10.1 Effects of Abstinence on the Brain: Quantitative MRI and MR Spectroscopic Imaging in Chronic Alcohol Abuse (31)
Structural brain damage, especially to white matter, is well documented in chronic alcohol abuse, and there is also evidence for brain metabolic abnormalities in this condition. It is unknown, however, to what extent these structural and metabolic changes are still detectable in long-term abstinent alcoholics compared to active chronic drinkers. Therefore we compared 12 recovering alcoholics, who had been abstinent from alcohol for an average of 2 years, to 8 active heavily drinking subjects with similar alcohol use variables.
Metabolite concentrations in whole-brain and in gray matter and white matter of brain lobes did not differ significantly between the recovering alcoholics and active drinkers. However, active heavily drinking subjects had less frontal white matter than abstinent alcoholics and less gray matter in the orbital frontal pole and postcentral gyrus. However, abstinent alcoholics had smaller gray matter volumes in the anterior cingulate than active heavy drinkers.
Our cross-sectional 1H MRSI measures were largely ineffective in revealing metabolic effects of abstinence on the alcohol-damaged brain. The study, however, suggests region-specific structural recovery from chronic alcohol-induced brain injury, but also region-specific long-term structural damage in abstinent alcoholics.
10.2 Brain Recovery During Abstinence from Alcohol (32)
In our ongoing studies of recovering alcoholics, we investigate the nature of brain injury in alcoholics and the potential improvements of brain metabolite concentrations and cognition during prolonged sobriety.
At one week of sobriety, NAA in alcoholics was lower by 6-19% in frontal, parietal and temporal gray matter and white matter, in the basal ganglia, the brain stem, and cerebellum, while Cho concentrations were lower by 7-13% in lobar grey and white matter regions and in the thalami. NAA deficits correlated with cognitive impairments.
Over the first month of sobriety, NAA, myo-inositol, and Cho concentrations in frontal white matter increased significantly and to a greater extent than in gray matter. Similarly, neurocognitive performance increased significantly and showed some correlation with neurochemical improvements. Seven months after cessation of drinking, abstinent alcoholics had normal concentrations of myo-inositol and Cho. Regional NAA concentrations in white and gray matter increased over 7 months of sobriety, however, they did not normalize. These long-term changes were accompanied by continued cognitive improvements in most domains except visuospatial learning and memory. Increases of Cho and myo-inositol concentrations over time are consistent with remyelination and astrocytosis. Slower increases of NAA suggest slower recovery from axonal and neuronal injury, and that NAA loss in alcoholics is not completely due to neuronal loss.
Abstinent alcoholics show regional NAA loss, primarily in frontal lobes and cerebellum. The main goals of this project were to investigate the effects of chronic active heavy drinking on NAA and other metabolites throughout the brain, and to determine if they are affected by family history (FH) of alcoholism and long-term drinking pattern.
We used quantitative MRI and multi-slice JH MRSI at a short echo-time to compare 46 chronic heavy drinkers (HD) and 52 light drinkers (LD) on regional, tissue-specific and atrophy-corrected concentrations of NAA, myo-inositol (mI), creatine- and choline-containing metabolites.
NAA in frontal white matter was 6% lower in HD than LD. NAA loss was greater in female than male heavy drinkers despite similar drinking severity and greater in FH-negative HD than FH-positive HD. FH-negative compared to FH-positive HD also had higher ml in the brainstem and tended to have lower NAA and higher ml in frontal GM. In addition, greater frontal NAA loss in HD was found as a function of age. Lower frontal white matter NAA in HD correlated with lower executive and working memory functions and with greater P3 latency.
Thus, heavy drinkers in their forties who are not in alcoholism treatment have frontal axonal injury, which is associated with lower brain function and is likely of behavioral significance. Family history of alcoholism modulates brain metabolite abnormalities. Brain injury in active heavy drinkers is less pronounced than in abstinent alcoholics and presents with a different spatial and metabolite pattern.
10.4 Magnetic Resonance Detects Brainstem Changes in Chronic, Active Heavy Drinkers (34)
Neuropathological and neuroimaging studies show cortical and subcortical volume loss in alcohol dependent individuals. The brainstem is considered critical in the development and maintenance of drug and alcohol dependence, but it has not been the focus of neuroimaging studies. Using quantitative MRI and JH MRSI, we compared the size and metabolite measures of potential cellular injury of the brainstem in 12 chronic, active heavy drinkers and 10 light drinkers. Chronic heavy drinking was associated with a significantly smaller overall brainstem volume and with significantly smaller midsagittal areas of the brainstem, midbrain, and pons. Heavy drinking was also associated with significantly lower ratios of N-acetyl-aspartate (NAA) and choline-containing metabolites (Cho) compared with creatine-containing compounds (Cr) in a region including midbrain and pons, independent of brainstem atrophy. These structural and metabolite findings are consistent with neuronal injury of the midbrain/pons of untreated chronic heavy drinkers.
