A New Therapeutic Approach for Improving Dementia of the ALZHEIMER TYPE

MAJOR BIOCHEMICAL CHANGES:
The major biochemical changes identified in SDAT is a deficiency of cholinergic neurotransmitters owing to the progressive loss of cholinergic presynaptic neurons located in the basal forebrain ( ⁴ ). There are similarities between the biochemical changes found in normal age and in SDAT. However, there are also functional disturbancies of the catecholaminergic system. It has been shown that catecholamine activity in the aged rat brain is reduced ( ^{5, 6, 7}). The enzymatic activity of tyrosine hydroxylase (TH) as well as dopade-carboxyase (DOD) has been found significantly decreased in post-mortem samples of human remains ( ⁸ ). Other post-mortem studies in humans have shown reduced levels of dopamine (DA) and noradrenaline (NA) related to age ( ^{9, 10} ). These observations indicate that there is a decrease of the concentrations of catecholamine in the normal aged brain.

In senile dementia of the Alzheimer type (SDAT), it was well shown already in 1969 that the metabolites of dopamine (DA) homovanilinic acid (HVA) was decreased in the cerebral spinal fluid (CSF) of the patients ( ¹¹ ). Furthermore, a study in Sweden revealed that the dopamine concentration was significantly reduced in the caudatus nucleus and in the hypothalamus. Noradrenaline was reduced in the hypothalamus, caudatus hippocampus, and gyri cinguli. Even more significantly reduced was 5-hydroxy-tryptamine (5-HT), also called serotonine in the same brain regions ( ¹² ). These findings were confirmed and extended in showing that dopamine and noradrenaline deficiency do not only occur in nucleus caudatus, hypothalamus, and gyri cinguli, but also in other brain regions such as globus pallidus, putamen, nucleus amygdale, substantia nigra, and basal ganglia ( ¹³ ). The levels of serotonine (5-HT) were reduced in nucleus caudatus, putamen, globus pallidus, substantia nigra, raphe and nucleus amygdale.

Reinikainnen ( ¹⁴ ) and coworkers found noradrenaline deficits in locus coeruleus, frontal cortex, temple cortex, hippocampus, and putamen. Dopamine deficits were found by Allard et al ( ¹⁵ ) in thalamus, hippothalamus, nucleus caudatus, and putamen in ponds. Deficit of 5-HT could be detected in putamen, cingular cortex, and raphe by Marcusson et al ( ¹⁶ ).

EVIDENCE OF A BIOCHEMICAL
CAUSE OF COGNITIVE DYSFUNCTION:
All these findings provide evidence that the biochemical cause of cognitive dysfunction and dementia in SDAT is not only confined to the acetylcholinergic system but also to the catecholaminergic system. This view is further supported by the clinical observation that in SDAT not only intellectual but also emotional and motoric impairments are observed. In particular, the motoric impairments accompanied with other Parkinsonian-like symptoms are observed in 50 percent of the Alzheimer patients ( ¹⁷ ). On the other hand, Parkinsonian patients develop symptoms of dementia ( ¹⁸ ). These similarities between Parkinson's and Alzheimer's disease instigated us to apply nicotinamide adenine dinucleotide (NADH) with patients suffering from senile dementia of the Alzheimer type. As shown by us in various clinical trials with more than 2000 Parkinsonian patients, NADH does not only alleviate the motoric impairment but also the cognitive dysfunction of these patients ( ^{19, 20, 21} ).

Nicotinamide adenine dinucleotide, in its reduced form abbreviated NADH, is also known as Coenzyme I. This coenzyme is present in all living cells and plays a central role in the cellular energy production. The NADH itself is a very energy rich compound. The reactive hydrogen atoms of NADH are oxidized to water yielding energy. In mammalian cells, this process takes place in the energy producing compartments, the mitochondria, and is performed by a mixture of enzymes called Complex I, NADH ubiquinon reductase, Complex II (Succinat. Dehydrogenase), Complex III (Ubiquinone cytochrome C-reductase), and Complex IV (cytochrome C-oxidase). The driving force in this energy production cascade is NADH. The more NADH a cell has available, the more energy it can produce, presupposing that all the enzymes of Complex I, II, III and IV are working properly. If one of these enzymes of Complex I, II, IV does not reach full activity, energy production in the mitochondria decreases.

According to Corbisier and Remacle ( ²² ), alterations of mitochondria lead to their uncoupling which is harmful to the cells and can induce degeneration and cell death. In 1934 NADH was first extensively described by Kaplan and has been used in pure form as diagnostic tool in clinical laboratories for the last 30 years. No therapeutical application had ever been considered until 1988. With the new concept of stimulating the endogenous L-Dopa biosynthesis, it has been successfully applied to Parkinsonian patients ( ^{13, 19, 23} ). In 90 percent of 161 patients, an improvement in their disability was observed. Concomitantly, with the clinical approvement of the disability, the urine HVA-level increased significantly indicating a stimulation of the endogenous L-Dopa biosynthesis. These first observations were confirmed and extended in 1990 with 415 Parkinsonian patients ( ^{24, 25} ).

More extensive clinical studies compared the effect of the oral form of NADH with intravenously applied NADH. A total of 885 Parkinsonian patients were included in an open label trial, 415 received NADH intravenously, to 470 NADH was given orally. In 80 percent of the patients, a beneficial clinical effect was observed ( ²¹ ). This new therapeutic concept was based on the assumption that NADH stimulates the endogenous dopamine biosynthesis. This assumption was first proved in tissue culture by showing that the dopamine production in pheochhromocytomacells (PC12) could be increased up to six times by adding NADH to the medium ( ²⁶ ). Furthermore, it was found in this study that the rate limiting enzyme of dopamine biosynthesis tyrosine hydroxylase (TH) is stimulated by NADH. In addition to this in vitro study, further evidence on the stimulatory effect of NADH on the biosynthesis of dopamine and noradrenaline was obtained in animal studies. It was found that NADH stimulates the biosynthesis of dopamine in the striatum of the rat brain by more than 40 percent after 14 days of intraperitoneal injection of NADH. On the basis of our new therapeutic concept of stimulating the endogenous catecholamine biosynthesis by NADH, patients with dementia of the Alzheimer type are being treated.

SUBJECTS and METHODS:
In an open label trial, 17 patients were studied, all of whom have been diagnosed at various neurological clinics as pre-senile and with senile dementia of the Alzheimer type. Before they were included into the study, the severity of the cognitive and functional impairment was assessed at our institute using the Mini Mental State Examination (MMSE) (²⁷ ) and the Global Deterioration Scale (GDS) (addition, all the subjects underwent physical, neurological, and psychiatric ^{28, 29, 30} ). In examinations performed before and after the treatment period; NADH (Synonyms: B-NADH, reduced DPN, Coenzyme I reduced form) was given in oral form as a tablet containing 5 mg NADH. The total dosage was 10 mg NADH per day, which was given in the morning 30 minutes before the first meal.

MATERIAL:
Nicotinamide adenine dinucleotide, reduced form (NADH) was obtained as disodium salt. It is produced of NAD by enzymatic reduction. NAD is extracted from yeast. The yeast extract is purified by ion exchange chromatography and preparative high performance liquid chromatography. The separation of B-NAD and alpha-NAD is performed by chromatography. The reference standard is NADH-NA2, grade 1, with a purity of over 99.5 percent.

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