Performance on measures of cognitive processing speed (CPS) slows with age, but the biological basis associated with this cognitive phenomenon remains incompletely understood. We assessed the hypothesis that the age-related slowing in CPS is associated with myelin breakdown in late-myelinating regions in a very healthy elderly population. An in vivo MRI biomarker of myelin integrity was obtained from the prefrontal lobe white matter and the genu of the corpus callosum for 152 healthy elderly adults. These regions myelinate later in brain development and are more vulnerable to breakdown due to the effects of normal aging. To evaluate regional specificity, we also assessed the splenium of the corpus callosum as a comparison region, which myelinates early in development and primarily contains axons involved in visual processing. The measure of myelin integrity was significantly correlated with CPS in highly vulnerable late-myelinating regions but not in the splenium. These results have implications for the neurobiology of the cognitive changes associated with brain aging.

Context

Imaging and post-mortem studies provide converging evidence that subjects with schizophrenia (SZ) have a dysregulated trajectory of frontal lobe myelination. Prior MRI studies suggested that early in treatment of SZ, antipsychotic medications initially increase frontal lobe white matter (WM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of WM decline associated with chronic disease may be due to medication non-adherence, it may be modifiable by long acting injection (LAI) formulations.

Objectives

Examine the impact of antipsychotic formulation on the myelination trajectory during a randomized six-month trial of LAI risperidone (RLAI) versus oral risperidone (RisO) in first-episode SZ subjects.

Design

Two groups of SZ subjects (RLAI, N=11; and RisO, N=13) that were matched in pre-randomization oral medication exposure and 14 healthy controls (HCs) were prospectively examined. Frontal lobe WM volume was estimated using inversion recovery (IR) MRI images. A brief neuropsychological battery that focused on reaction times was performed at the end of the study.

Main outcome measure

WM volume change scores.

Results

WM volume remained stable in the RLAI and decreased significantly in the RisO groups resulting in a significant differential treatment effect, while the HC had a WM change intermediate and not significantly different from the two SZ groups. WM increase was associated with faster reaction times in tests involving frontal lobe function.

Conclusions

The results suggest that RLAI may improve the trajectory of myelination in first-episode patients and have a beneficial impact on cognitive performance. Better adherence provided by LAI may underlie the modified trajectory of myelin development. In vivo MRI biomarkers of myelination can help clarify mechanisms of action of treatment interventions.

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON−) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON− status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=−0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON− group (r=−0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

Objective

Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age. This trajectory is most evident in vulnerable later myelinating association regions such as frontal lobes and may be the biological substrate for similar trajectories of cognitive processing speed. Speed of movement, such as maximal finger tapping speed (FTS), requires high-frequency action potential (AP) bursts and is associated with myelin integrity. We tested the hypothesis that the age-related trajectory of FTS is related to brain myelin integrity.

Methods

A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R2)) of frontal lobe white matter (FLwm) was measured in a sample of very healthy males (N = 72) between 23 and 80 years of age. To assess specificity, R2 of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured.

Results

FLwm R2 and FTS measures were significantly correlated (r = .45, p < .0001) with no association noted in the early-myelinating region (splenium). Both FLwm R2 and FTS had significantly quadratic lifespan trajectories that were virtually indistinguishable and both reached a peak at 39 years of age and declined with an accelerating trajectory thereafter.

Conclusions

The results suggest that in this very healthy male sample, maximum motor speed requiring high-frequency AP burst may depend on brain myelin integrity. To the extent that the FLwm changes assessed by R2 contribute to an age-related reduction in AP burst frequency, it is possible that other brain functions dependent on AP bursts may also be affected. Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate age-related functional declines.

The amyloid hypothesis (AH) of Alzheimer’s disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits.

Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides “upstream” treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.

Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer’s disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson’s disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON−) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON− men (p = 0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.

This review summarizes the scientific talks presented at the conference “Therapeutics for Cognitive Aging,” hosted by the New York Academy of Sciences and the Alzheimer’s Drug Discovery Foundation on May 15, 2009. Attended by scientists from industry and academia, as well as by a number of lay people—approximately 200 in all—the conference specifically tackled the many aspects of developing therapeutic interventions for cognitive impairment. Discussion also focused on how to define cognitive aging and whether it should be considered a treatable, tractable disease.

