Alzheimer's disease and type 2 diabetes: the association study of polymorphisms in tumor necrosis factor-alpha and apolipoprotein E genes.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two progressive disorders with high prevalence worldwide. Polymorphisms in tumor necrosis factor-alpha (TNF-α) and apolipoprotein E (ApoE) genes might be associated with both T2D and AD, representing possible genetic markers for the development of the AD in subjects with T2D. The aim was to determine ApoE and G-308A TNF-α gene polymorphisms in unrelated Croatian Caucasians: 207 patients with sporadic AD, 196 T2D patients and 456 healthy controls. Patients with AD had higher frequency of ApoE4 allele compared to T2D patients and controls. The significant association, observed between ApoE2 allele and T2D, disappeared after the data were adjusted for age and sex. The genotype or allele frequencies of G-308A TNF-α gene polymorphism were similar among the patients with AD, T2D and healthy controls. In conclusion, these results do not support the hypothesis that the A allele of G-308A TNF-α gene polymorphism is associated either with AD or T2D. Our data confirm the association between the ApoE4 allele and AD, and point out the E2 allele of ApoE gene as the possible risk factor for T2D.

Serum lipid levels in patients with Alzheimer's disease.

The role of lipids in the aetiology and progress of Alzheimer's disease (AD) is still unclear High lipid levels could be one of the risk factors for AD, but no association or even protective effects of high cholesterol levels in the development of the AD were also found. The aim of the study was to determine serum levels of total cholesterol, high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C) and triglycerides (TG) in female patients with AD and in healthy elderly controls. The 50 patients met the diagnostic criteria of probable AD according to the NINDS-ADRDA and DSM-IV criteria. Cognitive impairment was evaluated using the Mini Mental State Examination (MMSE). Patients were subdivided into two groups of 19 patients in the middle (MMSE 10-19) and 31 patients in the late (MMSE 0-9) phase ofAD. Psychotic and non-psychotic features, evaluated by means of Neuropsychiatric Inventory, were presented in 13 and 37patients with AD, respectively. Control group consisted of 58 subjects without cognitive impairment (MMSE >27) and with lipid levels within normal range. Serum lipid levels were determined by the enzymatic colour tests and by the enzymatic clearance assay. Significantly lower lipid levels were found in patients with AD, than in controls. Patients in the late phase of AD had significantly lower entire lipid profile than controls and significantly lower cholesterol and LDL-C levels than patients in the middle stage ofAD. There was no difference in lipid levels between patients with and without psychotic features. The significant positive correlations were found between MMSE scores and cholesterol, LDL-C levels and age in all AD patients. The results support the presumption that lipid profile might be connected with the aetiology and progress of AD and showed the association between low serum cholesterol and LDL-C levels and cognitive decline in patients with AD. Further studies are needed to confirm the relationship between lipid levels and cognition, and to validate the lipid profile as a biological marker for the progress of AD.

How do we treat people with dementia in Croatia.

The current clinical view on pharmacological treatment and the Croatian reality regarding approved antidementia drugs is presented. Dementia is a syndrome of high incidence and Alzheimer's disease is the most common cause of dementia. New data show that dementia prevalence will nearly double every 20 years, and we believe that current estimated number of persons with dementia (PWD) for Croatia is more than 80,000. The standard treatment with antidementia drugs is unavailable in Croatia, for the majority of PWD, because antidementia drugs are not on the reimbursement list, although Croatian algorithm for psychopharmacological treatment and Alzheimer Disease Societies Croatia recommend early and adequate treatment. Alzheimer's dementia is becoming a world's health priority in 21st century, so we strongly believe that antidementia drugs should be reimbursed in Croatia.

Cognitive impairment and general anaesthesia - Case report.

