Prefrontal Cortex Gray Matter Research Articles

Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

It has been hypothesized that Alzheimer disease (AD) is primarily a disorder of the synapse. However, assessment of the synaptic proteome in AD subjects has been limited to a small number of proteins and often included subjects with end-stage pathology. Protein from prefrontal cortex gray matter of 59 AD subjects with mild to moderate dementia and 12 normal elderly subjects was assayed using targeted mass spectrometry to quantify 191 synaptically expressed proteins. The profile of synaptic protein expression clustered AD subjects into two groups. One of these was characterized by reduced expression of glutamate receptor proteins, significantly increased synaptic protein network coexpression, and associated withApolipoprotein E*4 (APOE*4) carrier status. The second group, by contrast, showed few differences from control subjects. A subset of AD subjects had altered prefrontal cortex synaptic proteostasis for glutamate receptors and their signaling partners. Efforts to therapeutically target glutamate receptors in AD may have outcomes dependent on APOE*4 genotype.

Prefrontal Lobe Gray Matter, Cognitive Control and Episodic Memory in Healthy Cognition

Objective: We combined neuropsychological and structural magnetic resonance imaging (MRI) measures to examine the neural and informational processes underlying episodic memory in healthy participants. Method: The Doors-and-People Test (DPT) provided a detailed assessment of episodic memory, including recall and recognition tasks of matched difficulty for social (e.g., people) and non-social (e.g., shape) content. The Wisconsin Card Sorting (WCS) test provided a measure of category learning that relies heavily on executive control and inhibition. A subset of participants also had available high-resolution, 3-T MRI gray matter volume studies of prefrontal cortex (PFC) parcellated into four regions: 1) frontal pole; 2) superior frontal gyrus; 3) middle frontal gyrus; and 4) inferior frontal gyrus. Results: Bivariate neuropsychological correlations revealed a highly statistically significant relationship of reduced WCS perseverative errors and stronger recall for people but not for shapes. By contrast, WCS perseveration did not correlate with any recognition measures. Hierarchical regression revealed that perseverative errors and people recall test scores combined to account for approximately 29.98% to 57.78% of the variance in left PFC gray matter volume. Conclusions: These results may point to an important role of the PFC in mnemonic process of retrieval inhibition in episodic memory for recall of social content in healthy participants.

Emotion recognition and theory of mind are related to gray matter volume of the prefrontal cortex in schizophrenia

Investigations of social cognition in schizophrenia have demonstrated consistent impairments compared to healthy controls. Functional imaging studies in schizophrenia patients and healthy controls have revealed that social cognitive processing depends critically on the amygdala and the prefrontal cortex (PFC). However, the relationship between social cognition and structural brain abnormalities in these regions in schizophrenia patients is less well understood. Measures of facial emotion recognition and theory of mind (ToM), two key social cognitive abilities, as well as face perception and IQ, were assessed in 166 patients with schizophrenia and 134 healthy controls. MRI brain scans were acquired. Automated parcellation of the brain to determine gray matter volume of the amygdala and the superior, middle, inferior and orbital PFC was performed. Between-group analyses showed poorer recognition of angry faces and ToM performance, and decreased amygdala and PFC gray matter volumes in schizophrenia patients as compared to healthy controls. Moreover, in schizophrenia patients, recognition of angry faces was associated with inferior PFC gray matter volume, particularly the pars triangularis (p=0.006), with poor performance being related to reduced pars triangularis gray matter volume. In addition, ToM ability was related to PFC gray matter volume, particularly middle PFC (p=0.001), in that poor ToM skills in schizophrenia patients were associated with reduced middle PFC gray matter volume. In conclusion, reduced PFC, but not amygdala, gray matter volume is associated with social cognitive deficits in schizophrenia.

Prefrontal and Hippocampal Brain Volume Deficits: Role of Low Physical Activity on Brain Plasticity in First-Episode Schizophrenia Patients.

