Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis

BACKGROUND: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage. OBJECTIVES: To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters. METHODS: 36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. RESULTS: On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ (r = -0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function. CONCLUSIONS: Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.     

Early neuropsychological signs of childhood adrenoleukodystrophy (ALD)

Objective: To identify the very early signs of childhood cerebral adrenoleukodystrophy (CALD) in asymptomatic boys. Methods: Subjects were 8 neurologically and radiologically asymptomatic CALD patients. They were chosen from 22 ALD patients before hematopoietic stem cell transplantation (HSCT) treatment. Wechsler Intelligence Scale tests and other neuropsychological tests were performed. Their IQ data were compared with those of symptomatic ALD children with apparent brain lesions. Results: All asymptomatic CALD showed normal FIQ. PIQ was significantly lower than VIQ in 2 patients. Occipital lesioned patients often showed normal VIQ with low PIQ. Gestalt Closure in The Kaufman Assessment Battery for Children and Constancy of Shape in the Frostig Developmental Test of Visual Perception seemed to be effective for detecting visual cognitive dysfunction in asymptomatic CALD whose difference of VIQ and PIQ was within the normal range. Conclusions: Follow-up of asymptomatic ALD boys with neuropsychological tests along with previously reported neurophysiological tests may help in determining the timing of therapeutic intervention. Neuropsychological abnormalities seemed to precede the appearance of clinical and MRI alterations.     

A novel temporal pattern of childhood cerebral X-linked adrenoleukodystrophy

We report a 9-year-old boy, with childhood cerebral X-linked adrenoleukodystrophy (CCALD), presenting with an episode of loss of consciousness, fixed gaze, hypotonia and vomit with spontaneous resolution and post-ictal sleep. Behavioural impairment has been observed since the previous five months. Magnetic Resonance Images (MRI) revealed isolated bilateral, symmetric, confluent temporal white matter lesions involving also corticospinal tracts, with sparing of the parieto-occipital and frontal white matter. This report outlines an atypical neuroradiological localization of X-linked adrenoleukodystrophy and neuropsychological findings not specifically related to the brain involvement seen at the MRI.     

Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy

BACKGROUND AND PURPOSE: Cerebral microangiopathy, indicated on MRI by lacunar infarctions (LI) and deep white matter lesions (DWML), is said to lead to vascular dementia. METHODS: Fifty-seven patients with proven cerebral microangiopathy were assessed for changes in regional cerebral blood flow (rCBF) and glucose metabolism (rMRGlu) and compared with 19 age-matched controls. The findings were correlated with results of extensive neuropsychological testing, as well as with MRI findings. A special head holder ensured reproducibility of positioning during rCBF (single-photon emission CT [SPECT]), rMRGlu (positron emission tomography [PET]), and MR imaging. White matter and cortex were quantified with regions of interest defined on MRI and superimposed to corresponding PET/SPECT slices. LI and DWML were graded by number and extent. RESULTS: Even with severe DWML and multiple LI, rCBF and rMRGlu values were not reduced. ANOVAs identified brain atrophy and neuropsychological deficits as the main determinants for reduced rCBF and rMRGlu values in both cortex and white matter. Neuropsychological deficits correlated well with decreased rCBF and rMRGlu, whereas MRI patterns such as LI and DWML did not. Factor analysis revealed no correlation of LI and DWML with rCBF, rMRGlu, atrophy, and neuropsychological deficits, showing instead positive correlations between rCBF, rMRGlu, and neuropsychological performance and negative correlations of the latter 3 with brain atrophy. CONCLUSIONS: From these data, we conclude that LI and DWML are epiphenomena that may morphologically characterize cerebral microangiopathy but do not in themselves indicate cognitive impairment. Dementia or neuropsychological deficits, by contrast, are reflected exclusively by functional imaging parameters (rCBF, rMRGlu) and cerebral atrophy.     