Degeneration of cholinergic receptors causes memory disorders and irreversible impairment in cognitive functions, whose advancement can lead to clinically recognizable Alzheimer's disease (AD). Very often, the first symptoms of AD are mood swings and hence depression should be excluded by differential diagnosis since it can also cause memory disorders and cognitive deficits. Due to the characteristic clinical picture of AD, its diagnosis should not be a problem, except at the very beginning of the disease. Many AD patients are never diagnosed and therefore are not adequately treated in clinical practice. Agents used for general anaesthesia reduce cholinergic transmission, which is manifested by loss of consciousness, pain, voluntary movements and memory. In patients with compromised memory and cognitive functionality, general anaesthesia can postoperatively have an adverse effect on the prognosis of degenerative cerebral disease. A patient is described whose preoperative impaired memory and cognitive functioning deteriorated after general anaesthesia and whose clinical picture reached the extent of AD.

Infection or idiosyncratic reaction to antiepileptic drugs?

Idiosyncratic reactions are serious, unpredicted adverse effects of antiepileptic drugs which are in use in psychiatry as mood stabilizers. Severe idiosyncratic reactions can manifest as systemic symptoms or Dress syndrome clinically manifested with increased body temperature, peripheral lymphadenopathy and potential one or multiple organ failure. We present a 36 years old patient, who was hospitalized for the first time in our hospital after he attempted suicide by hanging. Patient was diagnosed as Bipolar affective disorder, current episode depressive with psychotic features and high suicidal risk. At the time of admission he was taking olanzapine and venlafaxine. Psychopharmacs were cross titrated to clozapine, valproic acid and lamotrigine. Two weeks later, patient's mood was stabilized but his somatic status worsened dramatically. He was forwarded to Clinic for Infective Diseases where he was diagnosed with severe sepsis. Dress syndrome, although initially suspected was not verified, but has to be taken into consideration in each patient prescribed with antiepileptic drugs.

Venlafaxine - quetiapine combination in the treatment of complicated clinical picture of enduring personality changes following PTSD in comorbidity with psychotic depression.

PTSD is a complex disorder, which frequently occurs in comorbidity with anxious disorder, personality disorder, addiction or substance abuse disorder, depressive disorder with or without psychotic symptoms and psychotic disorder. PTSD symptoms may result from deregulation of several different neurotransmitter systems. Pharmacotherapy of PTSD depends on clinical features and the presence of comorbid disorders. Pharmacotherapy of PTSD involves use of anxiolytics, adrenergic receptor antagonists, antidepressants, anticonvulsants and novel antipsychotics. Serotoninergic effect of antidepressants is not only effective in treating depression, but also appears to be helpful in PTSD treatment, particularly in reduction of intrusive symptoms, emotional reactivity, impulsiveness, aggression and suicidal ideation. Anypsychotics with serotoninergic-dopaminergic antagonism are being prescribed often in treatment of psychotic depression, while in PTSD treatment they are proved to be efficient in relieving intrusive symptoms and nightmares. Quetiapine as serotoninergic-dopaminergic antagonist is efficient in treatment of chronic insomnia as well as in reduction of aggressiveness. Considering PTSD refractoriness to therapy, high incidence of comorbidity and significant functional impairment, it is important to search for new psychopharmacological combinations in order to improve mental status of the patient. The paper presents 46 years old male patient with the diagnosis of Enduring personality changes following war PTSD (F62.0) in comorbidity with Recurrent depressive disorder with psychotic symptoms (F33.3), who was treated with combination of venlafaxine and quetiapine.

Suicidality and side effects of antidepressants and antipsychotics.

