Alcohol-induced dementia (alcohol-induced cognitive impairment).
- Diagnostic criteria
- Structural neuroimaging
- Functional neuroimaging
- Neuropsychological deficits
Alcoholic brain damage was, until fairly recently, viewed as existing in two major forms: the alcoholic Korsakoff syndrome and alcoholic ‘dementia'. Most ‘alcoholics' suffering long-term cognitive impairment were thought to fit into the clearly defined Korsakoff category. A smaller proportion, with ‘widespread cerebral dysfunction of an uncertain nature' was included in the poorly defined category of alcoholic ‘deterioration' or ‘dementia'. (1,2)
The alcoholic Korsakoff syndrome, caused by thiamine deficiency, has been the focus of comprehensive research (it should be noted that the chronic Korsakoff syndrome does not respond to thiamine). Research into the aetiology of alcoholic ‘dementia' has been less rigorous, but evidence for the direct neurotoxic effect of alcohol has been suggested by neuropathological and neuroimaging studies, and by animal experiments. (The Korsakoff syndrome is considered in the article about amnesic syndromes)
Diagnostic criteria for ‘substance-induced persisting dementia' are included in DSM-IV (3) (Table 1), which also states that there must be evidence from the history, physical examination, or laboratory findings that the deficits are aetiologically related to the persisting effects of substance use (in this case alcohol). The amnesic (Korsakoff) syndrome is listed separately in ICD-10, (4) whereas alcoholic ‘dementia' is included under the ‘residual and late-onset psychotic disorder' category, where diagnostic guidelines can be found.
Table 1: DSM-IV diagnostic criteria for substance-induced persisting dementia
A. The development of multiple cognitive deficits manifested by both
- memory impairment (impaired ability to learn new information or to recall previously learned information)
- one (or more) of the following cognitive disturbances: (a) aphasia (language disturbance) (b) apraxia (impaired ability to carry out motor activities despite intact motor function) (c) agnosia (failure to recognize or identify objects despite intact sensory function) (d) disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting)
B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
C. The deficits do not occur exclusively during the course of a Delirium and persist beyond the usual duration of Substance Intoxication or Withdrawal.
D. There is evidence from the history, physical examination, or laboratory findings that the deficits are etiologically related to the persisting effects of substance use (e.g., a drug of abuse, a medication).
Early neuropathological studies of the alcoholic brain described fairly uniform cerebral atropy, mainly over the dorsolateral frontal regions, widened sulci, a narrowed cortical ribbon, and enlargement particularly of the anterior horns of the lateral ventricles. (1) Air encephalographic studies indicated that between half and three-quarters of subjects showed cortical changes or ventricular enlargement. (5,6) In comparison with controls, brain weights of alcoholics are reduced at autopsy. (7,8) Brain volume, estimated by the volume of the pericerebral space—the cerebrospinal fluid-filled region between the brain and the skull—is also reduced. (9) This indirect measure of cerebral atrophy is, however, mostly described in alcoholics with liver disease or Wernicke's encephalopathy.
The reduction in cerebral volume seen in the alcoholic brain is due mainly to the loss of white matter in the cerebral hemispheres. (10,11) The corpus callosum, in particular, is reduced in thickness. (12) Cortical grey matter appears also to be affected, although the evidence is more equivocal. The selective neuronal loss in the superior frontal cortex reported in one study (13) was not confirmed in another. (11) However, there is evidence that individual neurones are shrunken in regions where neuronal numbers are normal, such as the superior frontal, cingulate, and motor cortices. (13,14)
Animal research suggests that alcohol has a direct neurotoxic effect on the brain. Chronic ingestion of ethanol by well-nourished rats has been shown to be toxic to cholinergic projection neurones (15) and to reduce the complexity of dendritic arborization in hippocampal pyramidal neurones. (16) In the former study, transplantation of cholinergic neurones into the hippocampus and neocortex corrected the cholinergic deficits and memory abnormalities. In the latter, abstinence led to an increase in dendritic arborization.