Our objective in the present study was to conduct the first empirical study of the effects of regular physical activity habits and their relationship with brain volume and cortical thickness in patients in the early phase of schizophrenia. Relationships between larger brain volumes and higher physical activity levels have been reported in samples of healthy and aging populations, but have never been explored in first-episode schizophrenia patients. We collected MRI structural scans in 14 first-episode schizophrenia patients with either self-reported low or high physical activity levels. We found a reduction in total gray matter volume, prefrontal cortex (PFC), and hippocampal gray matter volumes in the low physical activity group compared to the high activity group. Cortical thickness in the dorsolateral and orbitofrontal PFC were also significantly reduced in the low physical activity group compared to the high activity group. In the combined sample, greater overall physical activity levels showed a non-significant tendency with better performance on tests of verbal memory and social cognition. Together these pilot study findings suggest that greater amounts of physical activity may have a positive influence on brain health and cognition in first-episode schizophrenia patients and support the implementation of physical exercise interventions in this patient population to improve brain plasticity and cognitive functioning.

Physical activity, fitness, glucose homeostasis, and brain morphology in twins.

The main aim of the present study (FITFATTWIN) was to investigate how physical activity level is associated with body composition, glucose homeostasis, and brain morphology in young adult male monozygotic twin pairs discordant for physical activity. From a population-based twin cohort, we systematically selected 10 young adult male monozygotic twin pairs (age range, 32-36 yr) discordant for leisure time physical activity during the past 3 yr. On the basis of interviews, we calculated a mean sum index for leisure time and commuting activity during the past 3 yr (3-yr LTMET index expressed as MET-hours per day). We conducted extensive measurements on body composition (including fat percentage measured by dual-energy x-ray absorptiometry), glucose homeostasis including homeostatic model assessment index and insulin sensitivity index (Matsuda index, calculated from glucose and insulin values from an oral glucose tolerance test), and whole brain magnetic resonance imaging for regional volumetric analyses. According to pairwise analysis, the active twins had lower body fat percentage (P = 0.029) and homeostatic model assessment index (P = 0.031) and higher Matsuda index (P = 0.021) compared with their inactive co-twins. Striatal and prefrontal cortex (subgyral and inferior frontal gyrus) brain gray matter volumes were larger in the nondominant hemisphere in active twins compared with those in inactive co-twins, with a statistical threshold of P < 0.001. Among healthy adult male twins in their mid-30s, a greater level of physical activity is associated with improved glucose homeostasis and modulation of striatum and prefrontal cortex gray matter volume, independent of genetic background. The findings may contribute to later reduced risk of type 2 diabetes and mobility limitations.

Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress

The prefrontal cortex (PFC) provides top-down regulation of behavior, cognition, and emotion, including spatial working memory. However, these PFC abilities are greatly impaired by exposure to acute or chronic stress. Chronic stress exposure in rats induces atrophy of PFC dendrites and spines that correlates with working memory impairment. As similar PFC grey matter loss appears to occur in mental illness, the mechanisms underlying these changes need to be better understood. Acute stress exposure impairs PFC cognition by activating feedforward cAMP-calcium- K+ channel signaling, which weakens synaptic inputs and reduces PFC neuronal firing. Spine loss with chronic stress has been shown to involve calcium-protein kinase C signaling, but it is not known if inhibiting cAMP signaling would similarly prevent the atrophy induced by repeated stress. The current study examined whether inhibiting cAMP signaling through alpha-2A-adrenoceptor stimulation with chronic guanfacine treatment would protect PFC spines and working memory performance during chronic stress exposure. Guanfacine was selected due to 1) its established effects on cAMP signaling at post-synaptic alpha-2A receptors on spines in PFC, and 2) its increasing clinical use for the treatment of pediatric stress disorders. Daily guanfacine treatment compared to vehicle control was found to prevent dendritic spine loss in layer II/III pyramidal neurons of prelimbic PFC in rats exposed to chronic restraint stress. Guanfacine also protected working memory performance; cognitive performance correlated with dendritic spine density. These findings suggest that chronic guanfacine use may have clinical utility by protecting PFC gray matter from the detrimental effects of stress.

