Felix Potocnik

Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors

Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population. Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (>or=5%) in certain Asian and Latin American countries, but consistently low (1-3%) in India and sub-Saharan Africa; Alzheimers disease accounts for 60% whereas vascular dementia accounts for approximately 30% of the prevalence. Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa. Illiteracy remains a risk factor for dementia. The APOE epsilon4 allele does not influence dementia progression in sub-Saharan Africans. Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia. Use of traditional diets and medicinal plant extracts might aid prevention and treatment. Dementia costs in developing countries are estimated to be US

FUS and TDP43 genetic variability in FTD and CBS.

73 billion yearly, but care demands social protection, which seems scarce in these regions.

Serum concentrations of some metals and steroids in patients with chronic fatigue syndrome with reference to neurological and cognitive abnormalities

This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls.

Genetic variability in CHMP2B and frontotemporal dementia.

Chronic fatigue syndrome is defined by the Atlanta Centers for Disease Control (Atlanta, GA, USA) as debilitating fatigue lasting for longer than 6 months. Symptoms include disturbances of cognition. Certain factors have in the past been shown to influence cognition, including metals such as aluminum, iron, and zinc; and steroids such as dehydroepiandrosterone. In the present study, concentrations of these factors were determined in the serum and plasma of patients and their age- and gender-matched healthy controls (10 women and 5 men in each group). In addition, copper, dehydroepiandrosterone sulphate, cortisol, cholesterol, hemoglobin, ferritin and transferrin concentrations, as well as transferrin genetic subtypes were determined in both groups. The results indicate that patients had significantly increased serum aluminum and decreased iron compared to controls. In the females, serum iron and dehydroepiandrosterone sulphate were significantly decreased and correlated. Total cholesterol was significantly increased, and significantly negatively correlated with dehydroepiandrosterone sulphate. There were no differences in zinc, copper, cortisol, hemoglobin, transferrin and ferritin concentrations, or in transferrin genetic subtypes.

5- and 6-Glycosylation of transferrin in patients with Alzheimer's Disease.

A nonsense/protein chain-terminating mutation in the CHMP2B gene has recently been reported as a cause of frontotemporal dementia (FTD) in the single large family known to show linkage to chromosome 3. Screening for mutations in this gene in a large series of FTD families and individual patients led to the identification of a protein-truncating mutation in 2 unaffected members of an Afrikaner family with FTD, but not in their affected relatives. The putative pathogenicity of CHMP2B mutations for dementia is discussed.

Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis

Transferrin is a glycosylated metal-carrying serum protein. One of the biological functions of glycosylation is to regulate the life span of proteins, less glycosylation leading to a faster clearance of a protein from the circulation. In the case of transferrin, this would indirectly also influence iron homeostasis. Higher glycosylation has been demonstrated in patients with Parkinsons disease and rheumatoid arthritis. A genetic variant of transferrin, TfC2, occurs with increased frequency in patients with Alzheimers disease (AD), rheumatoid arthritis, and other diseases associated with a free radical etiology. Investigations have so far not revealed the reason for the pro-oxidative qualities of TfC2. In this study the glycosylation of Tf in AD (TfC1 homozygotes and TfC1C2 heterozygotes) was compared with alcohol-induced dementia (AID) patients and nondemented, age-matched controls, using isoelectric focusing followed by blotting with anti-Tf antibodies. In TfC1 homozygotes a shift was found toward higher sialylation, but in TfC1C2 heterozygotes the 5- and 6-sialylated bands were less concentrated. The decreased sialalytion found for TfC1C2 heterozygotes, may indicate that the pro-oxidative TfC2 molecules are removed from the circulation at a faster rate than TfC1. This may be of benefit to AD patients having TfC2, but still does not explain why this Tf variant is pro-oxidative.

Biochemical Model for Inflammation of the Brain: The Effect of Iron and Transferrin on Monocytes and Lipid Peroxidation

Some subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient study suggest that iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites for this process are iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine iron status, folate and homocysteine in MS subjects, and to evaluate the effect on MS symptoms if deficiencies were addressed. Results: In relapsing-remitting MS subjects, serum iron concentration correlated significantly with age at diagnosis (r=0.49; p=0.008). In Caucasian female MS subjects, serum iron and ferritin concentrations were significantly lower than in matched controls. In a 6-month pilot study, 12 subjects taking a regimen of nutritional supplements designed to promote myelin regeneration, improved significantly neurologically as measured by the Kurzke EDSS (Total Score means 3.50 to 2.45, 29.9%; p=0.021). These were significantly improved (p=0.002) compared to 6 control group patients taking multivitamins (Kurzke Score increased by 13.9% from 4.83 to 5.50). Both groups had significantly reduced homocysteine concentrations at 6 months, suggesting that methylation is necessary but not sufficient for myelin regeneration.

Earlier Age of Onset of Alzheimer's Disease in Patients with Both the Transferrin C2 and Apolipoprotein E‐ɛ4 Alleles

Cerebral inflammation plays a role in diseases such as multiple sclerosis (MS), Alzheimers disease (AD), and depression. Iron is involved in infection and inflammation through free radical production. Theoretically transferrin should prohibit iron from participating in oxidative reactions, but transferrin has also been found to promote free radical damage. We reported previously that isolation of transferrin from plasma by ion exchange column chromatography produced a broad pink protein band that subsequently separated on a gel filtration column into three proteins containing many metals. In this study some properties of the three proteins were studied in 20 volunteers. Protein 3 (identified as transferrin by nephelometry) contained the most iron while Protein 1 (called “toxiferrin”) contained significantly less iron (p < 0.00001). Plasma from volunteers obtained under conditions of infection/inflammation with fever (n = 5) had a significantly increased toxiferrin to transferrin ratio compared to healthy volunteers (n = 15; p < 0.001). In vitro, Protein 2 and transferrin inhibited lipid peroxidation, while toxiferrin (possibly a protease degradation product of transferrin), enhanced lipid peroxidation. Also, toxiferrin (1 mg/mL) caused a significant increase in viability of monocytes as measured by the 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) reduction test, as well as the morphological transformation of monocytes to macrophages.

Use of the selective serotonin reuptake inhibitor citalopram in a possible animal analogue of obsessive-compulsive disorder.

Abstract: The etiology of Alzheimers disease is now known to be multifactorial. The genetic factors transferrin C2 (TfC2) and apolipoprotein E ɛ4 (ApoE‐ɛ4) have both been associated with Alzheimers disease (AD). Transferrin is the carrier protein for iron in the blood, while ApoE is involved with the transport and redistribution of lipids. In the present study, the polymerase chain reaction (PCR) method was used to determine the frequency of both TfC2 and ApoE‐ɛ4 in 27 AD patients, 9 vascular dementia (VaD) patients, and 27 controls. Patients were diagnosed according to the criteria as set out in the 4th edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM‐IV).

The effect of iron and aluminum on transferrin and other serum proteins as revealed by isoelectric focusing gel electrophoresis.

Canine acral lick dermatitis (ALD) has been suggested as an animal analogue of obsessive‐compulsive disorder (OCD). A series of dogs with ALD or similar conditions were treated with citalopram, the most selective of the selective serotonin reuptake inhibitors. Six of nine (66.7%) dogs showed significant improvement. Given the apparent efficacy of citalopram in the treatment of OCD and related disorders, these data provide further evidence that ALD is a useful animal analogue of OCD. Depression and Anxiety 8:39–42, 1998.