Carl-Gerhard Gottfries

Biochemical changes in Dementia disorders of Alzheimer type (AD/SDAT)

In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.

Membrane Lipids, Selectively Diminished in Alzheimer Brains, Suggest Synapse Loss as a Primary Event in Early‐Onset Form (Type I) and Demyelination in Late‐Onset Form (Type II)

Abstract: Major membrane lipids were quantified in frontal (Brodmann area 9) and temporal (Brodmann areas 21 and 22) cortices, caudate nucleus, hippocampus, and frontal white matter of 12 cases with Alzheimers disease (AD) type I (early onset), 21 cases with AD type II (late onset), and 20 age‐matched controls. The concentration of gangliosides—a marker for axodendritic arborization—was reduced to 58–70% of the control concentration in all four gray areas (p < 0.0001) and to 81 % in frontal white matter (p < 0.01) of AD type I cases, whereas it was only significantly reduced in temporal cortex (p < 0.01), hippocampus (p < 0.05), and frontal white matter (p < 0.05) in AD type II cases. The concentration of phospholipids was also significantly reduced (p < 0.01–0.0001) in all four gray areas of AD type I cases but in no area of AD type II cases. The loss of cholesterol was only 50% of the corresponding phospholipid diminution in AD type I. These results suggested a pronounced loss of nerve endings in AD type 1. The characteristic membrane lipid disturbance in AD type II was a loss of myelin lipids. This is the first time a fundamental biochemical difference has been shown between the two major forms of AD.

Treatment of Alzheimer’s Disease with Clioquinol

As heavy metal ions may be implicated in the formation of senile plaques in Alzheimer-afflicted brains, treatment with clioquinol was tested in 20 patients with Alzheimer’s disease. Clioquinol is a chelator that crosses the blood-brain barrier and has greater affinity for zinc and copper ions than for calcium and magnesium ions. Treatment was given for 21 days at doses of 20 mg/day to 10 patients and 80 mg/day to another 10 patients. The study was blind to the dosages but included no controls. Cerebrospinal fluid (CSF) investigations revealed a significant increase at day 7 and a decrease at day 21 in Tau protein and growth-associated protein (GAP43). These proteins are increased in Alzheimer’s disease and considered as rather stable markers. The initial increase may indicate a temporary cytotoxicity to the brain and/or an increased release into the CSF from stores in the tissue, possibly from senile plaques where the proteins are accumulated. The levels of CSF-Tau protein correlated positively and significantly with the serum levels of copper and also with the serum copper/zinc ratio. Clinical ratings showed slight improvement after 3 weeks treatment with clioquinol in this open study.

The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains

Two synaptic-vesicle proteins, rab3a and synaptophysin, have been studied on post-mortem brain tissues of schizophrenics and healthy controls. We found significantly reduced levels of rab3a in thalamus (p<0.001); for both proteins in gyrus cinguli and hippocampus (p<0.0001); for rab3a in frontal and parietal cortex (p<0.05); and no differences in temporal cortex or cerebellum in schizophrenics compared with controls. Reduced synaptic density may be a prominent feature of the molecular neuropathology of schizophrenia.

Stepwise Comparative Status Analysis (STEP): A Tool for Identification of Regional Brain Syndromes in Dementia

A method for clinical examination of patients with dementia, stepwise comparative status analysis (STEP), is presented. It combines psychiatric and neurologic status examination methods to identify certain common dementia symptoms by which the patients regional brain symptom profile can be determined. Fifty status variables (items) are estimated with respect to occurrence and severity. The analysis is performed in three steps. The scores on the primary variables reflect observations of single dementia symptoms. These scores form the basis for the assessment of the ‘compound’ variables, which in turn form the basis for evaluation of the ‘complex’ variables, one of which describes the patients regional (predominant) brain syndrome (subcortical, frontosubcortical, frontal, frontoparietal, parietal, or global). In 96 mildly and moderately demented inpatients, the global (42%) and frontosubcortical (31%) were the most common. Ninety-one percent of the patients with vascular dementia had a predominant frontal and/or subcortical symptomatology

Vitamin B12-B6-Folate Treatment Improves Blood-Brain Barrier Function in Patients with Hyperhomocysteinaemia and Mild Cognitive Impairment

