelets were measured in 50 patients with AD, 15 patients with vascular dementia and 25 control subjects. A pilot longitudinal study was performed to monitor the progression of AD in a subgroup 11 patients with AD. RESULTS: The mean Aß40, Aß42 and Aß42/Aß40 levels were not significantly altered in patients with AD compared with controls. The mitochondrial respiratory rate in intact platelets was significantly reduced in patients with AD compared to controls, particularly the basal respiratory rate, maximum respiratory capacity, and respiratory reserve; however, the flux control ratio for basal respiration was increased. A correlation between the plasma Aß42 concentration and mitochondrial respiration in both intact and permeabilized platelets differs in controls and patients with AD. CONCLUSIONS: Based on our data, (1) mitochondrial respiration in intact platelets, but not the Aß level itself, may be included in a panel of biomarkers for AD; (2) dysfunctional mitochondrial respiration in platelets is not explained by changes in plasma Aß concentrations; and (3) the association between mitochondrial respiration in platelets and plasma Aß levels differs in patients with AD and controls. The results supported the hypothesis that mitochondrial dysfunction is the primary factor contributing to the development of AD.

Mitochondrial Dysfunction in Blood Platelets of Patients with Manic Episode of Bipolar Disorder.

OBJECTIVES: The bipolar affective disorder (BAD) pathophysiology is multifactorial and has not been fully clarified. METHOD: We measured selected mitochondrial parameters in peripheral blood components. The analyses were performed for patients suffering from a manic episode during remission and were compared to those performed for healthy controls. BAD was clinically evaluated using well-established diagnostic scales and questionnaires. Mitochondrial respiration was examined in intact and permeabilized blood platelets using high-resolution respirometry. The citrate synthase (CS) and electron transport system (ETS) complex (complex I, II, and IV) activities were examined in platelets. RESULTS: The CS, complex II and complex IV activities were decreased in the BAD patients, complex I activity was increased, and the ratio of complex I to CS was significantly increased. In the intact platelets, respiration after complex I inhibition and residual oxygen consumption were decreased in the BAD patients compared to the healthy controls. In the permeabilized platelets, a decreased ETS capacity was found in the BAD patients. No significant differences were found between BAD patients in mania and remission. CONCLUSION: Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. We conclude that complex I and its abnormal activity contribute to defects in cellular energy metabolism during a manic episode and that the deficiency in the complex's functioning, but not the availability of oxidative phosphorylation substrates, seems to be responsible for the decreased ETS capacity in BAD patients. The observed parameters can be further evaluated as 'trait' markers of BAD.

Disturbances of mitochondrial parameters to distinguish patients with depressive episode of bipolar disorder and major depressive disorder.

BACKGROUND: Mitochondrial dysfunctions are implicated in the pathophysiology of mood disorders. We measured and examined the following selected mitochondrial parameters: citrate synthase (CS) activity, electron transport system (ETS) complex (complexes I, II, and IV) activities, and mitochondrial respiration in blood platelets. PATIENTS AND METHODS: The analyses were performed for 24 patients suffering from a depressive episode of bipolar affective disorder (BD), compared to 68 patients with MDD and 104 healthy controls. BD and unipolar depression were clinically evaluated using well-established diagnostic scales and questionnaires. RESULTS: The CS, complex II, and complex IV activities were decreased in the depressive episode of BD patients; complex I and complex I/CS ratio were significantly increased compared to healthy controls. We observed significantly decreased complex II and CS activities in patients suffering from MDD compared to controls. Decreased respiration after complex I inhibition and increased residual respiration were found in depressive BD patients compared to controls. Physiological respiration and capacity of the ETS were decreased, and respiration after complex I inhibition was increased in MDD patients, compared to controls. Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. CONCLUSION: We can conclude that complex I and its abnormal activity contribute to the defects in cellular energy metabolism during a depressive episode of BD. The observed parameters could be used in a panel of biomarkers that could selectively distinguish BD depression from MDD and can be easily examined from blood elements.

Alzheimer's disease and blood-based biomarkers - potential contexts of use.

Alzheimer's disease (AD) is an irreversible, incurable, progressive neurodegenerative illness, where dementia symptoms gradually worsen over a number of years. The research of validated biomarkers for AD is essential to improve diagnosis and accelerate the development of new therapies. Biochemical markers including neuroimaging could facilitate diagnosis, predict AD progression from a pre-AD state of mild cognitive impairment, and be used to detect the efficacies of disease-modifying therapies. Established biomarkers of AD from cerebrospinal fluid and neuroimaging are highly accurate, but barriers to clinical implementation exist. The focus on blood-based AD biomarkers has grown exponentially during the past few decades. An ideal diagnostic test for AD should be noninvasive and easily applicable. Clinical cost-effectiveness also needs to be established.

Interplay between the APOE Genotype and Possible Plasma Biomarkers in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the ε4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders. OBJECTIVE: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD. METHOD: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls. RESULTS: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE ε4 allele, regardless of the presence of depression or the severity of dementia in AD. CONCLUSION: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.

Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy.

