Neurodegeneration from Mitochondrial Insufficiency:
Nutrients, Stem Cells, Growth Factors, and Prospects
for Brain Rebuilding Using Integrative Management

This section is compiled by Frank M. Painter, D.C.
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FROM:   Alternative Medicine Review 2005 (Dec); 10 (4): 268–293 ~ FULL TEXT

Parris M. Kidd, PhD

University of California, Berkeley, PhD, cell biology; contributing editor, Alternative Medicine Review; health educator; biomedical consultant to the dietary supplement industry. Correspondence address: 847 Elm Street, El Cerrito, CA 94530 E-mail:

Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.

From the FULL TEXT Article

      Alzheimer’s and Mitochondrial Failure – Strength of the Evidence

A consensus is emerging that Alzheimer’s disease (AD) and the other dementias have multifactorial etiologies. [8, 13, 14] In contrast to normal aging, which features very little cell death, the extent of nerve cell and whole circuit dropout in AD is widespread and sometimes catastrophic. During normal aging, the brain suffers morphological and functional modifications affecting dendritic trees and synapses, neurotransmitters, tissue perfusion and metabolism, motor and sensory systems, sleep, memory and learning, and demonstrates lipofuscin accumulation with moderate amounts of amyloid. Many studies implicate ROS and mitochondrial decline as the basis for these changes (see Barja, 2004 for a comprehensive review [15]). AD manifests as an exaggeration of these changes – and more.

Progressive formation of neurofibrillary tangles and the secretion of beta-amyloid that condenses to form plaques characterize the pathology of AD. Amyloid formation has been convincingly linked to oxidative damage. [16] Energetic decline is one of the earliest changes evident in the AD brain, and mitochondrial abnormalities have been detected all across the brain cortical zones.

      Energetic Impairments in Alzheimer’s Disease

Some of the most direct evidence for mitochondrial abnormalities in AD comes from non-invasive, in vivo, positron emission tomography (PET) imaging. These findings were reviewed in 2005 by Sullivan and Brown. [16] In particular, the temporal and parietal cortical zones consistently exhibit metabolic abnormalities. Some PET reports document abnormally high oxygen utilization in comparison to the amounts of glucose utilized, indicating impairment of the OXPHOS process in the mitochondria. The decrements in brain metabolism seen with non-invasive imaging tend to precede both the neuropsychological impairment and anatomical changes of AD, such as atrophy. The frontal cortex and middle temporal gyrus, areas that manifest the most prominent metabolic abnormalities via PET, are also the areas that most strongly exhibit synaptic dysfunction and circuit loss seen in AD brains on morphological examination.

The brain’s ongoing viability is dramatically dependent on energy from glucose. In both AD and the closely related vascular dementia (VD), bioenergetic impairment can appear early and progress rapidly, consistent with a primary defect. [17] A similar pattern is evident in Wernicke-Korsakoff syndrome, a dementia associated with thiamine depletion and often seen in alcoholics. [18] Alterations in mitochondrial enzymes are consistently linked to dementia. As early as 1980, enzyme assays using tissue homogenates from autopsied AD brain revealed decreases of pyruvate dehydrogenase (PDH) activity in the frontal, temporal, and parietal cortex. [19] PDH, the enzyme crucial to driving the citric acid cycle (CAC), is markedly affected in vascular dementia as well as in Alzheimer’s dementia. [17]

Alpha-ketoglutarate dehydrogenase (KGD) is the probable rate-limiting enzyme of the citric acid cycle. Gibson and coworkers found KGD significantly decreased in the AD temporal and parietal cortex. [20, 21] Other CAC enzymes are also found impaired in AD, and the overall degree of metabolic impairment tends to correlate with clinical status.22

Beyond the water-phase CAC enzymes of the mitochondrial matrix, the enzymes that make up complexes I-V in the inner mitochondrial membrane are indispensable for ATP generation. Various studies have catalogued impairments of all five complexes in multiple zones of the AD brain. 16, 23-26] Most widely involved was complex IV (cytochrome c oxidase), for which the enzyme activity was found significantly decreased in the frontal, temporal, parietal, and occipital cortex from AD brains compared to agematched controls. [25, 26] Complex I protein levels were significantly reduced in the temporal, parietal, and occipital zones; [24] complex III protein was significantly reduced in the temporal cortex; [25] and complex V proteins were significantly reduced in the hippocampus (reviewed in Kim et al [25]). Kim et al also demonstrated lowered biosynthesis of one subunit of complex I in the temporal and occipital cortices, and of a different complex I subunit in the parietal cortex. [24]

It is unclear to what extent these marked energetic impairments of AD could be constitutive, versus secondarily acquired (from heavy metal or other toxic cumulative damage, for example). After much investigation, no abnormal mitochondrial genes or gene clusters have been identified for later-onset AD, which represents the majority of cases. A recent study, however, reported mitochondrial DNA from the brain tissue of AD patients had significantly greater damage compared to controls. [27]

Although there still is no “smoking gun,” it is tempting to speculate that exogenous oxidative toxins play a role in AD. Especially worthy of investigation is mercury. This toxic heavy metal has a continued presence in dental amalgams throughout the population, is still being added to vaccines and other injectable preparations, and has a ubiquitous environmental presence from industrial emissions. Mercury is uniquely toxic to nerve cells, with its accumulation in the mitochondria linked to cell destruction. [28] Elevated blood mercury levels in childhood correlate with lifelong cognitive impairment. [29] While still not providing definitive proof, a small German study found blood mercury levels were significantly elevated more than two-fold in AD patients compared to age-matched, non-AD controls. [30] Early-onset AD patients demonstrated a significant three-fold higher mercury elevation.

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