Clinical evaluation of childhood cerebral adrenoleukodystrophy with balint’s symptoms

BackgroundChildhood cerebral adrenoleukodystrophy (CCALD) is the most common phenotype of adrenoleukodystrophy (ALD) and is characterized by the progression of intellectual, psychic, visual, and gait disturbances. Progression of this intractable disease can only be prevented by hematopoietic stem cell transplantation during the early stages of the disease. The aim of this study was to clinically evaluate children with CCALD who have visual symptoms to enable early diagnosis.MethodsWe enrolled 41 Japanese children with CCALD who had visual symptoms. We retrospectively analyzed age of onset, past medical history, initial symptoms, visual symptoms and findings on brain magnetic resonance imaging.ResultsThe median age of disease onset was 7 years (range 5–10 years). The most common visual symptom was strabismus (n = 22). There was only one patient with the triad of symptoms of Balint’s syndrome. Seventeen patients had incomplete Balint’s syndrome and showed one or two of the triad of symptoms. Almost all patients with complete or incomplete Balint’s syndrome showed bilateral parieto-occipital white matter lesions.ConclusionsCCALD could develop into Balint’s syndrome, especially the incomplete form. Therefore, CCALD should be considered when boys show new symptoms, including lack of eye contact or bumping into objects.     

Brain MRI and electrophysiologic abnormalities in preclinical and clinical adrenomyeloneuropathy.

We describe the neurophysiologic abnormalities in 17 patients with clinical adrenomyeloneuropathy (AMN), an adult phenotype of X-linked adrenoleukodystrophy (ALD). These abnormalities also allowed the early recognition of the AMN phenotype in three asymptomatic boys with biochemically proven ALD. In 14/16 adult AMN patients, there were cerebral white matter abnormalities on MRI which were severe and comparable with cerebral ALD in four of the patients.     

Regional white matter and neuropsychological functioning across the adult lifespan.

BACKGROUND: The current study utilized magnetic resonance imaging (MRI) to more fully elucidate the relationship among age, regional white matter, and neuropsychological functioning. METHODS: One hundred ninety-nine neurologically healthy adults received MRI and standardized neuropsychological assessment. MR images were spatially normalized and segmented by tissue type; relative white matter values in each of the four cerebral lobes in each hemisphere were computed. Subjects were divided into Younger (ages 21-30), Middle (ages 31-54), and Older (ages 55-79) age groups. RESULTS: The Older group had significantly less overall relative white matter than the Middle group, who had significantly less overall relative white matter than the Younger participants (F (2, 193) = 5.42, p = 0.005). Differences in frontal lobe white matter were of largest magnitude, followed by temporal lobe (F (6, 579) = 3.32, p = 0.003). Age and frontal and temporal lobe white matter were primarily associated with performance on neuropsychological tests of executive functioning and memory. Mediational analysis suggested that frontal lobe white matter mediated the relationship between age and performance on tasks of executive functioning and memory. CONCLUSIONS: The results confirm age-associated decline in frontal and temporal white matter, and age-related cognitive decline in several domains. Decline in neuropsychological functioning is, in part, mediated by a relative age-related reduction in frontal white matter.     

Evaluation of preclinical onset in patients with the childhood form of cerebral adrenoleukodystrophy--usefulness of visual cognitive function and evoked potential tests