Apolipoprotein E (ApoE) ε4 genotype is a strong risk factor for developing Alzheimer’s disease (AD). Conversely, the presence of the ε2 allele has been shown to mitigate cognitive decline. Tensor-based morphometry (TBM), a novel computational approach for visualizing longitudinal progression of brain atrophy, was used to determine whether cognitively intact elderly participants with the ε4 allele demonstrate greater volume reduction than those with the ε2 allele. Healthy “younger elderly” volunteers, aged 55–75, were recruited from the community and hospital staff. They were evaluated with a baseline and follow-up MRI scan (mean scan interval = 4.72 years, s.d. = 0.55) and completed ApoE genotyping. Twenty-seven participants were included in the study of which 16 had the ε4 allele (all heterozygous ε3ε4 genotype) and 11 had the ε2ε3 genotype. The two groups did not differ significantly on any demographic characteristics and all subjects were cognitively “normal” at both baseline and follow-up time points. TBM was used to create 3D maps of local brain tissue atrophy rates for individual participants; these spatially detailed 3D maps were compared between the two ApoE groups. Regional analyses were performed and the ε4 group demonstrated significantly greater annual atrophy rates in the temporal lobes (p = 0.048) and hippocampus (p = 0.016); greater volume loss was observed in the right hippocampus than the left. TBM appears to be useful in tracking longitudinal progression of brain atrophy in cognitively asymptomatic adults. Possession of the ε4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits.

Objective

To compare the rates of depression in Alzheimer Disease (AD) determined using National Institute of Mental Health (NIMH) provisional criteria for depression in AD (NIMH-dAD) to those determined using other established depression assessment tools.

Design

Descriptive longitudinal cohort study.

Setting

The Alzheimer’s Disease Research Centers of California.

Participants

A cohort of 101 patients meeting NINDS-ADRDA criteria for possible/probable AD, intentionally selected to increase the frequency of depression at baseline.

Measurements

Depression was diagnosed at baseline and after 3 months using NIMH-dAD criteria and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders. Depressive symptoms also were assessed with the Cornell Scale for Depression in Dementia (CSDD), the Geriatric Depression Scale (GDS), and the Neuropsychiatric Inventory Questionnaire.

Results

The baseline frequency of depression using NIMH-dAD criteria (44%) was higher than that obtained using DSM-IV criteria for major depression (14%; Z = −5.50, df = 101, p <0.001) and major or minor depression (36%; Z = −2.86, df = 101, p = 0.021) or using established cut-offs for the CSDD (30%; Z = −2.86, df = 101, p = 0.004) or GDS (33%; Z = −2.04, df = 101, p = 0.041). The NIMH-dAD criteria correctly identified all patients meeting DSM-IV criteria for major depression, and correlated well with DSM-IV criteria for major or minor depression (κ = 0.753, p <0.001), exhibiting 94% sensitivity and 85% specificity. The higher rates of depression found with NIMH-dAD criteria derived primarily from its less stringent requirements for the frequency and duration of symptoms. Remission rates at 3 months were similar across instruments.

Conclusions

The NIMH-dAD criteria identify a greater proportion of AD patients as depressed than several other established tools.

Context

Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination. The hypothesis that typical and atypical medications may differentially impact brain myelination in adults with schizophrenia was previously assessed with inversion recovery (IR) images. Increased white matter (WM) volume suggestive of increased myelination was detected in the patient group treated with an atypical antipsychotic compared to a typical one.

Objective

In a follow-up reanalysis of MRI images from the original study, we used a novel method to assess whether the difference in WM volumes could be caused by a differential effect of medications on the intracortical myelination process.

Design, setting, and participants

Two different male cohorts of healthy controls ranging in age from 18–35 years were compared to cohorts of subjects with schizophrenia who were treated with either oral risperidone (Ris) or fluphenazine decanoate (Fd).

Main outcome measure

A novel MRI method that combines the distinct tissue contrasts provided by IR and proton density (PD) images was used to estimate intracortical myelin (ICM) volume.

Results

When compared with their pooled healthy control comparison group, the two groups of schizophrenic patients differed in the frontal lobe ICM measure with the Ris group having significantly higher volume.

