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.

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.

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.

Neuroanatomical correlates of emotional blunting in behavioral variant frontotemporal dementia and early-onset Alzheimer's disease.

BACKGROUND: Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia. OBJECTIVE: We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimer's disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume. METHODS: Twenty-five individuals with bvFTD (n = 11) and early-onset AD (n = 14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry. Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores. RESULTS: The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant. CONCLUSIONS: Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB appears to measure symptoms of emotional blunting that are localized to the right anterior temporal lobe.

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 differences in white matter breakdown between frontotemporal dementia and early-onset Alzheimer's disease.

BACKGROUND: White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). OBJECTIVE: Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting. METHODS: We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale for Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants. RESULTS: Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group. CONCLUSIONS: The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.

Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer's disease detected in vivo with magnetic resonance imaging.

BACKGROUND: Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimer's disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined. OBJECTIVE: To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls. METHODS: Thirty-one AD and sixty-eight healthy control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2) was used as an index of tissue damage. RESULTS: Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p = 0.019) but not Th (p = 0.637), and significantly decreased R2 in Hipp (p < 0.001) but not Th (p = 0.37). In the entire sample, FDRI and R2 were negatively correlated. CONCLUSION: The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD.

What dementia reveals about proverb interpretation and its neuroanatomical correlates.

OBJECTIVE: Neuropsychologists frequently include proverb interpretation as a measure of executive abilities. A concrete interpretation of proverbs, however, may reflect semantic impairments from anterior temporal lobes, rather than executive dysfunction from frontal lobes. The investigation of proverb interpretation among patients with different dementias with varying degrees of temporal and frontal dysfunction may clarify the underlying brain-behavior mechanisms for abstraction from proverbs. We propose that patients with behavioral variant frontotemporal dementia (bvFTD), who are characteristically more impaired on proverb interpretation than those with Alzheimer's disease (AD), are disproportionately impaired because of anterior temporal-mediated semantic deficits. METHODS: Eleven patients with bvFTD and 10 with AD completed the Delis-Kaplan Executive Function System (D-KEFS) Proverbs Test and a series of neuropsychological measures of executive and semantic functions. The analysis included both raw and age-adjusted normed data for multiple choice responses on the D-KEFS Proverbs Test using independent samples t-tests. Tensor-based morphometry (TBM) applied to 3D T1-weighted MRI scans mapped the association between regional brain volume and proverb performance. Computations of mean Jacobian values within select regions of interest provided a numeric summary of regional volume, and voxel-wise regression yielded 3D statistical maps of the association between tissue volume and proverb scores. RESULTS: The patients with bvFTD were significantly worse than those with AD in proverb interpretation. The worse performance of the bvFTD patients involved a greater number of concrete responses to common, familiar proverbs, but not to uncommon, unfamiliar ones. These concrete responses to common proverbs correlated with semantic measures, whereas concrete responses to uncommon proverbs correlated with executive functions. After controlling for dementia diagnosis, TBM analyses indicated significant correlations between impaired proverb interpretation and the anterior temporal lobe region (left>right). CONCLUSIONS: Among two dementia groups, those with bvFTD, demonstrated a greater number of concrete responses to common proverbs compared to those with AD, and this performance correlated with semantic deficits and the volume of the left anterior lobe, the hub of semantic knowledge. The findings of this study suggest that common proverb interpretation is greatly influenced by semantic dysfunction and that the use of proverbs for testing executive functions needs to include the interpretation of unfamiliar proverbs.

Similar verbal fluency patterns in amnestic mild cognitive impairment and Alzheimer's disease.

Disproportionately greater deficits in semantic relative to phonemic verbal fluency are seen in Alzheimer's disease (AD) and have been attributed to neurodegenerative changes in the temporal lobe. Amnestic (AMN) mild cognitive impairment (MCI), which often represents incipient AD, is also characterized by early temporal lobe neuropathology, but previous comparisons of verbal fluency between AD and AMN MCI have yielded mixed results. We examined semantic and phonemic verbal fluency performance in 399 individuals (78 AD, 138 AMN MCI, 72 non-amnestic MCI, and 111 cognitively normal controls). Similar verbal fluency patterns were seen in AMN MCI and AD; both groups exhibited disproportionately poorer performance on semantic verbal fluency relative to normal controls. However, relative verbal fluency indices performed more poorly than individual semantic or phonemic verbal fluency indices for discriminating AMN MCI or AD participants from normal controls, suggesting that they are unlikely to provide additional utility for predicting progression from MCI to 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.

Normative data for healthy older adults and an abbreviated version of the Stroop test.

Normative data for the Kaplan version of the Stroop Test are presented for 153 healthy, cognitively intact older adults aged 50-89 years. Increasing age was associated with decreased performance on all three subtests (Stroop A, Stroop B, and Stroop C), while years of education was only associated with Stroop B performance. Hence the normative data were stratified by age into three groups (50-64, 65-74, 75-89). Completion times for the first half of each trial (half-time scores) were found to have good split-half reliability and correlated highly with the original full administration scores. Means and standard deviations for the half-time administration are also presented for this sample. The current study provides more comprehensive normative data for older adults than previously available, as well as normative information for half-time scores that may have future clinical utility as an alternative, abbreviated version of the Kaplan Stroop Test.

Estimating sample sizes for predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative.

This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.

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.

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.

Cross validation of the Lu and colleagues (2003) Rey-Osterrieth Complex Figure Test effort equation in a large known-group sample.