Antidepressants and antipsychotics can cause side effects in various organs and organic systems, and some (and) in the central nervous system, which can also be clinically manifested by suicidal behavior as well. Tricyclic antidepressants particularly of imipramine and clomipramine can have pro-suicidal effect, which is believed to be the consequence of their own hypothetic asynchronous cognitive-psychomotor pharmacodynamic action. Antidepressants from the group of selective serotonin reuptake inhibitors can at the beginning of administration as monotherapy also have pro-suicidal effects in patients with hints of suicidality or suicidal behavior, by increasing the intensity of already present suicidal predictors, such as dysphoria, anxiety, impulsiveness, agitation etc. Antipsychotics can act stimulatingly upon predictors of suicidal behavior, that is, pro-suicidal in an indirect way through side effects they cause indirect pro-suicidal neurological and consecutive psychological impact, as it is called. It is particularly valid for classic antipsychotics causing primarily neurological, i.e. extrapyramidal side effects, along which consecutive psychological side effects can occur as well. However, new antipsychotics in comparison to classic ones, have less pronounced neurological, extrapyramidal symptoms and signs but more somatic-metabolic side effects, and thereby their action can be mostly manifested as indirect pro-suicidal neurological and somatic-metabolic as well as consecutive psychological activity.

Side effects of approved antidementives.

The aim of this review is to describe side effects of five antidementives which are approved by the United States Food and Drug Administration (FDA); four acetylcholinesterase inhibitors and one glutamate - or N-metyl-D-aspartat receptor antagonist - memantine. The antidementives are well tolerated and undesired effects are rare; except hepatotoxicity of tacrine and gastrointestinal side effects of donepezil, rivastigmine, galantamin and tacrine that result from acetylcholinesterase inhibition. Nausea, diarrhea, vomiting, and weight loss are the most common side effects of the acetylcholinesterase inhibitors. Significant cholinergic side effects can occur in patients receiving higher doses; often they are related to the rate of initial titration of medication. Memantine is the first noncholinesterase inhibitor indicated for Alzheimer's disease. The side effects which may occur during the treatment with memantine are constipation, dizziness, headache and confusion. These effects if appears are mild end transient.

Involuntary emotional expression disorder in Alzheimer's disease - psychopharmacotherapy aspects.

Involuntary emotional expression disorder (IEED) is syndrome characterized with relatively stereotypical episodes of uncontrollable crying and/or laughing. Additionally, this syndrome can include irritability, anger and frustration. This syndrome is common among a number of neurologic diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer's disease (AD), and motor disorders such as Parkinson's disease (PD). IEED is very common but misdiagnosed and consequently undertreated. Prevalence of IEED in AD is between 15-39%. Recent controlled clinical studies suggest that dextromethorphan (DM) and quinidine (Q) is an effective treatment for IEED. United States Food and Drug Administration (FDA) has accepted for filing and review its New Drug Application (NDA) for Zenvia (dextromethorphan hydrobromide and quinidine sulfate capsules) for the treatment of IEED. In Republic of Croatia current treatment involves antidepressants (tricyclic and selective serotonin reuptake inhibitors), antipsychotic agents, anxiolytics, antidementives and mood stabilizers. New promising treatment can reduce the frequency of episodes and improve the quality of life of patients and their families and caregivers.

Platelet serotonin and monoamine oxidase in Alzheimer's disease with psychotic features.

Post mortem brain studies indicate that alterations in serotonergic and catecholaminergic systems might be associated with Alzheimer's disease (AD). The aim of the study was to determine serotonin (5-HT) levels and monoamine oxidase type B (MAO-B) activity in platelets of psychotic and non-psychotic patients with AD, established according to the NINCDS-ADRDA and DSM-IV-TR criteria. Cognitive impairment and psychotic features were evaluated using Mini Mental Status Examination and Neuropsychiatric Inventory. Platelet 5-HT concentration and MAO-B activity were determined spectrofluorimetrically in 116 (51 male, 65 female) healthy subjects and 70 psychotic (10 male, 60 female) and 151 non-psychotic (32 male, 119 female) patients. Psychotic and non-psychotic female and psychotic male patients had significantly lower platelet 5-HT concentration than corresponding sex matched control subjects. Platelet MAO-B activity was significantly increased in both male and female non-psychotic patients compared to the sex matched controls. Non-psychotic female patients had significantly higher platelet MAO-B activity than psychotic female patients. Our data suggest that platelet MAO-B activity, but not platelet 5-HT concentration, could differentiate between psychotic and non-psychotic subtypes of AD.