Exact pathophysiological mechanisms of bipolar disorder have not been sufficiently clarified. We review the evidence of mitochondrial dysfunctions on the relation between both disease and pharmacotherapy. Mitochondria produce the most of energy-rich molecules of adenosine triphosphate (ATP), apart from energy production they are involved in other functions: regulation of free radicals, antioxidant defenses, lipid peroxidation, calcium metabolism and participate in the intrinsic pathway of apoptosis. According to increasing evidence dysfunctions of mitochondria are associated with affective disorders, a hypothesis of impaired mitochondrial functions has been proposed in bipolar disorder pathogenesis. Mitochondrial DNA mutations and/or polymorphisms, impaired phospholipid metabolism and glycolytic shift, decrease in ATP production, increased oxidative stress and changes of intracellular calcium are concerned in mood disorders and effects of mood stabilizers. Recent studies have also provided data about the positive effects of chronic treatment by mood stabilizers on mitochondrial functions.

Mitochondrial Respiration in the Platelets of Patients with Alzheimer's Disease.

Mitochondrial dysfunctions significantly contribute to the pathogenesis of Alzheimer's disease (AD). Here, we studied the relationship between AD and changes in the mitochondrial rates of respiration in blood platelets, respiratory chain complexes activity, and coenzyme Q10 plasma concentrations. In intact platelets obtained from AD patients, we observed a decrease in endogenous basal respiration rates, a decrease in the maximal capacity of the electron transport system (ETS), and higher respiratory rates after inhibiting complex I of the ETS. When normalized for citrate synthase activity, rotenone inhibited respiratory rates and complex I activity was significantly altered. In permeabilized platelets, mitochondrial respiration was completely rescued by the addition of complex I substrates. The changes in mitochondrial respiratory parameters were not associated with the progression of AD except for the capacity of the ETS in permeabilized platelets. In AD, complex I activity was increased, complex IV activity was decreased, and coenzyme Q10 plasma concentrations were decreased. Our data indicate that both insufficiency in substrates entering into the oxidative phosphorylation system and functional disturbances in the ETS complex are responsible for the decrease in respiration observed in intact platelets in AD patients. Analyses of complex IV activity, the respiratory rates of intact platelets, and the capacity of the ETS in permeabilized platelets may enable the characterization of mitochondrial dysfunctions in the initial stage of AD.

GSK3ß, CREB, and BDNF in peripheral blood of patients with Alzheimer's disease and depression.

BACKGROUND: Glycogen synthase kinase-3ß (GSK3ß), cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) play critical roles in neuronal survival, synaptic plasticity and memory and participate in the pathophysiology of both depressive disorder and Alzheimer's disease (AD). METHODS: This study was designed to determine the association of GSK3ß activity, CREB activity and BDNF concentration in peripheral blood of patients with AD with or without depressive symptoms and in depressive patients without AD. GSK3ß activity in platelets, CREB activity in lymphocytes and BDNF concentration in plasma, platelet-rich plasma or platelets were measured in 85 AD patients (36 of whom displayed co-morbid depressive symptoms), 65 non-AD patients with depressive disorder and 96 healthy controls. AD patients were clinically assessed for stage of dementia, cognitive impairment and severity of depressive symptoms. Depressive patients were clinically assessed for severity of depression. RESULTS: We observed increased CREB activity and GSK3ß activity in AD with depressive symptoms or in AD at mild stage of dementia. Decreased BDNF concentration was found in platelet-rich plasma of AD patients at moderate to severe stages of dementia or in AD without depressive symptoms. An association was revealed of the severity of cognitive impairment with the increase of GSK3ß in the platelets of AD patients with mild dementia. In depressive patients, a lower concentration of phosphorylated GSK3ß was associated with a higher severity of depression. Association was confirmed between severity of depression, CREB activation, and BDNF concentration in drug-naïve depressive patients. CONCLUSION: Our data demonstrated that AD is accompanied by increased CREB activity in lymphocytes and a decreased concentration of BDNF in platelet-rich plasma. The decreased BDNF concentration appears to correlate with moderate to severe stages of dementia in AD. Observation of decreased phosphorylation of GSK3ß in platelets of both AD patients with depressive symptoms and depressive patients after treatment confirms the role of increased GSK3ß activity in the pathophysiology of both AD and depressive disorder. Associations were confirmed between AD and platelet GSK3ß activity, lymphocyte CREB activity and plasma BDNF. CREB activity and platelet BDNF concentration seems to be related to depressive disorder.

Mitochondrial respiration in blood platelets of depressive patients.

Recent evidences include mitochondrial dysfunctions in pathophysiology of mood disorders. We examined association between depressive disorders and mitochondrial respiration using both intact and permeabilized blood platelets. In intact platelets, physiological respiration, maximal capacity of electron transport system and respiratory rate after complex I inhibition were decreased in depressive patients, who reached partial remission, compared to healthy controls. Respiratory rates were unchanged in several respiratory states in permeabilized platelets. Results indicate that changes in respiratory rate in intact platelets can be used as biological marker of depressive disorder. The hypothesis that decreased mitochondrial respiratory rate participate in pathophysiology of depression was supported.