Longitudinal declines in instrumental activities of daily living in stable and progressive mild cognitive impairment.

BACKGROUND: Previous cross-sectional studies suggest that assessments of instrumental activities of daily living (IADLs) may be useful for operationalizing the differences in functional deficits seen in mild cognitive impairment (MCI) and dementia. However, their utility for longitudinal changes in IADLs in the transition between MCI and dementia remains unclear. METHODS: We analyzed longitudinal IADL data with the Functional Activities Questionnaire (FAQ) in stable (MCI-S; n = 1,318) or progressive (MCI-P; n = 1,108) MCI patients. RESULTS: Larger increases in FAQ scores were seen in the MCI-P group across a 14.5-month interval, but overlapping distributions in the two groups yielded poorer discriminatory power than prior cross-sectional reports. CONCLUSION: Our findings emphasize the difficulties in operationalizing the criterion of 'essentially intact' IADLs in MCI, which may complicate the interpretation of disease progression in MCI treatment trials.

Methodological improvements in voxel-based analysis of diffusion tensor images: applications to study the impact of apolipoprotein E on white matter integrity.

PURPOSE: To identify regional differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) using customized preprocessing before voxel-based analysis (VBA) in 14 normal subjects with the specific genes that decrease (apolipoprotein [APO] E ε2) and that increase (APOE ε4) the risk of Alzheimer's disease. MATERIALS AND METHODS: Diffusion tensor images (DTI) acquired at 1.5 Tesla were denoised with a total variation tensor regularization algorithm before affine and nonlinear registration to generate a common reference frame for the image volumes of all subjects. Anisotropic and isotropic smoothing with varying kernel sizes was applied to the aligned data before VBA to determine regional differences between cohorts segregated by allele status. RESULTS: VBA on the denoised tensor data identified regions of reduced FA in APOE ε4 compared with the APOE ε2 healthy older carriers. The most consistent results were obtained using the denoised tensor and anisotropic smoothing before statistical testing. In contrast, isotropic smoothing identified regional differences for small filter sizes alone, emphasizing that this method introduces bias in FA values for higher kernel sizes. CONCLUSION: Voxel-based DTI analysis can be performed on low signal to noise ratio images to detect subtle regional differences in cohorts using the proposed preprocessing techniques.

Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer's disease mutations.

BACKGROUND: Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer's disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer's disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives. METHODS: Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects. RESULTS: MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume. CONCLUSIONS: Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD.

Patterns of brain atrophy in clinical variants of frontotemporal lobar degeneration.

BACKGROUND/AIMS: The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups. METHODS: Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects. RESULTS: Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology. CONCLUSION: The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.

Myelin breakdown mediates age-related slowing in cognitive processing speed in healthy elderly men.

BACKGROUND: To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimer's disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS). MATERIALS AND METHODS: The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An in vivo MRI biomarker of myelin integrity (transverse relaxation rates; R(2)) of LMWM was obtained for 38 very healthy elderly adult men (mean age=66.3 years; SD=6.0; range=55-76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test. RESULTS: LMWM R(2) and CPS measures were significantly correlated (r=.515, p=.0009), but no significant association between R(2) and CPS was detected in the splenium (p=.409). LMWM R(2), but not SWM R(2), was a significant mediator of the relationship between age and CPS (p=.037). CONCLUSIONS: In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium.

Reduced quality-of-life ratings in mild cognitive impairment: analyses of subject and informant responses.