Involuntary emotional expression disorder - new/old disease in psychiatry and neurology.

Involuntary emotional expression disorder (IEED) is underrecognized by clinicians, misdiagnosed as depression or bipolar disorder and undertreated, because clinicians are unfamiliar with the disorder. An important clinical consideration for IEED is that of distinguishing mood from affect. IEED describes a syndrome of relatively stereotypical episodes of uncontrollable crying and/or laughing, resulting from lesions of multiple types, in multiple brain regions, without an apparent stimulus to trigger such responses. This syndrome is common among a number of neurological diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer;s disease (AD), and motor disorders such as Parkinson;s disease (PD). The neuropathological cause and neurochemistry of the disorder remains unclear. There is general agreement that IEED is the result of an injury to the neurological pathways that control the expression of emotions. Adequate treatment can reduce the frequency and improve the quality of life of patients and caregivers.

Genotype-independent decrease in plasma dopamine beta-hydroxylase activity in Alzheimer's disease.

The noradrenergic system is involved in the etiology and progression of Alzheimer's disease (AD) but its role is still unclear. Dopamine beta-hydroxylase (DBH) as a catecholamine-synthesizing enzyme plays a central role in noradrenaline (NA) synthesis and turnover. Plasma DBH (pDBH) activity shows wide inheritable interindividual variability that is under genetic control. The aim of this study was to determine pDBH activity, DBH (C-970T; rs1611115) and DBH (C1603T; rs6271) gene polymorphisms in 207 patients with AD and in 90 healthy age-matched controls. Plasma DBH activity was lower, particularly in the early stage of AD, compared to values in middle and late stages of the disease, as well as to control values. Two-way ANOVA revealed significant effect of both diagnosis and DBH (C-970T) or DBH (C1603T) genotypes on pDBH activity, but without significant diagnosis×genotype interaction. No association was found between AD and DBH C-970T (OR=1.08, 95% CI 1.13-4.37; p=0.779) and C1603T (OR=0.89; 95% CI 0.36-2.20; p=0.814) genotypes controlled for age, gender, and ApoE4 allele. The decrease in pDBH activity, found in early phase of AD suggests that alterations in DBH activity represent a compensatory mechanism for the loss of noradrenergic neurons, and that treatment with selective NA reuptake inhibitors may be indicated in early stages of AD to compensate for loss of noradrenergic activity in the locus coeruleus.

Brain derived neurotrophic factor Val66Met polymorphism and psychotic symptoms in Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder with a high prevalence. Since behavioral disturbances, such as psychotic symptoms, represent a key feature of AD, genes related to dopamine, serotonin and brain derived neurotrophic factor (BDNF), are considered as candidate genes for AD. BDNF is a neurotrophin that regulates neurodevelopment, neuroplasticity, and neuronal functions. BDNF is involved in the etiopathogenesis of psychiatric and neurodegenerative disorders. A single base pair polymorphism (BDNF Val66Met) was reported to be associated with AD and/or schizophrenia, as well as other psychoses, although some studies failed to replicate these findings. The aim of the study was to evaluate the association between BDNF Val66Met variants and AD, as well as onset of AD or presence of psychotic symptoms in AD. METHOD: BDNF Val66Met was analyzed in 211 patients with AD and in 402 aged healthy control subjects. All subjects were ethnically homogenous Caucasians from Croatia, and were subdivided according to the gender, onset of AD, and presence of psychotic symptoms. A χ(2) test, with Bonferroni correction and standardized residuals were used to evaluate the data. RESULTS: Distribution of the BDNF Val66Met genotypes differed significantly between male and female AD patients with or without psychotic symptoms. This difference was due to the significant contribution of the Met/Val genotype and the combined Met/Met and Met/Val genotypes between psychotic and non-psychotic symptoms in male, but not in female patients with AD. The frequency of the gene variants of the BDNF Val66Met did not differ significantly among male and female patients with AD and control subjects, or between male and female patients with early or late onset AD. There were significant sex related differences in age, duration of illness and scores of dementia between patients with AD. CONCLUSION: Our male patients were younger, had shorter duration of illness, and had less severe dementia and higher cognitive performance than female AD patients. The gene variants of the BDNF Val66Met polymorphism were significantly associated with the presence of psychotic symptoms in male, but not in female patients with AD. The results had adequate statistical power to suggest that BDNF Val66Met was not related to susceptibility to AD or the onset of AD, but that presence of one or two Met alleles of BDNF Val66Met polymorphism might present a risk factor for psychosis in AD.