11. EFFECTS OF EPILEPSY ON NAA 11.1 Identification of the Epileptogenic Focus
From the first studies in the early 1990's on, the most consistent finding in the epileptogenic focus has been a reduction of NAA. This has been first demonstrated in temporal lobe epilepsy (TLE) with evidence for hippocampal atrophy or mesial temporal sclerosis (MTS) where hippocampal NAA reductions correctly identify the epileptogenic hippocampus in up to 100%. Because early studies found a strong correlation between the degree of neuronal loss and the degree of NAA reduction, the NAA reduction in the epileptogenic hippocampus was thought to represent mainly neuronal loss (35). However, newer evidence suggests that a substantial component of the NAA reduction is due to a not further specified, potentially reversible neuronal dysfunction in the epileptogenic tissue. This is also supported by studies in TLE without MRI evidence for MTS where histopathological studies show only mild neuronal loss despite clear hippocampal NAA reductions. However, NAA reductions in TLE without MTS are different from those found in TLE with MTS as has been demonstrated by a recent study from our laboratory. This study compared patterns of hippocampal NAA loss in 10 TLE without MTS with the patterns found in 15 TLE with MTS. The number of voxels with reduced NAA/(Cr+Cho) in the ipsilateral hippocampus was higher in TLE with MTS than in TLE without MTS (1.9 ± 1.3 vs 0.6± 1.3, p = 0.02). Furthermore, the NAA reductions in TLE without MTS were more often diffuse (p = 0.007) and less often concordant (p = 0.015) to the epileptogenic hippocampus than in TLE with MTS.
Consequently, hippocampal NAA reductions in TLE without MTS are less accurate for the identification of the epileptogenic focus but nonetheless helpful for predicting the chance of becoming seizure free after epilepsy surgery. A study in 15 TLE without MTS from our laboratory (36) found that patients who became not seizure free had lower ipsilateral hippocampal NAA/(Cr+Cho) z scores than contralateral (p = 0.04). Furthermore, in comparison with patients who became seizure free, patients who did not had lower ipsilateral (p= 0.005) and contralateral (p=0.02) hippocampal NAA/(Cr+Cho) z sores. Taken together, TLE patients without MTS who became seizure free had milder and less well lateralized hippocampal NAA reductions than patients who did not.
Preliminary results show, that NAA reductions may also be helpful for focus identification in patients suffering from neocortical epilepsy (NE), i.e., a form of epilepsy where identification of the seizure focus is often challenging, particularly in patients with no structural abnormality on the MRI. We studied 21 patients with NE (10 with evidence for cortical malformations on the MRI, 11 with normal MRI) and 19 age-matched controls. In controls, NAA/Cr and NAA/Cho of all voxels of a given lobe was expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals for NAA/Cr and NAA/Cho. Voxels with NAA/Cr or NAA/Cho below the 95% prediction interval were defined as "pathological". Z-scores were used to identify regions with a high percentage of pathological voxels. MRSI correctly identified the lobe containing the epileptogenic focus as defined by EEG in 62% of the NE patients. MRSI localization of the focus was correct in 70% of the patients with a lesion on the MRI and in 55% of the patients with normal MRI.(37)
NAA reductions are also a common finding in different types of cortical malformations. These lesions result from a disruption of the developmental processes during neuroblast proliferation and differentiation, neuroblast migration, or postmigrational cortical organization. Using a similar method as for focus localization in NE, 30% (range 0 - 78%) of all voxels in cortical malformations (8 patients with 10 malformations) were found to be metabolically abnormal. The most common abnormalities were areas with reduced NAA or increased Cho which were interspersed within metabollically normal areas. Cortical malformations are not only characterized by a disturbed tissue architecture but also by an intrinsic epileptogenicity and those NAA and Cho abnormalities probably reflect both disturbances/38-'
11.2 NAA in Brain Regions Secondarily Involved Seizure Spread
Recent studies found NAA reduction not to be restricted to the focus but also in brain areas which are involved in seizure spread. This is well known in the TLE where in up to 50% of the patients NAA reductions are not only found in the ipsilateral hippocampus but also contralateral^/39 These contralateral NAA reductions increase to normal values after successful epilepsy surgery, but stay decreased, if surgery did not lead to seizure freedom (40). This finding further supports the hypothesis that NAA reductions in epileptic tissue are not necessarily due to neuron loss but rather present the disturbance of the neuronal metabolism caused by epileptogenic activity. Those extrafocal NAA reductions are not restricted to the limbic system but may involve even more remote brain areas as a study done in our laboratory recently demonstrated.
In this study, we used MR spectroscopic imaging in combination with tissue segmentation in 14 TLE patients with MTS, 7 TLE patients without MTS and 12 age-matched controls. To identify voxels with abnormally low NAA, NAA/(Cr+Cho) of all voxels of a given lobe was expressed as a function of white matter content to determine the 95% prediction interval for any additional voxel of a given tissue composition. Voxels with NAA/(Cr+Cho) below the lower limit of the 95% prediction interval were defined as "pathological". Z-scores were used to identify regions with a higher percentage of pathological voxels than in controls. Additional regions with reduced NAA/(Cr+Cho) were found in the ipsilateral temporal and parietal lobes and bilaterally in insula and frontal lobes. Temporal abnormalities identified the epileptogenic focus in 70% in TLE with MTS and 83% of TLE without MTS. Extratemporal abnormalities identified the hemisphere containing the epileptogenic focus in 78% of TLE with MTS but in only 17% of TLE without MTS. Therefore, temporal and extratemporal NAA/(Cr+Cho) reductions might be helpful for focus lateralization in TLE (41). Because volumetric studies found no evidence for tissue atrophy beyond the ipsilateral temporal lobe (42), it is reasonable that these NAA reductions probably also reflect neuronal dysfunction rather than actual neuronal loss. Furthermore, smaller, extrafocal areas with metabolic abnormalities were also found in 24% of the NE patients/37-*
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