OBJECTIVES: To determine whether quality-of-life (QOL) ratings are reduced in mild cognitive impairment (MCI) and analyze correlations between QOL ratings and cognitive, neuropsychiatric, and functional indices in MCI. DESIGN: Cross-sectional. SETTING: The Easton Center for Alzheimer's Disease Research at the University of California, Los Angeles. PARTICIPANTS: A total of 205 individuals who met criteria for normal cognition (n = 97) or MCI (n = 108). The MCI group included amnestic (n = 72) and nonamnestic (n = 36) MCI. MEASUREMENTS: QOL was assessed using subject and informant ratings on the Quality of Life-Alzheimer's Disease (QOL-AD) scale. Cognitive performance was assessed with the National Alzheimer's Disease Coordinating Center Uniform Data Set neuropsychological battery. Neuropsychiatric symptoms were assessed with the Geriatric Depression Scale (GDS) and the Neuropsychiatric Inventory. Functional abilities were assessed with the Functional Activities Questionnaire (FAQ). RESULTS: The normal cognition group had significantly higher QOL-AD scores than the MCI group on both subject and informant assessments. Individual item analyses indicated that the largest group differences were seen on the mood and memory items. Similar QOL-AD scores were seen in the amnestic and nonamnestic MCI subgroups. Multiple regression analyses within the MCI group indicated that QOL-AD ratings were not correlated with neuropsychological performance. Subject QOL-AD ratings were inversely correlated with GDS scores and informant QOL-AD ratings were inversely correlated with GDS, Neuropsychiatric Inventory, and FAQ scores. CONCLUSIONS: Significant declines in QOL are seen in MCI and are associated with neuropsychiatric symptoms and functional decline. Interventions targeting mood symptoms and/or instrumental activities of daily living may improve QOL in MCI.

Subtle deficits in instrumental activities of daily living in subtypes of mild cognitive impairment.

BACKGROUND/AIMS: Greater cognitive and functional deficits in mild cognitive impairment (MCI) are associated with higher rates of dementia. We explored the relationship between these factors by comparing instrumental activities of daily living (IADLs) among cognitive subtypes of MCI and examining associations between IADL and neuropsychological indices. METHODS: We analyzed data from 1,108 MCI and 3,036 normal control subjects included in the National Alzheimer's Coordinating Center Uniform Data Set who were assessed with the Functional Activities Questionnaire (FAQ). RESULTS: IADL deficits were greater in amnestic than nonamnestic MCI, but within these subgroups, did not differ between those with single or multiple domains of cognitive impairment. FAQ indices correlated significantly with memory and processing speed/executive function. CONCLUSIONS: IADL deficits are present in both amnestic MCI and nonamnestic MCI but are not related to the number of impaired cognitive domains. These cross-sectional findings support previous longitudinal reports suggesting that cognitive and functional impairments in MCI may be independently associated with dementia risk.

Utility of the functional activities questionnaire for distinguishing mild cognitive impairment from very mild Alzheimer disease.

Current criteria for mild cognitive impairment (MCI) require "essentially intact" performance of activities of daily living (ADLs), which has proven difficult to operationalize. We sought to determine how well the Functional Activities Questionnaire (FAQ), a standardized assessment of instrumental ADLs, delineates the clinical distinction between MCI and very mild Alzheimer disease (AD). We identified 1801 individuals in the National Alzheimer's Coordinating Center Uniform Data Set with MCI (n=1108) or very mild AD (n=693) assessed with the FAQ and randomized them to the development or test sets. Receiver-operator curve (ROC) analysis of the development set identified optimal cut-points that maximized the sensitivity and specificity of FAQ measures for differentiating AD from MCI and were validated with the test set. ROC analysis of total FAQ scores in the development set produced an area under the curve of 0.903 and an optimal cut-point of 5/6, which yielded 80.3% sensitivity, 87.0% specificity, and 84.7% classification accuracy in the test set. Bill paying, tracking current events, and transportation (P's<0.005) were the FAQ items of greatest diagnostic utility. These data suggest that the FAQ exhibits adequate sensitivity and specificity when used as a standardized assessment of instrumental ADLs in the diagnosis of AD versus MCI.

Time-lapse mapping of cortical changes in schizophrenia with different treatments.

Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.

Persistence of neuropsychological testing deficits in mild cognitive impairment.

BACKGROUND: The significant variability across studies of mild cognitive impairment (MCI) in rates of progression to Alzheimer's disease (AD) and reversion to normal cognition may be due to differences in specific neuropsychological tests and thresholds used to define MCI. METHODS: We assessed 115 subjects with amnestic (AMN) or non-amnestic (NON) MCI on a standardized neuropsychological battery at baseline and after a mean follow-up of 16.4 months to determine the prevalence and persistence of deficits identified with specific tests. RESULTS: The prevalence of impaired performance varied widely across tests. Deficits were more persistent in the AMN group than in the NON group. Baseline deficits in Visual Reproduction II and the California Verbal Learning Test were the best predictors of persistent memory impairment. Subjects who at baseline were impaired on multiple memory tests or had poorer overall memory performance were more likely to exhibit persistent memory deficits. CONCLUSIONS: The use of different neuropsychological tests and thresholds to diagnose MCI identified subsets of subjects with different rates of persistence of cognitive impairment. Standardization of the operational definition of cognitive impairment in MCI may result in more consistent predictions of progression to AD.