Neuroimaging studies (CT and magnetic resonance imaging (MRI)) comparing recently detoxified alcoholics without obvious cognitive impairment with age-matched controls confirm that the alcoholics show evidence of reduced cortical brain volume affecting both grey and white matter, and also increased cerebrospinal fluid spaces. (17) These changes in brain structure are evident in young ‘social drinkers', (18) but are more prominent in older age groups. Women appear to be particularly vulnerable. However, clinico-radiological comparisons have been equivocal, with measures of radiological change failing to correlate consistently with either duration of drinking or the severity of cognitive impairment. The role of concurrent liver disease is likewise poorly understood. Abstinence leads to reversibility of brain shrinkage;(19) this is most marked in younger individuals and in women. (20) However, many abstinent alcoholics continue to have enlarged ventricles. CT studies have also reported altered absorption densities in the alcoholic brain, (2) the significance of which is not fully understood.
MRI studies have reported volume reductions in localized cortical and subcortical structures, especially the frontal lobes, (21) the mesial temporal lobe structures, (22) the anterior hippocampus, (23) mammillary bodies and cerebellum, (24,25) and corpus callosum, (26) particularly in older age groups. A controlled 5-year follow-up study of alcohol-dependent (n = 16) and control (n = 26) subjects found that both groups showed evidence of age-related reductions in cortical grey matter at follow-up (especially in the prefontal cortex), also enlargement of the lateral and third ventricles. (27) While the alcohol-dependent subjects showed additional loss in the anterior superior temporal cortex, the alcohol-dependent subjects who maintained sobriety over the follow-up period had similar rates of change in ventricular volume as the controls. Continued alcohol abuse in the dependent group resulted in cortical grey-matter volume loss, the degree of which was predicted by the amount of alcohol consumed.
Functional imaging studies have shown hypometabolism in the frontal and parietal cortices of chronic alcoholics without major neurological impairment when compared with normal controls. (28,29 and 30) These abnormalities improve following abstinence, (30,31) mainly during the 16 to 30 days after the last use of alcohol. Metabolic recovery is most marked in the frontal area. (30)
Proton magnetic resonance spectroscopy can be combined with MRI, allowing in vivo insight into brain metabolism. (32,33 and 34) The metabolic changes observed in the few magnetic resonance spectroscopy studies that have been carried out suggest neuronal loss and compensatory gliosis.
Many individuals with a history of chronic excessive alcohol consumption show evidence of moderate impairment in short- and long-term memory, learning, visuoperceptual abstraction, visuospatial organization, the maintenance of cognitive set, and impulse control. (35) This tendency for alcoholics to show proportionally greater visuospatial than language-related impairments suggests that alcohol might have a selective effect on the right hemisphere : the so-called ‘right hemisphere hypothesis'. (36) However, right hemisphere functions also decline with ageing and the current view is that the functional lateralities of ‘alcoholics' and ageing individuals are similar to normal controls. (36)
Neuropsychological performance improves with abstinence but impairments are still detectable even after 5 years of abstinence. (37) Performance on neuropsychological tests has generally been poorly correlated with structural imaging changes, (19,38) particularly with changes in grey-matter volume. However, one MRI study reported significant correlations between cortical (sulcal) and subcortical (ventricular) fluid volumes and some cognitive measures. (22) Another study using a combination of structural (CT or MRI) and functional imaging (positron emission tomography) together with neuropsychological tests in older alcohol-dependent patients who were abstinent found a significant correlation between degree of atrophy/metabolic functioning in the cingulate gyrus, and performance on the Wisconsin Card Sort Test. (39)
Neuropsychological test scores do not predict outcome in alcohol-dependent patients. (40,41)
Individuals with alcohol-induced brain damage and cognitive impairment are a heterogeneous group. The underlying mechanisms are probably numerous, complex, and interrelated. Alcohol and acetaldehyde neurotoxicity, thiamine depletion, and metabolic factors, such as hypoxia, electrolyte imbalance, and hypoglycaemia, which result from acute or chronic intoxication and withdrawal are all important. Recurrent alcohol withdrawal has been hypothesized to have a kindling effect. (42) During alcohol withdrawal there is increased N-methyl-D-aspartate (NMDA) function which is postulated to lead to increased neuronal excitability and to glutamate-induced neurotoxicity. (43) The way in which alcohol interferes with glutamatergic neurotransmission, especially through the NMDA receptor, is probably central to an understanding of its long-term effects on the brain.
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