Is Schizophrenia a Neurodegenerative Disease? Evidence from Age-Related Decline of Brain-Derived Neurotrophic Factor in the Brains of Schizophrenia Patients and Matched Nonpsychiatric Controls

Background: Brain-derived neurotrophic factor (BDNF) protein levels decline in the brain during senescence and are also shown to be reduced in schizophrenia patients. BDNF is present in both the gray and white matters of the brain. It is unclear whether BDNF abnormalities in schizophrenia are specific to gray and/or white matter. Objective: We hypothesized that the age-related BDNF decline is abnormal and contributes to the reduced BDNF in schizophrenia. Methods: We tested this hypothesis by measuring BDNF protein levels in postmortem gray and white matter, using the prefrontal cortex (PFC) and the genu of the corpus callosum as regions of interests, from 20 schizophrenia patients and 20 matched nonpsychiatric controls. Samples were selected across the adult lifespan - from 20 to 80 years of age. Results: PFC gray matter BDNF protein levels were significantly lower in older age in both nonpsychiatric comparisons and patients, while BDNF in white matter did not decrease significantly with age in either group. PFC BDNF was linearly lower from 20 to 80 years of age in nonpsychiatric comparisons. In schizophrenia, the age effect was similarly linear in younger patients but a decline did not occur in older patients. Conclusion: PFC BDNF does not follow a normative linear age effect in schizophrenia patients as they grow older, which may represent a ‘floor effect' due to earlier decline or a survivor cohort of older patient donors who are less susceptible to a schizophrenia-related pathological aging process.

Lower subcortical gray matter volume in both younger smokers and established smokers relative to non-smokers.

Although established adult smokers with long histories of nicotine dependence have lower neural tissue volume than non-smokers, it is not clear if lower regional brain volume is also observed in younger, less established smokers. The primary goal of this study was to investigate neural tissue volume in a large group of smokers and non-smokers, with a secondary goal of measuring the impact of age on these effects. We used voxel-based morphometry to compare regional gray matter volume in 118 individuals (59 smokers, 59 age- and gender-matched non-smokers). Younger smokers had significantly lower gray matter volume in the left thalamus and the left amygdala than their non-smoking peers (family-wise error-corrected clusters, P < 0.05). There was no correlation between smoking use variables and tissue volume among younger smokers. Established smokers had significantly lower gray matter volume than age-matched non-smokers in the insula, parahippocampal gyrus and pallidum. Medial prefrontal cortex gray matter volume was negatively correlated with pack-years of smoking among the established smokers, but not the younger smokers. These data reveal that regional tissue volume differences are not limited exclusively to established smokers. Deficits in young adults indicate that cigarette smoking may either be deleterious to the thalamus and amygdala at an earlier age than previously reported, or that pre-existing differences in these areas may predispose individuals to the development of nicotine dependence.

Illness-course modulates suicidality-related prefrontal gray matter reduction in women with bipolar disorder.

Explore interrelationships between suicide attempt history (Objective 1) or suicide attempt severity (Objective 2) with prefrontal cortex gray matter (PFCGM ) volume and illness-course in patients with bipolar disorder (BD). Ninety-three women with BD-I or -II diagnosis (51 with and 42 without suicide attempt history) underwent structural MRI and filled out questionnaires. Measured were GM volumes of 11 PFC regions, BD illness-course, and attempt history and severity. Effects were examined with repeated measures GLM or logit analyses. Objective 1: Attempt history was associated with increased trait impulsivity and aggression, and higher prevalence of BD-I, past drug use disorder, and past psychiatric hospitalization. PFCGM volume was lower in patients with than without attempt history in those with past psychiatric hospitalization. PFCGM volume was higher in patients with than without attempt history in those without hospitalization. Higher trait aggression predicted attempt history. Objective 2: Increased frontal pole volume and younger age at first hospitalization predicted many suicide attempts. Attempt history in patients with BD related to PFCGM volume reduction or increase. Volume modulation by psychiatric hospitalization could reflect effects of illness-course or care. Attempt severity was not related to volume reduction. Research on suicidality-brain relationships should include illness-course and attempt severity measures.