We examined both visual evoked potential (VEP) and neuropsychological tests in 18 patients with X-linked adrenoleukodystrophy (ALD). Patients consisted of 10 boys with apparent lesions in the posterior white matter on MR imaging, 3 with lesions in the frontal white matter area and 5 that were neurologically asymptomatic with no apparent brain MRI abnormalities. Almost all patients with posterior WM lesion showed patterns of lower PIQ than VIQ on WISC-III and lower scores on scales for simultaneous processing than for sequential processing on Kaufman Assesment Battery for Children (K-ABC). Four of 5 asymptomatic patients showed PIQ/VIQ patterns similar to those in the posterior group. Patients with a difference more than 13 between PIQ and VIQ also showed poor results on Frostig developmental test of visual perception (DTVP). There was a prolongation of the peak latency of P100 on flash VEP in many patients with posterior whitematter lesions, however, asymptomatic patients did not show any abnormality of P100 latency but there was an increased amplitude of N75-P100 on flash and pattern reversal stimuli VEP. One patient with abnormally high VEP (31.4 microV; + 3.6 SD) gradually improved to the normal range (11.4 microV; 0SD) after hematopoietic stem cell transplantation. These cognitive and neurophysiological examinations could be useful in the detection of preclinical onset of childhood ALD before the appearance of MRI lesions on MRI.     

Neuropsychological assessment in multiple sclerosis: a follow-up study with magnetic resonance imaging

Summary Nineteen moderately impaired patients with clinically definite multiple sclerosis and an initially relapsing-remitting course were included in a neuropsychological and magnetic resonance imaging (MRI) follow-up study. The average test/re-test interval was about 2 years. The neuropsychological findings were indicative of a very mild overall impairment; the patients, as a group, showed no evidence of cognitive deterioration in the follow-up period. A numerical estimation of the severity of cerebral demyelination shown by MRI did not indicate a significant change. No correlation between cognitive performance variations and MRI changes was found.     

Neuropsychological outcome after a first symptomatic ischaemic stroke with ‘good recovery’

Background: Neuropsychological impairment after stroke when no motor, sensory or language deficits are left remains understudied. The primary aim of this study was to assess neuropsychological outcome in a specific population of patients after a first symptomatic stroke without previous cognitive decline and with a good motor, linguistic, and functional recovery (i.e. ‘good outcome’). The secondary aims were to identify the profile of this potential impairment and relations between brain lesions and neuropsychological outcome. Methods: Sixty consecutive patients were evaluated by a comprehensive neuropsychological assessment focusing specifically on executive and attentional functions but also on memory 109 days, on average, after the infarct. Patients were compared with 40 healthy controls matched for age and education. Results: Patients showed lower performance in every cognitive domain compared with controls. Along with an important executive deficit, patients were also impaired on attention and memory. Patients were not more depressed than controls, although they were more apathetic. We also found a significant positive correlation between cognitive impairment and pre‐existing white matter brain lesions assessed by MRI. Conclusions: We report the first study examining the impact of a first stroke on cognition but also on psychiatric disorders in patients with good functional outcome. We found that patients considered as asymptomatic were, in fact, exhibiting a multidomain cognitive deficit that could impact return to life as before stroke.     

Cognitive dysfunction 24-31 years after isolated optic neuritis

OBJECTIVE: Cognitive dysfunction is common in multiple sclerosis (MS), but long-term data on cognition in patients with clinically isolated syndromes are sparse. METHODS: We determined cognitive functions in 22 patients 44-75 years old diagnosed with optic neuritis 24-31 years earlier but had no further clinical bouts and had not progressed clinically to MS. We used a neuropsychological test battery covering nine cognitive domains. Magnetic resonance imaging (MRI) of the brain had been performed earlier and was normal in six patients and showed two or more white matter abnormalities compatible with demyelinating lesions in 16 patients. RESULTS: On neuropsychological testing, one patient was within normal range on all tests, six subjects showed borderline results, and 15 patients (68%) showed significantly impaired performance in at least one cognitive domain. Seven patients showed significant impairment in two or more domains. Executive function, visuo-spatial ability, and information processing speed were the most frequently affected domains. There was no apparent correlation between MRI findings and cognitive function. CONCLUSIONS: We conclude that cognitive dysfunction is common in patients many years after clinically isolated optic neuritis. Cognitive dysfunction was found even in patients who had no apparent demyelinating lesions on follow-up MRI.     