Mosaicism for trisomy 21 in a patient with young-onset dementia: a case report and brief literature review.

OBJECTIVE: To describe a case of young-onset Alzheimer disease (AD) due to mosaicism for trisomy 21. DESIGN: Case report of a single patient. SETTING: Tertiary referral dementia clinic. PATIENT: A 55-year-old man with a mild degree of developmental delay but no previous diagnosis of Down syndrome and only minimal physical manifestations of Down syndrome presented with gradually progressive cognitive impairment consistent with probable AD. RESULTS: Fluorescent in situ hybridization analysis of interphase chromosomes revealed trisomy 21 in 10% of peripheral lymphocytes. CONCLUSIONS: As mosaicism for trisomy 21 can present with no or minimal manifestations of Down syndrome, it may be underdiagnosed as a cause of early-onset AD. Occult mosaicism for trisomy 21 may explain in part the previously described association between family history of Down syndrome and risk of AD. Screening for mosaicism with fluorescent in situ hybridization is indicated in selected patients with mild developmental delay and those with AD of young onset.

Abnormal Trajectory of Intracortical Myelination in Schizophrenia Implicates White Matter in Disease Pathophysiology and the Therapeutic Mechanism of Action of Antipsychotics.

BACKGROUND: Postmortem and imaging studies provide converging evidence that the frontal lobe myelination trajectory is dysregulated in schizophrenia (SZ) and suggest that early in treatment, antipsychotic medications increase intracortical myelin (ICM). We used magnetic resonance imaging to examine whether the ICM trajectory in SZ is dysregulated and altered by antipsychotic treatment. METHODS: We examined 93 subjects with SZ (64 men and 29 women) taking second-generation oral antipsychotics with medication exposures of 0-333 months in conjunction with 80 healthy control subjects (52 men and 28 women). Frontal lobe ICM volume was estimated using a novel dual contrast magnetic resonance imaging method that combines two images that track different tissue components. RESULTS: When plotted against oral antipsychotic exposure duration, ICM of subjects with SZ was higher as a function of medication exposure during the first year of treatment but declined thereafter. In the age range examined, ICM of subjects with SZ was lower with increased age, while ICM of healthy control subjects was not. CONCLUSIONS: In adults with SZ, the relationship between length of exposure to oral second-generation antipsychotics and ICM was positive during the first year of treatment but was negative after this initial period, consistent with suboptimal later adherence after initial adherence. This ICM trajectory resembles clinically observed antipsychotic response trajectory with high rates of remission in the first year followed by progressively lower response rates. The results support postmortem evidence that SZ pathophysiology involves ICM deficits and suggest that correcting these deficits may be an important mechanism of action for antipsychotics.

Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia.

CONTEXT: Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination even in adulthood. Atypical antipsychotics have been shown to have a wide spectrum of efficacy across multiple psychiatric diseases and to be particularly efficacious in treatment resistant cases of disorders such as schizophrenia. OBJECTIVE: To test the a priori hypothesis that antipsychotic medications may differentially impact frontal lobe myelination in patients with schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Participants ranged in age from 18-35 years, were all male, and were recruited by a single group of investigators using the same criteria. Two cohorts of subjects with schizophrenia early in their disease who were treated either with oral risperidone (Ris) or fluphenazine decanoate (Fd) were imaged in conjunction with cohorts of healthy controls. Each cohort was imaged using a different MRI instrument using identical imaging sequences. MAIN OUTCOME MEASURE: MRI measures of frontal lobe white matter volume. RESULTS: We estimated differences due to differences in the MRI instruments used in the two studies in the two healthy control groups matched to the patient samples, adjusting for age and other covariates. We then statistically removed those differences (which we assumed were due to instrument effects) from the data in the schizophrenia samples by subtraction. Relative to the differences seen in controls, the two groups of schizophrenic patients differed in their pattern of frontal lobe structure with the Ris-treated group having significantly larger white matter volume than the Fd group. CONCLUSIONS: The results suggest that the choice of antipsychotic treatment may differentially impact brain myelination in adults with schizophrenia. Prospective studies are needed to confirm this finding. MRI can be used to dissect subtle differences in brain tissue characteristics and thus could help clarify the effect of pharmacologic treatments on neurodevelopmental and pathologic processes in vivo.

Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia.

CONTEXT: Apolipoprotein E (APOE) genotype is the most influential Alzheimer disease (AD) risk factor after advanced age. The APOE4 alleles decrease and the APOE2 alleles increase age at onset of AD. Human and nonhuman primate data suggest that in midlife, the structural integrity of myelin sheaths begins breaking down, with an accelerating age-related trajectory most evident in the brain's later-myelinating association regions. This may result in a progressive "disconnection" of widely distributed neural networks that may underlie the age risk factor for AD. OBJECTIVE: To assess, using magnetic resonance imaging, whether the shift in age at onset of AD observed with the APOE genotype is associated with the trajectory of age-related myelin breakdown. DESIGN: Cross-sectional. SETTING: Metropolitan university medical center. PARTICIPANTS: Healthy individuals (N = 104) aged 55 to 75 years who underwent genotyping for APOE. MAIN OUTCOME MEASURES: Calculated transverse relaxation rates, an indirect measure of white matter structural integrity, for late-myelinating frontal lobe white matter (Fwm) and early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and the genu (Gwm). RESULTS: The presence of the protective APOE2 allele was associated with significantly higher relaxation rates in Fwm and Gwm but not in Swm. Furthermore, APOE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in Swm. In Fwm and Gwm, APOE4+ individuals had a steeper slope of decline in relaxation rates with age than APOE2+ individuals; those with APOE3/3 alleles had an intermediate slope. CONCLUSIONS: In later-myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE status and support the hypothesis that this process may contribute to age at onset of AD. Combining APOE status with noninvasive measures of myelin breakdown may be useful in assessing treatment strategies for the primary prevention of AD.

Human brain myelination and amyloid beta deposition in Alzheimer's disease.

We hypothesized that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte- and myelin-associated iron that promotes amyloid beta (A beta) oligomerization, its associated toxicity, and the deposition of oligomerized A beta and iron in neuritic plaques observed in Alzheimer's disease (AD). The model was tested by using published maps of cortical myelination from 1901 and recent in vivo imaging maps of A beta deposits in humans. The data show that in AD, radiolabeled ligands detect A beta deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the strikingly lower ability of this imaging ligand to bind A beta in animal models is consistent with the much lower levels of myelin and associated iron levels in rodents when compared with humans. The hypotheses derived from the "myelin model" are testable with current imaging methods and have important implications for therapeutic interventions that should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

The Role of Neuropsychology in the Assessment of the Cognitively Impaired Elderly.

Cognitive abilities decline with age and older adults, as a group, are at increased risk for developing age-related cognitive disorders. Neuropsychological evaluation provides objective quantification of the type and severity of cognitive deficits that can affect the elderly population and elucidates a pattern of scores that provides diagnostic clues regarding etiology. It can also detect mild cognitive impairment that may not be evident on bedside assessment or mental status examination and provides critical information regarding the progression of cognitive changes through serial evaluations. Such information assists in counseling patients and family members and can guide therapeutic decisions.

Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men.

CONTEXT: There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD). OBJECTIVE: To evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with mild AD and healthy elderly men. DESIGN: Twenty-four-week, randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Memory disorders clinics as well as general neurology and medicine clinics from University of California medical centers at Los Angeles, San Francisco, and Irvine. PATIENTS OR OTHER PARTICIPANTS: Sixteen male patients with AD and 22 healthy male control subjects. Healthy elderly control men were recruited from the community through advertisements as well as through the university-based clinics. INTERVENTION: Testosterone and placebo, in the form of hydroalcoholic gel (75 mg), were applied daily to the skin of the participants. MAIN OUTCOME MEASURES: Instruments assessing cognitive functioning (Alzheimer's Disease Assessment Scale-Cognitive Subscale, California Verbal Learning Test, Block Design Subtest, Judgment of Line Orientation, Developmental Test of Visual-Motor Integration), neuropsychiatric symptoms (Neuropsychiatric Inventory), global functioning (Clinician's Interview-Based Impression of Change), and quality of life (Quality of Life-Alzheimer Disease Scale). RESULTS: For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale (P = .01). No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo. In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group (P = .09) compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures. Testosterone treatment was well tolerated with few adverse effects relative to placebo. CONCLUSIONS: Results suggest that testosterone replacement therapy improved overall quality of life in patients with AD. Testosterone had minimal effects on cognition.

Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder.

BACKGROUND: The efficacy and safety of risperidone was evaluated in veteran patients with chronic combat-related posttraumatic stress disorder (PTSD) who were referred to a residential treatment program. METHODS: Seventy-three subjects volunteered to participate in this double-blind, placebo-controlled study, which comprised of a 5 week residential program followed by a 3-month outpatient follow-up. Risperidone was added to a stable psychotropic medication regimen in 92% of subjects. Primary outcome measures were the Clinician-Administered PTSD scale (CAPS-total) and its three subscales; B (Re-experiencing), C (Avoidance) and D (Arousal). Secondary outcome measures were the Hamilton Anxiety (HAM-A) and Depression (HAM-D) scales, and the Positive and Negative Syndrome Scale, Positive Subscale (PANSS-P). RESULTS: Sixty-five subjects were randomized and 48 completed the 4-month study. Significantly greater improvement in symptoms was observed in subjects receiving risperidone compared to placebo on the CAPS-total and CAPS-D subscale scores and also on HAM-A and PANSS-P. Numerically greater improvements in all the remaining measures were noted with risperidone, but the differences did not reach statistical significance. Risperidone was well tolerated. CONCLUSIONS: These results suggest that adjunctive risperidone improved a broad range of psychiatric symptoms in patients with chronic combat-related PTSD. The data support the concept that atypical antipsychotic medications may have a wider therapeutic spectrum that goes beyond the treatment of psychosis.

Dysregulated brain development in adult men with schizophrenia: a magnetic resonance imaging study.

BACKGROUND: Recent imaging evidence suggests that normal brain development/maturation of the frontal lobes and association areas is a well-regulated process consisting of continued myelination and expansion of white matter volumes into the late 40s accompanied by complementary reductions in gray matter volumes. The possibility that a dysregulation of this process may contribute to the syndrome of schizophrenia was investigated using magnetic resonance imaging. METHODS: Fifty-two normal adult males and 35 males with schizophrenia underwent magnetic resonance imaging. Coronal images were acquired using pulse sequences that maximized myelin signal. The age-related change in the gray to white matter ratio was used as a measure of developmental dysregulation in the schizophrenic subjects and contrasted to the age-related changes of the normal control group. RESULTS: Regression analyses on frontal and temporal gray to white matter ratio yielded highly significant interactions of diagnosis and age for both regions (p =.0003 and p =.01, respectively). In the normal group, both frontal and temporal gray to white matter ratios decreased significantly and linearly across the age range. In contrast, neither ratio showed meaningful age-related change in the schizophrenia group. Thus, differences in gray to white matter ratio between the groups increased markedly with age, driven primarily by the absence of a white matter volume expansion in the patient group. CONCLUSIONS: The absence of the normal complementary volume changes in the gray and white matter with age in the schizophrenic sample suggests that this dynamic developmental process is dysregulated in adult schizophrenic subjects. The importance of myelination to the continued maturation and normal functioning of the brain has implications for the diagnosis, treatment, and prognosis of schizophrenia.

Brain maturation may be arrested in chronic cocaine addicts.

BACKGROUND: Animal and human newborn studies suggest that exposure to cocaine in utero delays glial maturation and white matter myelination. Postmortem data show that in the frontal and temporal lobes, white matter myelination continues into middle age. Recent magnetic resonance imaging (MRI) data have confirmed continued white matter volume increase in these regions, reaching a maximum at age 47. METHODS: Thirty-seven male cocaine dependent (CD) and 52 normal control subjects between ages 19 and 47 were evaluated with MRI. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray/white matter contrast. RESULTS: Highly significant positive correlations between white matter volume and age were observed in both the frontal and temporal lobes of the control group (r =.52, p =.0001 and r =.54, p =.0001, respectively); however, CD subjects did not demonstrate any age-related increase in white matter volume of the frontal (r = -.001; p =.99) and temporal (r = -.07; p =.67) lobes in this age range. CONCLUSIONS: The age-related expansion in white matter volume occurring in normal control subjects was absent in CD subjects. The findings suggest that in adults, cocaine dependence may arrest normal white matter maturation in the frontal and temporal lobes of addicts who continue using cocaine.