A neurogenetics approach to defining differential susceptibility to institutional care

An individual’s neurodevelopmental and cognitive sequelae to negative early experiences may, in part, be explained by genetic susceptibility. We examined whether extreme differences in the early caregiving environment, defined as exposure to severe psychosocial deprivation associated with institutional care compared to normative rearing, interacted with a biologically informed genoset comprising BDNF (rs6265), COMT (rs4680), and SIRT1 (rs3758391) to predict distinct outcomes of neurodevelopment at age 8 (N = 193, 97 males and 96 females). Ethnicity was categorized as Romanian (71%), Roma (21%), unknown (7%), or other (1%). We identified a significant interaction between early caregiving environment (i.e., institutionalized versus never institutionalized children) and the a priori defined genoset for full-scale IQ, two spatial working memory tasks, and prefrontal cortex gray matter volume. Model validation was performed using a bootstrap resampling procedure. Although we hypothesized that the effect of this genoset would operate in a manner consistent with differential susceptibility, our results demonstrate a complex interaction where vantage susceptibility, diathesis stress, and differential susceptibility are implicated.

Medial prefrontal cortex gray matter volume is associated with lifetime substance use severity in abstinent addiction treatment patients

Medial prefrontal cortex gray matter volume is associated with lifetime substance use severity in abstinent addiction treatment patients

Individual differences in regional prefrontal gray matter morphometry and fractional anisotropy are associated with different constructs of executive function

Although the relationship between structural differences within the prefrontal cortex (PFC) and executive function (EF) has been widely explored in cognitively impaired populations, little is known about this relationship in healthy young adults. Using optimized voxel-based morphometry (VBM), surface-based morphometry (SBM), and fractional anisotropy (FA) we determined the association between regional PFC grey matter (GM) morphometry and white matter tract diffusivity with performance on tasks that tap different aspects of EF as drawn from Miyake et al.'s three-factor model of EF. Reductions in both GM volume (VBM) and cortical folding (SBM) in the ventromedial PFC (vmPFC), ventrolateral PFC (vlPFC), and dorsolateral PFC (dlPFC) predicted better common EF, shifting-specific, and updating-specific performance, respectively. Despite capturing different components of GM morphometry, voxel- and surface-based findings were highly related, exhibiting regionally overlapping relationships with EF. Increased white matter FA in fiber tracts that connect the vmPFC and vlPFC with posterior regions of the brain also predicted better commonEF and shifting-specific performance, respectively. These results suggest that the neural mechanisms supporting distinct aspects of EF may differentially rely on distinct regions of the PFC, and at least in healthy young adults, are influenced by regional morphometry of the PFC and the FA of major white matter tracts that connect the PFC with posterior cortical and subcortical regions.

Correspondence of executive function related functional and anatomical alterations in aging brain

Neurocognitive aging studies have focused on age-related changes in neural activity or neural structure but few studies have focused on relationships between the two. The present study quantitatively reviewed 24 studies of age-related changes in fMRI activation across a broad spectrum of executive function tasks using activation likelihood estimation (ALE) and 22 separate studies of age-related changes in gray matter using voxel-based morphometry (VBM). Conjunction analyses between functional and structural alteration maps were constructed. Overlaps were only observed in the conjunction of dorsolateral prefrontal cortex (DLPFC) gray matter reduction and functional hyperactivation but not hypoactivation. It was not evident that the conjunctions between gray matter and activation were related to task performance. Theoretical implications of these results are discussed.

Brain structural basis of cognitive reappraisal and expressive suppression

Cognitive reappraisal and expressive suppression, two major emotion regulation strategies, are differentially related to emotional well-being. The aim of this study was to test the association of individual differences in these two emotion regulation strategies with gray matter volume of brain regions that have been shown to be involved in the regulation of emotions. Based on high-resolution magnetic resonance images of 96 young adults voxel-based morphometry was used to analyze the gray matter volumes of the a priori regions of interest, including amygdala, insula, dorsal anterior cingulate and paracingulate cortex, medial and lateral prefrontal cortex (PFC) and their association with cognitive reappraisal and expressive suppression usage as well as neuroticism. A positive association of cognitive reappraisal with right and tendentially left amygdala volume and of neuroticism with left amygdala volume (marginally significant) was found. Expressive suppression was related to dorsal anterior cingulate/paracingulate cortex and medial PFC gray matter volume. The results of this study emphasize the important role of the amygdala in individual differences in cognitive reappraisal usage as well as neuroticism. Additionally, the association of expressive suppression usage with larger volumes of the medial PFC and dorsal anterior/paracingulate cortex underpins the role of these regions in regulating emotion-expressive behavior.