White matter volumes and periventricular white matter hyperintensities in aging and dementia

OBJECTIVE: To determine the relationship between MRI periventricular white matter hyperintensities, cerebral white matter volumes, neuropathologic findings, and cognitive status in aged individuals. BACKGROUND: The significance of periventricular white matter hyperintensities seen on MR images in aged individuals remains controversial. The Nun Study is a longitudinal cohort aging study in which all 678 initially enrolled participants agreed to autopsy neuropathologic examination. METHODS: We used MRI to measure white matter volumes of the cerebral hemispheres in 52 formaldehyde-fixed brains for correlation with white matter and neocortical pathology, postmortem MRI observations, and cognitive measures. RESULTS: Reduced white matter volume is associated with dementia, but periventricular white matter hyperintensities were not related to white matter volume, stroke, or dementia. CONCLUSIONS: Our results do not support the hypothesis that periventricular hyperintensities seen on MR images have deleterious consequences in these aged individuals.     

Cognitive impairment and associated loss in brain white microstructure in aircrew members exposed to engine oil fumes

Cabin air in airplanes can be contaminated with engine oil contaminants. These contaminations may contain organophosphates (OPs) which are known neurotoxins to brain white matter. However, it is currently unknown if brain white matter in aircrew is affected. We investigated whether we could objectify cognitive complaints in aircrew and whether we could find a neurobiological substrate for their complaints. After medical ethical approval from the local institutional review board, informed consent was obtained from 12 aircrew (2 females, on average aged 44.4 years, 8,130 flying hours) with cognitive complaints and 11 well matched control subjects (2 females, 43.4 years, 233 flying hours). Depressive symptoms and self-reported cognitive symptoms were assessed, in addition to a neuropsychological test battery. State of the art Magnetic Resonance Imaging (MRI) techniques were administered that assess structural and functional changes, with a focus on white matter integrity. In aircrew we found significantly more self-reported cognitive complaints and depressive symptoms, and a higher number of tests scored in the impaired range compared to the control group. We observed small clusters in the brain in which white matter microstructure was affected. Also, we observed higher cerebral perfusion values in the left occipital cortex, and reduced brain activation on a functional MRI executive function task. The extent of cognitive impairment was strongly associated with white matter integrity, but extent of estimated number of flight hours was not associated with cognitive impairment nor with reductions in white matter microstructure. Defects in brain white matter microstructure and cerebral perfusion are potential neurobiological substrates for cognitive impairments and mood deficits reported in aircrew.     

Neuropsychological correlates of MRI measures in the continuum of cognitive decline at old age

OBJECTIVE: To investigate the independent associations between medial temporal lobe atrophy and white matter hyperintensities (WMH) and cognitive functions in the elderly. METHODS: Cognitive functions of 41 Alzheimer's disease patients, 20 patients with mild cognitive impairment and 28 elderly subjects without memory complaints were assessed using a neuropsychological test battery. Quantitative MRI measures of medial temporal lobe volume and WMH were obtained. Multiple regression analyses were performed to assess the independent contribution of MRI measures to impairment in several cognitive functions. RESULTS: Scores on the Wechsler Memory Scale and Trails B depended selectively on medial temporal lobe volume, whereas WMH selectively contributed to performance on Trails A. Medial temporal lobe volume and WMH both contributed to scores on the Cambridge Cognitive Examination and the Boston naming task. CONCLUSIONS: MRI measures suggestive of Alzheimer-type pathology and microvascular pathology independently contribute to cognitive decline at old age. Memory impairment as measured using the Wechsler Memory Scale and performance on Trails B primarily depended on medial temporal lobe atrophy. Psychomotor slowness, as measured using Trails A, mainly depended on WMH. These results suggest that vascular pathology and Alzheimer-type pathology each have specific cognitive correlates.     

MRI white matter hyperintensities: three-year follow-up of the Austrian Stroke Prevention Study.

