[Show abstract][Hide abstract] ABSTRACT: Epigenetics (i.e. DNA methylation) together with the environmental and genetic factors are the key to understanding the pathogenesis of many diseases including dementia. Disturbances in DNA methylation have been already implicated in dementia. Homocysteine metabolism, with folate and vitamin B12 as essential cofactors, is integral to methylation processes. We evaluated the association of global DNA methylation, homocysteine, folate and B12 status with dementia. Selected polymorphisms of genes previously associated with dementia development and the influence of various factors on DNA methylation were also investigated. 102 patients with dementia (53 with Alzheimer’s disease, 17 with vascular dementia and 32 with mixed dementia) were recruited. The control group consisted of 45 age-matched subjects without dementia and 46 individuals with mild cognitive impairment. Global DNA methylation was determined by Imprint Methylated DNA Quantifcation Kit (Sigma-Aldrich). Serum homocysteine, folate, B12, creatinine, fasting glucose were determined by standard methods. Plasma and erythrocyte 5-methyltetrahydrofolate and plasma methylmalonic acid (markers of folate and B12 status) were measured by HPLC. APOE, PON1 p.Q192R, MTHFR c.677C > T and IL1B-511C > T polymorphisms were identified using PCR-RFLP.
Subjects with dementia had significantly higher homocysteine (p = 0.012) and methylmalonic acid (p = 0.016) and lower folate (p = 0.002) and plasma 5-methyltetrahydrofolate (p = 0.005) than controls. There was no difference in DNA methylation between patients and controls. A tendency to higher DNA methylation in patients with vascular dementia (p = 0.061) was noted. Multivariate regression analysis of the whole group of investigated individuals demonstrated significant associations between DNA methylation and folate (p = 0.003), erythrocyte 5-methyltetrahydrofolate (p = 0.036), creatinine (p = 0.003) and glucose (p = 0.007) concentrations and IL1B-511C > T (p = 0.002) and PON1 p.Q192R (p = 0.044) genotypes. The association with MTHFR c.677C > T was significant only in controls (p = 0.017). The biochemical results showed significantly lower folate and B12 status in demented patients than controls. Global DNA methylation was associated with markers of folate status, creatinine, glucose and PON1 and IL1B polymorphisms.
[Show abstract][Hide abstract] ABSTRACT: AimsSelisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers.Methods
This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers.ResultsSelisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen.Conclusions
Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.
No preview · Article · Sep 2014 · British Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Background The homozygosity for CAG expansion is a very rare finding in HD patients. It is assumed, that homozygous cases show similar age at onset in comparison to the heterozygotes with the same expansion length but the disease progression seems to be more rapid with pronounced psychiatric symptoms, probably due to wider neuronal degeneration. We present the clinical course of two HD patients harbouring two mutant alleles, diagnosed in the Institute of Psychiatry and Neurology (IPN), Warsaw, Poland.
Case history Two patients were clinically and genetically evaluated while being enrolled into the REGISTRY EHDN project. They showed different clinical presentation and course of the disease.
The first subject (28 y.o.) with 38 and 63 CAG repeats presented with juvenile HD phenotype. Symptoms began at age of 12, with rapid development of dystonia and rigidity (Baseline TMS 74), the presence of epileptic seizures, cognitive impairment, severe irritability and obsessive-compulsive disorder.
The second patient (44 y.o.) with 40 and 42 CAG repeats showed first symptoms at the age of 40. Until now the patient is affected with a mild motor symptoms (TMS 23). The depression with suicidal ideations and psychotic symptoms (delusions) seem to be the most important clinical problem. The rate of decline of cognitive abilities is not different from these observed in heterozygous patients.
Conclusions Our study on two homozygous HD cases revealed, that the clinical course of motor symptoms in them does not differ significantly from the relevant cohorts of heterozygotic subjects. However, it confirmed suggestions from other reports that the psychiatric component of HD clinical presentation may be more severe in homozygous subjects.
No preview · Article · Sep 2014 · Journal of Neurology Neurosurgery & Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Objective Studies of TCS report changes of the echotexture of mesencephalic raphe in patients with major depression and depressive symptoms in some neurodegenerative disorders (Parkinson’s disease (PD), Wilson’s disease (WD)). The aim of this study was to test the usefulness of TCS in diagnosing of patients with genetically confirmed HD and concomitant psychiatric disorder. It is well established that the presence of reduced nucleus raphe echogenicity correlates with signs of depression in patients with affective as well as neurodegenerative disorders (Walter et al., 2010). TCS may be helpful in selection of the patients at risk of depression and can be useful in monitoring and management of HD patients.
