Naa As A Marker For Neuronal Health

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The relatively high concentration of NAA permits its noninvasive detection by magnetic resonance spectroscopy (MRS), which combined with its predominant neuronal localization has enabled use of NAA as a diagnostic marker for neuronal dysfunction/loss in a variety of neurological disorders.4,5,7 NAA levels measured by MRS have been reported to be altered in patients suffering from various neurological disorders40-51 (Table 3). These studies have mostly detected decreases in NAA, but in case of Canavan disease

(CD)52 relative increases in NAA levels are common. The diseases in which NAA levels are decreased include Alzheimer's disease, epilepsy, schizophrenia, multiple sclerosis and AIDS dementia complex (Table 1). Earlier, the decreases in NAA were interpreted to represent irreversible loss of neurons. However, more recent evidence indicates that these decreases also could represent reversible neuronal mitochondrial dysfunction. 53

Canavan Naa Metabolism
Figure 8. Schematic of the energetics model for NAA synthesis in neuronal mitochondria. The thick lines indicate the path of NAA synthesis and further its fate, the thin lines indicate other possible pathways the substrates can take.

In support of this view, some evidence has been presented showing that NAA levels are restored when patients recovered clinically49. These observations bring up a central question in NAA research. Does NAA play a part in the functional recovery, or is it just a marker for the recovery of mitochondrial energy metabolism?

The proposed bioenergetic model12 described above suggests plausible pathways in mitochondria that are associated with the synthesis of NAA, and relies considerably on reported experimental evidence supporting the direction of reactions. There are reports of a positive correlation between neuronal ATP and NAA at the level of oxidative

38 39 54

phosphorylation and the responses observed following brain injury. , A subsequent investigation carried out on healthy individuals on the indices of mitochondrial/neuronal energetics did not, however, find a positive correlation between NAA levels and ATP.55

The lack of correlation between brain ATP and NAA levels was based entirely on in vivo MRS data. In addition, the determined concentration levels of free ADP and ATP varied by a factor of 1000. In terms of concentration however, NAA levels were comparable to that of ATP rather than ADP. On the other hand, in vivo studies on the application and withdrawal of the mitochondria toxin 3-nitropropionic acid (3-NP) were more striking. Rat and primate models were used in the study of progressive striatal degeneration induced by 3NP, and NAA levels were determined by proton MRS. While

Table 3. Changes in NAA levels in neurological disorders:


Increase/Decrease in NAA level

Area of the Brain

Alzheimer's disease 40'43


Medial temporal lobe, parietal lobe, hippocampus

Schizophrenia 46'47


Thalamus, prefrontal cortex

Multiple sclerosis 45


Lesioned brain areas

Post traumatic stress disorder 41



AIDS dementia complex 48


Medial frontal cortex

Stroke 51


Infarcted area

Huntington's disease 50



Amyotrophic lateral sclerosis 49


Primary motor cortex

Gulf War Syndrome 44


Basal ganglia, brain stem

Canavan Disease 52


White matter of brain

cell loss and dying cells were not detected, significant decreases in NAA concentrations were specifically restricted to the striatum and were associated with the appearance of motor symptoms by the 3rd day of treatment. The withdrawal of the toxin partially restored the NAA levels after 4 weeks.53 These experimental data are consistent with the proposed bioenergtics model of NAA synthesis in neurons, and suggest a connection between NAA synthesis and ATP synthesis.

Although, a convincing link has been demonstrated between dysmyelination and the impaired catabolism of NAA in CD56 (also see Chapter by Namboodiri et al., this volume), the exact link between the decreasing levels of NAA and the observed neurological impairments in other diseases remains to be established. Progress in the molecular characterization of Asp-NAT is expected to provide the necessary tools, such as antibodies and gene knockout models, to help unravel the neurobiology of NAA and its functional roles in the nervous system.

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