Conclusions

The data suggest that in adults with schizophrenia antipsychotic treatment choice may be specifically and differentially impacting later-myelinating intracortical circuitry. In vivo MRI can be used to dissect subtle differences in brain tissue characteristics and thus help clarify the effect of pharmacologic treatments on developmental and pathologic processes.

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 × time interactions.

Background

Previous studies revealed microstructural abnormalities in prefrontal white matter and corpus callosum of long-term abstinent chronic methamphetamine abusers. In view of the importance of the early abstinence period in treatment retention, we compared 23 methamphetamine-dependent subjects abstinent from methamphetamine for 7–13 days with 18 healthy comparison subjects. As certain metabolic changes in the brain first manifest after early abstinence from methamphetamine, it is also possible that microstructural white-matter abnormalities are not yet present during early abstinence.

Methods

Using diffusion tensor imaging at 1.5 T, fractional anisotropy (FA) was measured in prefrontal white matter at four inferior–superior levels parallel to the anterior commissure–posterior commissure (AC–PC) plane. We also sampled FA in the corpus callosum at the midline and at eight bilateral, fiber-tract sites in other regions implicated in effects of methamphetamine.

Results

The methamphetamine group exhibited lower FA in right prefrontal white matter above the AC–PC plane (11.9% lower; p = 0.007), in midline genu corpus callosum (3.9%; p = 0.019), in left and right midcaudal superior corona radiata (11.0% in both hemispheres, p’s = 0.020 and 0.016, respectively), and in right perforant fibers (7.3%; p = 0.025). FA in left midcaudal superior corona radiata was correlated with depressive and generalized psychiatric symptoms within the methamphetamine group.

Conclusions

The findings support the idea that methamphetamine abuse produces microstructural abnormalities in white matter underlying and interconnecting prefrontal cortices and hippocampal formation. These effects are already present during the first weeks of abstinence from methamphetamine and are linked to psychiatric symptoms assessed during this period.

We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse, and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques that include manual tracing, pattern matching, voxel-based, tensor-based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3-4-methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine-rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common, and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross-sectional designs, which cannot infer causality. Potential confounding influences include effects of pre-existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimer's disease. Magnetic resonance imaging (MRI), (18F)-fluorode-oxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquiredat multiple time points. All data will be cross-linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications thatguided protocol development. A major effort was devoted toevaluating 3D T1-weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced-scale clinical trial. The protocol selected for the ADNI study includes: back-to-back 3D magnetization prepared rapid gradient echo (MP-RAGE) scans; B1-calibration scans when applicable; and an axial proton density-T2 dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom-based monitoring of all scanners could be used as a model for other multisite trials.

Current concepts of addiction focus on neuronal neurocircuitry and neurotransmitters and are largely based on animal model data, but the human brain is unique in its high myelin content and extended developmental (myelination) phase that continues until middle age. The biology of our exceptional myelination process and factors that influence it have been synthesized into a recently published myelin model of human brain evolution and normal development that cuts across the current symptom-based classification of neuropsychiatric disorders.

The developmental perspective of the model suggests that dysregulations in the myelination process contribute to prevalent early-life neuropsychiatric disorders, as well as to addictions. These disorders share deficits in inhibitory control functions that likely contribute to their high rates of comorbidity with addiction and other impulsive behaviors. The model posits that substances such as alcohol and psychostimulants are toxic to the extremely vulnerable myelination process and contribute to the poor outcomes of primary and comorbid addictive disorders in susceptible individuals.

By increasing the scientific focus on myelination, the model provides a rational biological framework for the development of novel, myelin-centered treatments that may have widespread efficacy across multiple disease states and could potentially be used in treating, delaying, or even preventing some of the most prevalent and devastating neuropsychiatric disorders.

We hypothesized that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte- and myelin-associated iron that promotes amyloid beta (Aβ) oligomerization, its associated toxicity, and the deposition of oligomerized Aβ 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 Aβ deposits in humans. The data show that in AD, radiolabeled ligands detect Aβ deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the strikingly lower ability of this imaging ligand to bind Aβ 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.

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 instrument artifacts) 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.