Methods TCS was performed in 55 patients with HD. The neurological and psychiatric examination was performed using the battery of tests Unified Huntington’s Disease Rating Scale (UHDRS motor, behavioural and cognitive), PBA-s (Problem Behaviours Assessment-Short), PBA-HD and HADS-SIS (Hospital Anxiety and Depression Scale combined with the Snaith Irritability Scale), the Hamilton Rating Scale for Depression, the Beck Depression Inventory and the Marin’s Apathy Evaluation Scale (AES).
Results Hypoechogenicity of raphe nucleus was found in 80% of patients with depression (16/20), 22% of patients with irritability (2/9), 30% of patients with OCD (3/10 number) and 12,5% of patients without present or past history of psychiatric disturbances (2/16).
Another finding, hyperechogenic substantia nigra was visualised in 45% and hyperechogenicity of lentiform nucleus was visualised in 55% of patients with genetically confirmed HD.
Conclusions Our preliminary findings seem to confirm the relationship between changes in mesencephalic raphe echogenicity and the presence of depressive symptoms also in patients with HD.
No preview · Article · Sep 2014 · Journal of Neurology Neurosurgery & Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Objectives. Co-occurrence of metabolic syndrome features and dementia was studied. Methods. In 151 demented patients and 64 control individuals the presence of metabolic syndrome was diagnosed according to the modified Grundy et al. criteria (hypertension, obesity, high triglyceride and low high density lipopoprotein (HDL) cholesterol serum levels, as well as hyperglycemia). The serum insulin level was determined and the HOMA-IR index of insulin resistance was calculated. Polymorphic forms of a gene candidating for a role in the insulin signaling pathway - the glycogen-associated regulatory subunit 3 of protein phosphatase 1 (PP1R3), and of the apolipoprotein E gene - ε2, ε3 and ε4 alleles - which are well-known strong genetic risk factors for Alzheimer's disease - were identified. Results. Metabolic syndrome was found more often in the group with vascular dementia (VaD) than in the controls. In the former group a tendency for higher HOMA-IR index values was observed. The most frequent characteristic of glucose metabolism differing all the patients from the controls was an increased 2-hour postload glucose level, which is a feature of prediabetes. No differences between the patients and controls were found in the frequency of particular polymorphic forms of the PPP1R3 gene. Low HDL cholesterol levels and glucose intolerance - two important metabolic syndrome features - were significantly more frequent only in the ε4 allele noncarriers, but not in the carriers of this allele. Conclusions. Metabolic syndrome features were observed most often in patients with dementia of vascular origin. Frequency of these characteristics was higher only in noncarriers of the apolipoprotein E ε4 allele.
No preview · Article · Jan 2012 · Postepy Psychiatrii i Neurologii
[Show abstract][Hide abstract] ABSTRACT: At 3 years after diagnosis, the risk of Alzheimer disease (AD) for patients with mild cognitive impairment (MCI) is estimated to be 18% to 30%. To improve treatment of patients at high dementia risk there is a need for a better prediction of the risk for transition from MCI to AD. Olfactory deficits are a hypothetical predictor of conversion form MCI to AD. Furthermore, several studies point at volumetric reduction of medial temporal lobe structures as predictors of conversion form MCI to AD. The primary aim of this study was to evaluate whether investigations of odor deficits in MCI combined with neuropsychological tests and MRI examinations can improve prediction of the development of dementia.
Changes in olfactory functions, cognitive functions, and volume of medial temporal lobe structures (hippocampus, parahippocampal gyrus, and amygdala) were evaluated in a 24-month follow-up study in 49 MCI patients and 33 controls.
In the MCI group, a prediction of strong cognitive functions deterioration based on poor performance in Olfactory Identification tests shows sensitivity of 57% and specificity of 88%. The test based on cognitive functions only shows a sensitivity of 44%, and 89%, respectively. Combined tests having a criteria of poor olfactory identification performance AND poor results of neuropsychological tests showed a sensitivity of 100% and specificity of 84%. Furthermore, correlation was found between the results of Olfactory Identification tests at baseline and deterioration of cognitive functions at follow up. Odor identification threshold did not appear to be a dementia predictor. A correlation of progress of cognitive function deterioration, odor identification deterioration, and decrease of volume of the hippocampus was also observed.
Prediction of MCI to dementia conversion can be improved by supplementing the neuropsychological tests with odor identification tests. A follow up study of hippocampus volume reduction, OI performance and cognitive functions deterioration will further increase prediction accuracy.
No preview · Article · May 2011 · Current Alzheimer research
[Show abstract][Hide abstract] ABSTRACT: Ninety one patients with stroke or transient ischemic attack (TIA) were screened for sleep-disordered breathing (SDB). Case fatality, rate of recurrence of cerebrovascular events, and functional outcome were analyzed during a 2-year follow-up. The patients were stratified into groups: without (AH < or =5) and with SDB (AHI >5). SDB was present in 61 (67.7%) patients with stroke or TIA. The rate of recurrence of TIA or stroke in patients with SDB was significantly higher (12 patients, OR=1.52, P<0.05) as compared with patients without SDB (3 patients) within two years of observation. Case-fatality rates were not significantly different (4 patients with SDB and 2 patients without SDB). Our data show that SDB significantly increases the incidence of recurrent cerebrovascular events in patients with TIA or stroke in a two-year follow-up. SDB in patient with stroke or TIA did not influence functional outcome of stroke during the long-term observation.