Altered Brain Microstructure Assessed by Diffusion Tensor Imaging in Patients With Diabetes and Gastrointestinal Symptoms

OBJECTIVEIn patients with long-standing diabetes mellitus (DM), there is increasing evidence for abnormal processing of gastrointestinal sensations in the central nervous system. Using magnetic resonance diffusion tensor imaging, we characterized brain microstructure in areas involved in visceral sensory processing and correlated these findings to clinical parameters.RESEARCH DESIGN AND METHODSTwenty-six patients with DM and gastrointestinal symptoms and 23 healthy control subjects were studied in a 3T scanner. The apparent diffusion coefficient (i.e., diffusivity of water) and fractional anisotropy (FA) (i.e., organization of fibers) were assessed in the “sensory matrix” (cingulate cortex, insula, prefrontal and secondary sensory cortex, amygdala, and corona radiata) and in corpus callosum.RESULTSPatients had decreased FA values compared with control subjects in 1) all areas (P = 0.025); 2) anterior (P < 0.001), mid- (P = 0.001), and posterior (P < 0.001) cingulate cortex; 3) prefrontal cortex gray matter (P < 0.001); 4) corona radiata (P < 0.001); 5) secondary sensory cortex (P = 0.008); and 6) anterior white matter (P = 0.045), anterior gray matter (P = 0.002), and posterior gray matter (P = 0.002) insula. No difference was found in corpus callosum (P > 0.05). The microstructural changes in some areas correlated with clinical parameters such as bloating (anterior insula), mental well-being (anterior insula, prefrontal cortex, and mid-cingulated and corona radiata), autonomic function based on electrocardiographic results (posterior insula and anterior cingulate), and presence of gastroparesis (anterior insula).CONCLUSIONSThe findings of this explorative study indicate that microstructural changes of brain areas involved in visceral sensory processing are associated with autonomic dysfunction and therefore may be involved in the pathogenesis of gastrointestinal symptoms in DM patients.

White Matter Tract Integrity of Anterior Limb of Internal Capsule in Major Depression and Type 2 Diabetes

A number of studies have shown an association between diabetes and depression. However, the underlying mechanisms are still unclear. Previous findings indicate a role for the prefrontal cortex and subcortical gray matter regions in type 2 diabetes and major depressive disorder (MDD). The purpose of this study was to examine the white matter integrity in the fibers that are part of the anterior limb of internal capsule (ALIC) in MDD and diabetic subjects using diffusion tensor imaging tractography. We studied 4 groups of subjects including 1) 42 healthy controls (HC), 2) 28 MDD subjects (MD), 3) 24 patients diagnosed with type 2 diabetes without depression (DC), and 4) 22 patients diagnosed with diabetes and depression (DD). Results revealed significantly decreased fractional anisotropy (FA; P=.021) and a trend towards significant increase in radial diffusivity (RD; P=.078) of the right ALIC in depressed subjects (MD+DD) compared to non-depressed subjects (HC+DC). While there were no significant diabetes effects or interactions between depression and diabetes, subjects with high depression ratings and high hemoglobin A1c levels had the lowest mean FA values in the right ALIC. In addition, we found a significant negative correlation between FA of the left ALIC with hemoglobin A1c in diabetic subjects (DC+DD; P=.016). Our study demonstrated novel findings of white matter abnormalities of the ALIC in depression and diabetes. These findings have implications for clinical manifestations of depression and diabetes as well as their pathophysiology.

The impulsivity behavior is correlated with prefrontal cortex gray matter volume reduction in heroin-dependent individuals