OBJECTIVE: To determine the rate, clinical predictors, and cognitive consequences of MRI white matter hyperintensity evolution over 3 years. METHODS: In the setting of the Austrian Stroke Prevention Study, 1.5-T MRI was performed at baseline and at a 3-year follow-up in 273 community-dwelling elderly (mean age, 60+/-6.1 years) without neuropsychiatric disease. At each visit individuals underwent a structured clinical interview and examination, EKG, echocardiography, extensive laboratory workup, and demanding neuropsychological testing. MR images were read by three independent raters, and the change of white matter hyperintensities from baseline was assessed by direct image comparison. The change was graded as absent, minor, or marked. Minor change was defined as a difference of no more than one to four punctate lesions between both scans. A change was considered to be marked if there was a difference of more than four abnormalities or a transition to early-confluent and confluent lesions. RESULTS: Combined ratings indicated lesion progression in 49 individuals (17.9%). Lesion progression was minor in 27 participants (9.9%) and was marked in 22 (8.1%). Regression of white matter hyperintensities did not occur. Diastolic blood pressure (odds ratio, 1.07/mm Hg) and early-confluent or confluent white matter hyperintensities at baseline (odds ratio, 2.62) were the only significant predictors of white matter hyperintensity progression. Lesion progression had no influence on the course of neuropsychological test performance over the observational period. CONCLUSIONS: White matter hyperintensities progress in elderly normal subjects. Our data may be used as a reference for future observational and interventional studies on white matter hyperintensity progression in various CNS diseases. The lack of an association between lesion progression and cognitive functioning needs to be explored further.     

Cerebral metabolism, anatomy, and cognition in monozygotic twins discordant for dementia of the Alzheimer type.

One pair of monozygotic twins discordant for dementia of the Alzheimer type (DAT) was studied using neuropsychological testing, quantitative x-ray computed tomography (QCT) and magnetic resonance imaging (MRI) of the brain. Cerebral glucose metabolism was measured using positron emission tomography (PET) and 2-[18-F]fluoro-2-deoxy-D-glucose (FDG). The affected twin had a seven year history of progressive cognitive impairment and was severely demented. Neuropsychological testing of the affected twin demonstrated marked deficits in all areas of cognitive function. The asymptomatic twin showed some impairment on tests of perceptual organisation and delayed recall. The affected twin had loss of gray matter and ventricular enlargement on QCT and MRI compared with healthy controls (p less than 0.05). He also had frontal and parietal lobe hypometabolism and increased asymmetry of metabolism on PET compared to both his twin and healthy age-matched controls (p less than 0.05). PET, QCT, and MRI distinguished changes in the twin with DAT compared with his brother and healthy controls. Although the subtle neuropsychological abnormalities of the asymptomatic twin may be signs of early DAT, they were not accompanied by any changes in regional cerebral metabolism or brain structure.     

Cerebral white matter lesions and subjective cognitive dysfunction: the Rotterdam Scan Study

OBJECTIVE: To determine the relationship between cerebral white matter lesions (WML) and subjective cognitive dysfunction. BACKGROUND: Subjective cognitive dysfunction is present when a person perceives failures of cognitive function. When annoying enough, these failures will be expressed as complaints. Subjective cognitive dysfunction may be a prelude to or coincide with objective cognitive impairment. WML have been related to objective cognitive impairment and dementia, but their relationship with subjective cognitive dysfunction is not clear. Previous population-based studies on the latter relationship have been limited in sample size, recording of subjective cognitive function, and assessment of WML severity. METHODS: We randomly sampled 1,049 elderly nondemented participants from the general population. Data on subjective cognitive dysfunction and its progression were derived from a 15-item questionnaire. Objective cognitive performance was assessed using a series of neuropsychological tests. WML were scored on MRI for periventricular and subcortical regions separately. RESULTS: WML were associated with more subjective cognitive failures. WML were more severe for participants reporting progression of these failures compared with participants without these failures, especially within participants with better than average cognitive performance (p = 0.008, for periventricular WML). Participants with severe WML reported progression of cognitive failures more than twice as often than did those with little or no WML. The relationship between the severity of WML and subjective cognitive failures was present for periventricular and subcortical WML. CONCLUSIONS: WML are associated with subjective cognitive failures and in particular with reporting progression of these failures, even in the absence of objective cognitive impairment.     