Full-text · Article · Dec 2008 · Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
[Show abstract][Hide abstract] ABSTRACT: Objective. To present an overview of studies on the relationship between tobacco smoking and risk of cerebral stroke. Review. Cigarette smoking is an independent risk factor for cerebral stroke. The relative risk of stroke increases with the number of cigarettes smoked, depends on the type of stroke, and is not distinctly related to gender. Middle-aged smokers as compared to non-smokers are the highest risk group. On smoking cessation the relative risk for stroke significantly decreases, which indicates a causative relationship between tobacco smoking and cerebral stroke onset. There is growing evidence that passive smoking is also a stroke risk factor. Conclusions. Nicotine dependence is a life-threatening condition that should be treated by all medical practitioners representing various specialties.
No preview · Article · Jan 2008 · Postepy Psychiatrii i Neurologii
[Show abstract][Hide abstract] ABSTRACT: Objective. Echinococcosis is a rather seldom detected parasitic disease affecting the CNS in 2% of cases only. Diagnostic difficulties occur if presentations in neuroimaging assessment are atypical, as in this disease serological tests can be negative for a long time since the onset of clinical symptoms. Cases. Two patients with echinococcosis are described: a 53-year-old man with an isolated cerebral form of echinococcosis and an atypical brain MRI scan showing disseminated focal lesions, and a woman aged 18, with an ophtalmic form of the disease and disseminated neurological signs. Commentary. Echinococcosis continues to be seen in Poland. Isolated intracerebral forms of this disease are very rare. The diagnosis should be based on neuroimaging findings, as well as serological test results and cerebrospinal fluid analysis. Oral treatment is an alternative method in non-operative cases.
No preview · Article · Jan 2008 · Postepy Psychiatrii i Neurologii
[Show abstract][Hide abstract] ABSTRACT: Fifty five patients with ischemic stroke and 15 patients with transient ischemic attacks (TIA) were screened for sleep related breathing disorders (SRBD). Apnea-hypopnea index (AHI) and desaturation index (DI) were analyzed. The clinical status was assessed with National Institute of Health Stroke Scale (NIHSS). The patients with stroke were stratified into groups: without (AHI<or=5), with mild (5<AHI<or=10), and with moderate or severe SRBD (AHI>10). SRBD were present in 36 patients with stroke and in 10 patients with TIA. There were significant differences in the clinical status on admission, as quantified with NIHSS, between stroke patients with mild and moderate or severe SRBD. AHI positively correlated with NIHSS on admission in stroke patients (r=0.54, P<0.01). The final NIHSS score was significantly greater in patients with moderate or severe SRBD than in those with mild SRBD: 3.4+/-1.9 and 1.8+/-1.2, respectively. Our data suggest that the severity of SRBD is related to the clinical status on admission and it influence the clinical outcome after ischemic stroke.
Full-text · Article · Dec 2007 · Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
[Show abstract][Hide abstract] ABSTRACT: Objectives. The aim of the present study was to investigate the causes of prolonged (lasting over 12 hrs) disturbances of consciousness in patients aged 60 and above, and to develop optimal diagnostic and therapeutic procedures to be used in such cases. Method. Analyzed were data obtained from patients with prolonged (over 12 hours) disturbances of consciousness, hospitalized in the 1st Neurological Department of the Institute of Psychiatry and Neurology between 01.11.2003 and 30.10.2005. The case series included 130 patients, mean age 75.7 ± 8.8 years, 82 (63.1%) women and 48 men. Results. In 28 patients prolonged disturbances of consciousness were due to a haemorrhagic stroke, mostly (in 90% of the cases) penetrating into the ventricular system, while in 27 patients previously diagnosed with epilepsy of non-vascular origin they were usually preceded by a convulsive seizure. The most numerous group in our study were 40 patients with cerebrovascular lesions. In this group 7 cases (17.5%) had been diagnosed earlier with post-stroke epilepsy. In the remaining patients disturbances of consciousness were caused by infectious diseases, cerebral tumours, acute ischemic stroke, and blood flow insufficiency in posterior regions of the brain. Conclusions. In the cases of prolonged disturbances of consciousness in persons aged over 60, a possibility of epilepsy should be taken into account in the differential diagnosis, especially in patients with a history of brain damage of vascular origin.
No preview · Article · Mar 2007 · Postepy Psychiatrii i Neurologii