A Rey-Osterrieth Complex Figure Test (ROCFT) equation incorporating copy and recognition was found to be useful in detecting negative response bias in neuropsychological assessments (ROCFT Effort Equation; Lu, P. H., Boone, K. B., Cozolino, L., & Mitchell, C. (2003). Effectiveness of the Rey-Osterrieth Complex Figure Test and the Meyers and Meyers recognition trial in the detection of suspect effort. Clinical Neuropsychologist, 17, 426-440). In the current cross validation of this validity, the credible patient group (n = 146; 124 with equation data) outperformed the noncredible group (n = 157; 115 with equation data) on copy, 3-min recall, total recognition correct and the Effort Equation, but the latter was most effective in classifying subjects. A cut-off of ≤50 maintained specificity of 90% and achieved sensitivity of 80%. Results of the current cross validation provide corroboration that the ROCFT Effort Equation is an effective measure of neurocognitive response bias.

Multimodal magnetic resonance imaging assessment of white matter aging trajectories over the lifespan of healthy individuals.

BACKGROUND: Postmortem and volumetric imaging data suggest that brain myelination is a dynamic lifelong process that, in vulnerable late-myelinating regions, peaks in middle age. We examined whether known regional differences in axon size and age at myelination influence the timing and rates of development and degeneration/repair trajectories of white matter (WM) microstructure biomarkers. METHODS: Healthy subjects (n = 171) 14-93 years of age were examined with transverse relaxation rate (R(2)) and four diffusion tensor imaging measures (fractional anisotropy [FA] and radial, axial, and mean diffusivity [RD, AxD, MD, respectively]) of frontal lobe, genu, and splenium of the corpus callosum WM (FWM, GWM, and SWM, respectively). RESULTS: Only R(2) reflected known levels of myelin content with high values in late-myelinating FWM and GWM regions and low ones in early-myelinating SWM. In FWM and GWM, all metrics except FA had significant quadratic components that peaked at different ages (R(2) < RD < MD < AxD), with FWM peaking later than GWM. Factor analysis revealed that, although they defined different factors, R(2) and RD were the metrics most closely associated with each other and differed from AxD, which entered into a third factor. CONCLUSIONS: The R(2) and RD trajectories were most dynamic in late-myelinating regions and reflect age-related differences in myelination, whereas AxD reflects axonal size and extra-axonal space. The FA and MD had limited specificity. The data suggest that the healthy adult brain undergoes continual change driven by development and repair processes devoted to creating and maintaining synchronous function among neural networks on which optimal cognition and behavior depend.

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.

Chinese-language montreal cognitive assessment for cantonese or mandarin speakers: age, education, and gender effects.

The Montreal Cognitive Assessment Chinese-Language Los Angeles version (MoCA-ChLA) was developed and administered during an in-home interview to 1,192 participants (mean age 62.5 years, mean education 11.6 years) in a population-based Chinese American Eye Study (CHES) in Los Angeles. The MoCA-ChLA score (mean ± SD) was 23.8 ± 4.2 with little ceiling and no floor effects. The score increased with higher education, decreased with advancing age, and was not related to gender. Compared to the education 1-6 years group, the mean MoCA-ChLA score was 2.6 and 4.6 higher in the education 7-11 and 12-20 years groups, respectively. The Mandarin- (n = 612) and Cantonese- (n = 612) speaking subgroups performed comparably; Cronbach's alpha of the MoCA-ChLA score was 0.78 and 0.79 for these two groups, respectively. Item response theory analysis showed good discriminating power for executive function and memory. These properties support the MoCA-ChLA as a useful screening tool for aging and dementia studies for Mandarin or Cantonese speakers.

Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia.

CONTEXT: Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in the treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable by long acting injection (LAI) formulations. OBJECTIVES: Assess the effect of risperidone formulation on the ICM trajectory during a six-month randomized trial of LAI (RLAI) versus oral (RisO) in first-episode SZ subjects. DESIGN: Two groups of SZ subjects (RLAI, N=9; and RisO, N=13) matched on pre-randomization oral medication exposure were prospectively examined at baseline and 6 months later, along with 12 healthy controls (HCs). Frontal lobe ICM volume was assessed using inversion recovery (IR) and proton density (PD) MRI images. Medication adherence was tracked. MAIN OUTCOME MEASURE: ICM volume change scores were adjusted for the change in the HCs. RESULTS: ICM volume increased significantly (p=.005) in RLAI and non-significantly (p=.39) in the RisO groups compared with that of the healthy controls. A differential between-group treatment effect was at a trend level (p=.093). SZ subjects receiving RLAI had better medication adherence and more ICM increases (chi-square p<.05). CONCLUSIONS: The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. In vivo MRI myelination measures can help clarify pharmacotherapeutic mechanisms of action.

Depressive symptoms in mild cognitive impairment predict greater atrophy in Alzheimer's disease-related regions.

BACKGROUND: Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and may be a marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Thus, we examined the neuroanatomical changes associated with depressive symptoms in MCI. METHODS: Two-hundred forty-three MCI subjects from the Alzheimer's Disease Neuroimaging Initiative who had brain magnetic resonance imaging scans at baseline and 2-year follow-up were classified into depressed (n = 44), nondepressed with other neuropsychiatric symptoms (n = 93), and no-symptom (NOSYMP; n = 106) groups based on the Neuropsychiatric Inventory Questionnaire. Tensor-based morphometry was used to create individual three-dimensional maps of 2-year brain changes that were compared between groups. RESULTS: Depressed subjects had more frontal (p = .024), parietal (p = .030), and temporal (p = .038) white matter atrophy than NOSYMP subjects. Those whose depressive symptoms persisted over 2 years also had higher conversion to AD and more decline on measures of global cognition, language, and executive functioning compared with stable NOSYMP subjects. Nondepressed with other neuropsychiatric symptoms and NOSYMP groups exhibited no differences in rates of atrophy. CONCLUSIONS: Depressive symptoms were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes, including prodromal AD, and may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.