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ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the $${\ell }_{{\bf{1}}}$$ ℓ 1 -norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer’s disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.

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.

Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.

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.

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 e2) and that increase (APOE e4) 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 e4 compared with the APOE e2 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. J. Magn. Reson. Imaging 2014;39:387–397. © 2013 Wiley Periodicals, Inc.

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.

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. © 2013 Elsevier Inc.

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.

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.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Background Mutations in the presenilin ( PSEN1 , PSEN2 ) and amyloid precursor protein ( APP ) genes cause familial Alzheimer9s disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer9s 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.

Iron is essential for triggering oligodendrocytes to myelinate, however, in gray matter (GM) iron increases with age and is associated with age-related degenerative brain diseases. Women have lower iron levels than men, both in the periphery and in the brain, particularly in white matter (WM), possibly due to iron loss through menstruation. We tested the hypothesis that hysterectomy could increase WM iron levels. We assessed 3 WM and 5 gray matter regions in 39 postmenopausal women, of whom 15 had premenopausal hysterectomy, utilizing a validated magnetic resonance imaging technique called field-dependent R2 increase (FDRI) that quantifies ferritin iron. A group of 54 matched male subjects was included for comparison. Amongst women, hysterectomy was associated with significantly higher frontal lobe WM iron. Men had higher iron levels than women without hysterectomy in 3 brain regions but did not differ from women with hysterectomy in any region. The results suggest that menstruation-associated blood loss is a source of gender differences in brain iron. It is possible that brain iron can be influenced by peripheral iron levels and may thus be a modifiable risk factor for age-related degenerative diseases.

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 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.

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.

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 magnetic resonance imaging (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.

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.

Apolipoprotein E (ApoE) e4 genotype is a strong risk factor for developing Alzheimer’s disease (AD). Conversely, the presence of the e2 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 e4 allele demonstrate greater volume reduction than those with the e2 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 e4 allele (all heterozygous e3e4 genotype) and 11 had the e2e3 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 e4 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 e4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits.

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.A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R(2))) 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, R(2) of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured.FLwm R(2) and FTS measures were significantly correlated (r=.45, p.0001) with no association noted in the early-myelinating region (splenium). Both FLwm R(2) 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.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 R(2) 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.

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.

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.

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.

Background: Neuropsychiatric disturbances are common in mild cognitive impairment (MCI). Depression and apathy may identify a subset of MCI subjects at higher risk of progression to Alzheimer’s disease (AD). However, it remains uncertain whether a broader spectrum of psychopathology is associated with progression to AD. Methods: Fifty-one MCI subjects were assessed for neuropsychiatric symptoms using the Neuropsychiatric Inventory. Subjects were followed for an average of 2 years. Twelve subjects (23.5%) progressed from MCI to possible/probable AD and 39 subjects (76.5%) remained stable or improved. Baseline Neuropsychiatric Inventory indices were compared between groups. Results: Subjects progressing to AD had a significantly higher prevalence of psychopathology than subjects who remained stable or improved (100 vs. 59%). Depression (67 vs. 31%) and apathy (50 vs. 18%) were more common in subjects who were later diagnosed with AD. After statistical adjustments for other baseline demographic variables, these specific symptoms were less robust predictors of progression to AD than the presence of any psychopathology. Conclusions: These findings suggest that neuropsychiatric symptoms in MCI are a predictor of progression to AD. Depression and apathy appear to be most useful for identifying MCI subjects at highest risk of developing dementia.

Background: Patients with Alzheimer disease consistently demonstrate impaired performance on tests of facial emotion processing. However, it remains unclear how early in the neurodegenerative process these deficits emerge. Methods: We approached this question by examining facial emotional processing in a ‘pre-dementia’ condition, amnestic mild cognitive impairment (MCI). Nine single-domain amnestic MCI subjects, 14 multiple-domain amnestic MCI subjects (MCI-MD), and 68 normal control subjects were assessed with the Florida Affect Battery. Results: After adjustment for age and gender, analyses of performance across the facial affect processing subtests of the Florida Affect Battery demonstrated intact performance in the single-domain MCI group but significantly impaired performance in the MCI-MD group, particularly on a test of facial affect discrimination. Within the MCI-MD group, men performed disproportionately worse than women. Performance on facial affect discriminations in the MCI-MD group correlated most robustly with performance on tests of frontal/executive function. Conclusion: These data suggest that facial emotion processing can be impaired in MCI prior to the more marked cognitive deficits seen with clinically diagnosed Alzheimer disease.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

The Mini-mental State Examination (MMSE) is a brief cognitive screening instrument frequently used to track Alzheimer disease (AD) progression. We investigated the structural neuroimaging correlates of MMSE performance in patients with clinical and preclinical AD. We analyzed structural magnetic resonance imaging data from 29 probable AD and 5 MCI patients who later converted to probable AD using an advanced 3D cortical mapping technique. MMSE scores were entered as covariates in a general linear model that predicted the gray matter density at each cortical surface point. The results were corrected for multiple comparisons by permutation testing. The global permutation-corrected significance for the maps linking gray matter loss and cognitive decline was P = 0.005 for the left and P = 0.012 for the right hemisphere. Strongest correlations between MMSE score and gray matter integrity were seen in the entorhinal, parahippocampal, precuneus, superior parietal, and subgenual cingulate/orbitofrontal cortices. Significant correlations were also seen bilaterally in the temporal, the middle frontal and the left angular and supramarginal gyri. As a global cognitive measure, MMSE depends on the integrity of widely distributed cortical areas in both brain hemispheres with left-sided predominance.