No association between histamine N-methyltransferase functional polymorphism Thr105Ile and Alzheimer's disease.

Several abnormalities, including lower histamine levels in brain, elevated serum histamine and degeneration of histaminergic neurons in tuberomammillary nucleus, were described in the histaminergic system of patients with Alzheimer's disease (AD). Histamine is a central neurotransmitter with several functions in brain including regulation of memory, cognition, locomotion, and is degraded in part by histamine N-methyltransferase (HNMT). A common Thr105Ile polymorphism within HNMT gene results in decreased enzyme activity. The Thr105Ile polymorphism was associated with Parkinson's disease, essential tremor, attention-deficit hyperactivity disorder (ADHD), asthma and alcoholism, thus we tested possible association of HNMT functional polymorphism with AD. We have tested 256 AD cases and 1190 healthy controls of Croatian origin. Thr105Ile polymorphism was determined by TaqMan RT-PCR Genotyping Assay and EcoRV digestion. Prevalence of functional HNMT polymorphism among all tested groups was similar and frequency of less active Ile105 variant was 11.5% among AD patients and 13.4% for healthy controls (p=0.26, X(2)=1.25). Our results indicate lack of the association of HNMT Thr105Ile functional polymorphism with Alzheimer's disease.

Current treatment options for people with Alzheimer's disease in Croatia.

About 16% of the population in Croatia is older than 65 years. Croatia has no register of persons with dementia (PWD), but based on a calculation that 10% of persons over 65 years are affected by dementia, the approximate number of PWD would be 80,000, the majority being patients with Alzheimer's disease (AD). Psychogeriatric departments exist in hospitals, but there are almost no nursing homes and an insufficient number of daily care centres for PWD. Antidementia drugs registered in Croatia are donepezil, rivastigmine and memantine. Clinical studies of new antidementia drugs have been conducted in Croatia since 1989. At present, studies of several antidementia drugs are underway at different testing stages.

Platelet serotonin concentration and monoamine oxidase type B activity in female patients in early, middle and late phase of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder with unclear aetiology. Cognitive impairment in AD might be associated with altered serotonergic system. The aim of the study was to determine platelet serotonin (5-HT) concentrations and platelet monoamine oxidase type B (MAO-B) activity in patients with different severity of AD. Platelet 5-HT concentrations and MAO-B activity were determined spectrofluorimetrically in 74 female patients with AD (NINCDS-ADRDA, DSM-IV-TR criteria), subdivided according to the Mini Mental State Examination (MMSE) scores in three groups with a) 23 patients in early (MMSE scores 19-24), b) 23 patients in middle (MMSE 10-18), and c) 28 patients in late (MMSE 0-9) phase of AD, and in 49 age-matched healthy women. Platelet 5-HT concentrations and MAO-B activity were similar between all patients with AD and healthy subjects, but were significantly lower in patients in the late phase of AD than in other phases of AD, and in healthy controls. The significant correlations were found between MMSE scores and platelet 5-HT concentrations, MAO-B activity and age. Lower platelet 5-HT concentration and MAO-B activity in the late phase of AD suggested that these markers might indicate severity and/or clinical progress of AD.