Brain Structure in Neuropsychologically Defined Subgroups of Schizophrenia and Psychotic Bipolar Disorder

Background:

Neuropsychological impairment is heterogeneous in psychosis. The association of intracranial volume (ICV) and total brain volume (TBV) with cognition suggests brain structure abnormalities in psychosis will covary with the severity of cognitive impairment. We tested the following hypotheses: (1) brain structure abnormalities will be more extensive in neuropsychologically impaired psychosis patients; (2) psychosis patients with premorbid cognitive limitations will show evidence of hypoplasia (ie, smaller ICV); and (3) psychosis patients with evidence of cognitive decline will demonstrate atrophy (ie, smaller TBV, but normal ICV).

Methods:

One hundred thirty-one individuals with psychosis and 97 healthy subjects underwent structural magnetic resonance imaging and neuropsychological testing. Patients were divided into neuropsychologically normal and impaired groups. Impaired patients were further subdivided into deteriorated and compromised groups if estimated premorbid intellect was average or below average, respectively. ICV and TBV were compared across groups. Localized brain volumes were qualitatively examined using voxel-based morphometry.

Results:

Compared to healthy subjects, neuropsychologically impaired patients exhibited smaller TBV, reduced grey matter volume in frontal, temporal, and subcortical brain regions, and widespread white matter volume loss. Neuropsychologically compromised patients had smaller ICV relative to healthy subjects, and neuropsychologically normal and deteriorated patient groups, but relatively normal TBV. Deteriorated patients exhibited smaller TBV compared to healthy subjects, but relatively normal ICV. Unexpectedly, TBV, adjusted for ICV, was reduced in neuropsychologically normal patients.

Conclusions:

Patients with long-standing cognitive limitations exhibit evidence of early cerebral hypoplasia, whereas neuropsychologically normal and deteriorated patients show evidence of brain tissue loss consistent with progression or later cerebral dysmaturation.Key words: psychosis, cognition, brain volume, neurodevelopmental, neuroprogressive     

Evidence for cortical "disconnection" as a mechanism of age-related cognitive decline

BACKGROUND: Normal aging is accompanied by a decline of cognitive abilities, and executive skills may be affected selectively, but the underlying mechanisms remain obscure and preventive strategies are lacking. It has been suggested that cortical "disconnection" due to the loss of white matter fibers may play an important role. But, to date, there has been no direct demonstration of structural disconnection in humans in vivo. METHODS: The authors used diffusion tensor MRI to look for evidence of ultrastructural changes in cerebral white matter in a group of 20 elderly volunteers with normal conventional MRI scans, and a group of 10 younger controls. The older group also underwent neuropsychological assessment. RESULTS: Diffusional anisotropy, a marker of white matter tract integrity, was reduced in the white matter of older subjects and fell linearly with increasing age in the older group. Mean diffusivity was higher in the older group and increased with age. These changes were maximal in anterior white matter. In the older group, anterior mean diffusivity correlated with executive function assessed by the Trail Making Test. CONCLUSIONS: These findings provide direct evidence that white matter tract disruption occurs in normal aging and would be consistent with the cortical disconnection hypothesis of age-related cognitive decline. Maximal changes in anterior white matter provide a plausible structural basis for selective loss of executive functions. In addition to providing new information about the biological basis of cognitive abilities, diffusion tensor MRI may be a sensitive tool for assessing interventions aimed at preventing cognitive decline.     

Therapy of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) onset leading to death within a few years, over adult-onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades, or adrenal insufficiency only. Approximately 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not prove to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Hormone-replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates for future X-ALD therapies.