Human and non-human primate data suggest that the structural integrity of myelin sheaths deteriorates during normal aging, especially in the late-myelinating association regions and may result in "disconnection" of widely distributed neural networks. Magnetic resonance imaging (MRI) was used to assess the heterogeneity of this process and its impact on brain aging and Alzheimer's disease (AD) by evaluating early- and later-myelinating regions of the corpus callosum, the splenium (Scc) and genu (Gcc), respectively. Calculated transverse relaxation rates (R2), an indirect measure of white matter structural integrity for the Gcc and Scc, were examined. The relationship between age and R2 differed in the two regions. A quadratic (inverted U) function with an accelerating rate of decline beginning at age 31 best represented the Gcc pattern while the Scc decline was three-fold smaller, gradual, and linear. These data suggest that the severity of age-related myelin breakdown is regionally heterogeneous, consistent with the hypothesis that differences in myelin properties make later-myelinating regions more susceptible to this process. In AD this process is globally exacerbated, consistent with an extracellular deleterious process such as amyloid beta-peptide toxicity. Non-invasive measures such as R2 may be useful in primary prevention studies of AD.

We analyzed the relationship between cocaine-induced euphoria and measures of frontal and temporal gray matter volumes in eleven cocaine-dependent (CD) patients who underwent magnetic resonance imaging (MRI). Self-reported ratings of the intensity of euphoric response to cocaine infusion were obtained from the CD subjects at 3, 10, and 30 minutes after cocaine infusion. Significant positive correlation between frontal and temporal cortical gray matter volume and the intensity of euphoria was observed at 10 minutes after IV cocaine. The data suggest that frontal and temporal lobe gray matter volume is associated with some of the reinforcing effects of cocaine. Given the well-established negative linear relationship between cortical gray matter volume and age, cortical gray matter volume may be a marker for the neurobiological substrate of the age-related reduction in addiction rates.

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.

We evaluated the hypothesis that ventricular and cortical CSF volume increases are associated with reductions in the magnitude of euphoric effects produced by intravenous IV cocaine infusion in cocaine dependent (CD) individuals. Eleven CD patients participating in a cocaine-infusion study and eleven control subjects underwent magnetic resonance imaging (MRI). Two CSF regions of interest (lateral ventricles and frontal cortex CSF) and two comparison regions (third ventricle and posterior cortex CSF) were measured. Self-reported ratings of the intensity of euphoric response ("high") were obtained from the CD subjects at 3, 10, and 30 minutes after IV administration of cocaine. A significant negative correlation was observed between the volume of the lateral ventricles and subjective ratings of the "high" experienced at 3 minutes, but not at 10 and 30 minutes after cocaine infusion. In contrast, a significant negative correlation between frontal cortex CSF volume and the intensity of euphoric response was observed at 30 minutes after IV cocaine. No significant associations were observed between the volumes of the two comparison regions and any subjective ratings of "high." No significant volume differences were observed between the CD and control groups in any region. The results suggest larger lateral ventricular volumes are associated with a decrease in immediate euphoria while larger frontal cortex CSF volumes are associated with a decrease in the duration of the euphoria induced by cocaine infusion. The age-related brain volume reductions underlying the volume increase in these two CSF spaces may be the neurobiological basis of the age-related reduction in the rates of addiction.

The study evaluated the relationship between age and frontal and temporal lobe volumes in young cohorts of cocaine-dependent (CD), amphetamine-dependent (Am), and normal control subjects. Ten CD, nine Am, and 16 age- and gender-matched control subjects underwent magnetic resonance imaging (MRI). The volume of the frontal and temporal lobes was measured from an identically positioned slab of seven contiguous 3-mm-thick coronal images. Follow-up measures of the gray and white matter subcomponents of these volumes were also obtained. Both CD and Am groups had a significantly smaller temporal lobe volumes, but only the CD group demonstrated a significantly greater decline in temporal lobe volume with age (intracranial volume, education, and race were controlled for in all statistical analyses). Segmenting the brain regions into gray and white matter revealed that the negative correlation between age and temporal lobe volume of CD patients was mostly due to a significant age-related decline in the gray matter subcomponent. Negative trends between age and gray matter volumes were also observed in the Am and normal groups. In the frontal lobes, age was negatively correlated with gray matter volume in the control, CD, and Am groups. Unlike the consistent decreases in gray matter volumes, white matter showed non-significant increases in volume with age. The data suggest that CD patients may have an accelerated age-related decline in temporal lobe gray matter volume and a smaller temporal lobe volume compared to normal controls. In the frontal lobe, age-related gray matter volume reductions occur in all three groups. These age-related cortical gray matter volume reductions may be a biological marker for the risk of addictive behavior, which also decreases with age.