PurposeChronic exposure to heroin induced cerebral structural abnormalities may underlie heroin-related behaviors. The aim of this study was to: (1) identify cerebral structural abnormalities in heroin-dependent individuals (HDIs) by an automated and unbiased morphometric technique. (2) Define the correlation between these cerebral structural abnormalities and the impulsivity characteristic in HDIs. Methods24 HDIs and 24 control subjects were completed with (1) high resolution structural magnetic resonance imaging scanning and analysis of gray matter volume using voxel-based morphometry implemented in Statistical Parametric Mapping and (2) a Chinese translation Barratt Impulsiveness Scale-11 questionnaire survey. Differences in regional gray matter volume were tested using an analysis of covariance model, co-varying for global gray matter and age. Statistical maps were set at p<0.05, corrected for multiple comparisons. The abnormal brain regions were correlated with the duration of heroin use and impulsivity scores. ResultsAfter adjusting for effects of age and total gray matter volume, cortical gray matter volume in the bilateral medial prefrontal cortex, bilateral dorsal lateral prefrontal cortex, and right fusiform cortex were significantly reduced in HDIs. Moreover, the gray matter volume in prefrontal cortex that showed group differences was negatively correlated with the duration of heroin use and negatively correlated with the impulsivity characteristic in HDIs. ConclusionThese findings reveal the prefrontal cortex was impaired in HDIs, meanwhile, indicate the changes in gray matter volume are relating to the duration of heroin use and the impulsivity characteristic of the HDIs.

Temporal and frontal cortical thickness associations with M100 auditory activity and attention in healthy controls and individuals with schizophrenia

BackgroundAlthough gray matter (GM) abnormalities are frequently observed in individuals with schizophrenia (SCZ), the functional consequences of these structural abnormalities are not yet understood. The present study sought to better understand GM abnormalities in SCZ by examining associations between GM and two putative functional SCZ biomarkers: weak 100ms (M100) auditory responses and impairment on tests of attention. MethodsData were available from 103 subjects (healthy controls=52, SCZ=51). GM cortical thickness measures were obtained for superior temporal gyrus (STG) and prefrontal cortex (PFC). Magnetoencephalography (MEG) provided measures of left and right STG M100 source strength. Subjects were administered the Trail Making Test A and the Connors' Continuous Performance Test to assess attention. ResultsA strong trend indicated less GM cortical thickness in SCZ than controls in both regions and in both hemispheres (p=0.06). Individuals with SCZ had weaker M100 responses than controls bilaterally, and individuals with SCZ performed more poorly than controls on tests of attention. Across groups, left STG GM was positively associated with left M00 source strength. In SCZ only, less left and right STG and PFC GM predicted poorer performance on tests of attention. After removing variance in attention associated with age, associations between GM and attention remained significant only in left and right STG. ConclusionsReduced GM cortical thickness may serve as a common substrate for multiple functional abnormalities in SCZ, with structural–functional abnormalities in STG GM especially prominent. As suggested by others, functional abnormalities in SCZ may be a consequence of elimination of the neuropil (dendritic arbors and associated synaptic infrastructure) between neuron bodies.

Prefrontal deviations in function but not volume are putative endophenotypes for schizophrenia

This study sought to systematically investigate whether prefrontal cortex grey matter volume reductions are valid endophenotypes for schizophrenia, specifically investigating their presence in unaffected relatives, heritability, genetic overlap with the disorder itself and finally to contrast their performance on these criteria with putative neuropsychological indices of prefrontal functioning. We used a combined twin and family design and examined four prefrontal cortical regions of interest. Superior and inferior regions were significantly smaller in patients. However, the volumes of these same regions were normal in unaffected relatives and therefore, we could confirm that such deficits were not due to familial effects. Volumes of the prefrontal and orbital cortices were, however, moderately heritable, but neither shared a genetic overlap with schizophrenia. Total prefrontal cortical volume reductions shared a significant unique environmental overlap with the disorder, suggesting that the reductions were not familial. In contrast, prefrontal (executive) functioning deficits were present in the unaffected relatives, were moderately heritable and shared a substantial genetic overlap with liability to schizophrenia. These results suggest that the well recognized prefrontal volume reductions are not related to the same familial influences that increase schizophrenia liability and instead may be attributable to illness related biological changes or indeed confounded by illness trajectory, chronicity, medication or substance abuse, or in fact a combination of some or all of them.

Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease

To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD). Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD. The Parkinson's Disease and Movement Disorders Center at the University of Pennsylvania. Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain. The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β = -0.37; P = .001), and PDD patients demonstrated hippocampal (β = -0.32; P = .004) and additional medial temporal lobe atrophy (β = -0.36; P = .003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P = .04) and a similar pattern to that of PDD patients (P = .81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume. Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.