Thirty patients had mild cognitive impairment and increased homocysteine levels in serum. On average, they were supplemented orally with a high dose of a vitamin B12-B6-folate combination for 270 days. All patients had normal serum B12 and folate levels at baseline. Cerebrospinal fluid levels of the tau protein (CSF-tau) and the albumin ratio were measured before and after treatment. The serum homocysteine levels were normalised after treatment. The albumin ratio significantly correlated with vascular risk factors. At baseline, the ratio was higher in the patients in comparison with age-matched controls. After treatment, the ratio was significantly reduced, which may indicate a tightening of the blood-brain barrier. The CSF-tau levels did not change significantly although there was a numeric decline. None of the patients progressed into dementia during the treatment period. When treated with a vitamin B12-B6-folate combination, patients with mild cognitive impairment and hyperhomocysteinaemia appear to improve their blood-brain barrier function. They may also stabilise their cognitive status. Further investigations are warranted on the role of blood-brain barrier dysfunction in the pathogenesis of dementia.

Protein Analysis in Cerebrospinal Fluid

To examine the possible influence of the blood-CSF barrier function on mathematical formulas for estimating intrathecal IgG production {IgG index, Tourtellotte’s formula [TOURT], Schuller and Sagar’s

Membrane Components Separate Early-Onset Alzheimer's Disease From Senile Dementia of the Alzheimer Type

Brain tissue from 12 subjects with pure Alzheimers disease (AD) and 21 subjects with senile dementia of the Alzheimer type (SDAT) was investigated for membrane lipids and compared with that in age-matched controls. In brain tissue from the patients with AD, phospholipids were significantly decreased compared with that from SDAT patients and controls, cholesterol was reduced compared with that in controls, and gangliosides were significantly reduced in all gray-matter areas investigated compared with those in both SDAT subjects and controls. A reduction in gangliosides also occurred in the SDAT group, but it was smaller. In the white matter, the pattern of changes was the opposite. Phospholipids, cholesterol, cerebroside, and sulfatide were significantly reduced in the frontal-lobe white matter in the SDAT group compared with that in age-matched controls and AD patients. Gangliosides in the cerebrospinal fluid also separated AD from SDAT and controls. The findings indicate synapse degeneration as an important pathogenetic factor in AD. This disorder should be separated from SDAT, in which white-matter degeneration appears to be more prominent.

The Role of the Polymorphic Genes Apolipoprotein E and Methylene- tetrahydrofolate Reductase in the Development of Dementia of the Alzheimer Type

The gene for apolipoprotein E (APOE) is polymorphic, and its variant APOE4 is a major risk factor for the development of Alzheimer-type dementia (AD). Another risk factor for AD appears to be negative cobalamin balance, which is very common in elderly people. Cobalamin and folate are interdependent and essential components of the one-carbon metabolism. Another important component is methylenetetrahydrofolate reductase (MTHFR), the gene for which is also polymorphic. Thermolabile MTHFR (tMTHFR), a gene variant that reduces the activity of its enzyme, is common in the general population. In the present study, 75% of 140 AD patients had at least one APOE4 allele. The numbers of APOE4 and tMTHFR alleles correlated significantly with the serum folate levels, however, in opposite directions. The significance of this was augmented by an inverse correlation between APOE4 and tMTHFR. Thus, not only MTHFR but also APOE appears to be related to the one-carbon metabolism, suggesting that APOE4 and insufficient one-carbon metabolism may be synergistic risk factors for AD.

Late life depression.

Depression has an overall prevalence of 5 -8%. The prevalence of late life depression is estimated among people 65 years of age to be 15%. There is a great under-diagnosis and under-treatment of late life depression with the most serious consequence being premature death. Depression is also an important and independent risk factor for mortality following myocardial infarction, while patients with stroke associated with depression also have a higher death rate. The suicide rate is increased in elderly especially elderly men with depression.The aetiology of depression is more heterogeneous than depression in younger adults. Obviously age-related changes in the brain increase the risk for depression. Patients with neurodegenerative disorders also run a higher risk for being depressed. In Alzheimer’s disease the frequency is around 50 %. Deficiency of essential nutrients like folic acid and vitamin B12 is an obvious risk factor for both disorders with cognitive impairment and depression.Treatment of depression in the elderly follows the same lines as treatment of depression in younger patients. Many different drugs may be prescribed; however, the risk of adverse events is greater in the elderly. The drugs of choice are the selective serotonin re-uptake inhibitors (SSRIs), which have a response rate of around 65%. Of interest is that emotional disturbances like irritability, aggressiveness and anxiety also respond to treatment with SSRIs. A comprehensive treatment of late life depression, which includes social and psychological support, has a response rate of 80 – 90%.