Although the detection of conscious fabrication (i.e., malingering) of cognitive symptoms has been the recipient of burgeoning interest within the last 10 years in the empirical and clinical neuropsychological literature, whether conversion/somatization results in similarly noncredible cognitive profiles has not been formally investigated. Two thirds (13 of 19) of subjects with cognitive complaints and 1-3/3-1 code types on the MMPI/MMPI-2 showed evidence of noncredible cognitive performance (i.e., failure on malingering tests and/or a “malingering’” pattern on standard neuropsychological tests). These results suggest that symptom fabrication associated with somatization/conversion personality orientations can extend to noncredible cognitive complaints and not just the oft-described physical manifestations.

Background: To evaluate the severity of choreoathetoid movements in cocaine dependent (CD) subjects and age-matched normal control subjects. Methods: Choreoathetoid movements were evaluated using the Abnormal Involuntary Movement Scale (AIMS) in samples of 71 CD, 56 normal control, and 9 amphetamine-dependent male subjects. Results: The CD subjects had a significantly increased nonfacial (limbs plus body) AIMS subscore. When the nonfacial AIMS scores of the two groups were compared in relation to age, a significant age by diagnosis interaction was observed, indicating that the differences between groups were most marked in the younger age groups. The facial AIMS scores were also increased but only in the youngest CD cohort (under 32 years of age). The comparison group of 9 younger amphetamine-dependent subjects also showed increased AIMS scores. Conclusions: Increases in choreoathetoid movements in younger cocaine and amphetamine-dependent subjects may be related to their psychostimulant use. The absence of differences in choreoathetoid movements between the older CD subjects and normal control subjects may represent an age-related self-selection effect.

Background: Cocaine and its metabolites can produce vasospasm. Cocaine-dependent (CD) patients are at increased risk for stroke, and a high frequency of brain perfusion defects has been observed in clinically asymptomatic CD subjects. This is the first controlled magnetic resonance imaging (MRI) study of clinically asymptomatic CD subjects. Methods: Two age-matched groups of male subjects (61 CD and 57 control) participated in the study. Subjects with a history of neurologic symptoms or major medical or neurologic illness, such as hypertension, diabetes, or significant head trauma, were excluded. The severity of hyperintense lesions observed on T2-weighted MRI images were rated on a 0–3-point scale by an experienced radiologist who was blind to all clinical data. Ratings of 3 were felt to be significant indicators of a possible disease process and were used in the data analysis. Three regions were separately rated: the cerebral white matter, subinsular white matter, and subcortical gray matter (basal ganglia and thalamus region). Results: Despite the exclusion criteria minimizing risk factors for cerebrovascular events, 17 of the 61 (27.9%) CD subjects and 4 of 57 (7%) of the control subjects had severe hyperintense lesions suggestive of subclinical or “silent” anoxic vascular events. Significant group differences were observed in the two white matter regions but not in the subcortical gray matter region. The risk of severe white matter lesions in the CD group increased with age, reaching 50% in the oldest age quartile (46–58 years), and this increase was not related to the number of years cocaine was used. Conclusions: The data suggest that asymptomatic CD patients are a heterogeneous population with a significantly increased age-related risk of white matter neurovascular toxicity. Premature neurovascular damage may impact treatment outcomes and, as the CD population ages, may manifest as an increased incidence of cognitive deficits.

This chapter provides an overview of dynamic interdependence and complex signaling between all of the brain’s cellular elements with a special focus on glia and especially oligodendrocytes and their roles in achieving optimal brain function as well as triggering degenerative brain processes. The evidence suggests that recently evolved vulnerable aspects of the human brain such as myelin and the homeostatic repair mechanisms triggered by its breakdown may drive the slow and continually progressive processes that result in age-related cognitive decline as well as the pathology that define prevalent degenerative diseases such as Alzheimer’s disease. Furthermore, by altering central-peripheral signaling these degenerative brain processes may also contribute to peripheral metabolic derangements such as hypertension, insulin resistance, and obesity (e.g., metabolic syndrome). By highlighting the role of glia, this chapter strives to rebalances the historic focus on neurons and gray matter and highlights the importance of a systems-level understanding of healthy brain functioning and the interdependent age-related shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent and devastating age-related diseases.

White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).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.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.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.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.

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.

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.

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 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.

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.