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1.  The Patterns of Cognitive and Functional Impairment in Amnestic and Non-amnestic Mild Cognitive Impairment in Geriatric Depression 
Depressed older adults are at risk for the development of mild cognitive impairment (MCI), but few studies have characterized MCI subtypes in geriatric depression. The objective of this study was to identify the clinical patterns of MCI in late-life depression.
Baseline demographic, clinical, and neuropsychological test data collected as part of a randomized antidepressant trial for geriatric depression.
UCLA-based outpatient clinic.
One hundred thirty-eight older adults with major depression.
A neuropsychological test battery and comprehensive evaluations of depression, apathy, quality of life, medical burden, and vascular risk factors.
Seventy-one participants (51%) had MCI and 67 (49%) were cognitively normal. Of subjects with MCI, 14 (20%) had amnestic MCI and 57 (80%) had non-amnestic MCI. Overall, patients with MCI had greater depression severity, poorer quality of life, and worse performance on the Mini-Mental State Exam than patients without MCI. Patients with non-amnestic MCI had significantly greater depression severity than patients without MCI. Across all subjects, depression severity correlated with impaired performance in language and visuospatial functioning.
Our findings suggest that MCI is associated with greater severity of depression, poorer quality of life, and worse global cognitive function. Overall, subtypes of MCI in geriatric depression differ in the patterns of functional impairment, which may require different therapeutic approaches.
PMCID: PMC4751142  PMID: 24315561
Geriatric depression; mild cognitive impairment
2.  Combined citalopram and methylphenidate improved treatment response compared to either drug alone in geriatric depression: a randomized double-blind, placebo-controlled trial 
The American journal of psychiatry  2015;172(6):561-569.
We evaluated the potential of methylphenidate to improve antidepressant response to citalopram in elderly depressed patients with respect to clinical and cognitive outcomes.
We conducted a 16-week randomized double-blind placebo-controlled trial for geriatric depression in 143 older outpatients diagnosed with major depression comparing treatment response in three groups: 1) methylphenidate and placebo (N=48); 2) citalopram and placebo (N=48); 3) methylphenidate and citalopram (N=47). Primary outcome was defined as the change in depression severity. Remission was defined as Hamilton Depression Rating Scale (HDRS-24) score of 6 or below. Secondary outcomes included measures of anxiety, apathy, quality of life, and cognition.
Citalopram daily doses ranged between 20–60 mg (mean 32 mg); methylphenidate daily doses ranged between 5–40 mg (mean 16 mg). All groups showed significant improvement in the severity of depression. However, the improvement in depression severity and the clinical global impression was more prominent in the methylphenidate and citalopram group compared to methylphenidate and placebo and citalopram and placebo (P<0.05). Additionally, the rate of improvement in the methylphenidate and citalopram group was significantly faster than that in the citalopram and placebo in the first 4 weeks of the trial. The groups did not differ on cognitive improvement or the number of side-effects.
Combined treatment with citalopram and methylphenidate demonstrated an enhanced clinical response profile in the mood and wellbeing, and the rate of response compared to either drug. All treatments led to an improvement in cognitive functioning, without additional benefit from the use of methylphenidate.
PMCID: PMC4451432  PMID: 25677354
geriatric depression; enhanced antidepressant response; accelerated rate of response; stimulants; methylphenidate; citalopram; SSRI; augmentation; combination; cognition
4.  APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer’s disease 
Psychiatry research  2013;214(3):10.1016/j.pscychresns.2013.09.006.
Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer’s disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer’s disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer’s disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer’s disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.
PMCID: PMC3851589  PMID: 24080518
Entorhinal cortex; Hippocampus; Magnetic resonance imaging; Cortical unfolding; APOE-4 allele
5.  Neurobehavioral comorbidities of pediatric epilepsies are linked to thalamic structural abnormalities 
Epilepsia  2013;54(12):2116-2124.
Neurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomical underpinning is unclear. Striatal and thalamic abnormalities have been associated with childhood-onset epilepsies, suggesting that epilepsy-related changes in the subcortical circuit might be associated with the combordities of children with epilepsy. We aimed to compare subcortical volumes and their relationship with age in children with complex partial seizures (CPS), childhood absence epilepsy (CAE), and healthy controls (HC). We examined the shared versus unique structural-functional relationships of these volumes with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes.
We investigated volumetric differences of caudate, putamen, pallidum, and thalamus in children with CPS (N= 21), CAE (N=20), and HC (N=27). Study subjects underwent structural MRI, intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, IQ, language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC.
Both children with CPS and CAE exhibited significantly smaller left thalamic volume compared to HC. In terms of developmental trajectory, greater thalamic volume was significantly correlated with increasing age in children with CPS and CAE but not in HC. With regard to the comorbidities, reduced left thalamic volumes were related to more social problems in children with CPS and CAE. Smaller left thalamic volumes in children with CPS were also associated with poor attention, lower IQ and language scores, and impaired peer interaction.
Our study is the first to directly compare and detect shared thalamic structural abnormalities in children with CPS and CAE. These findings highlight the vulnerability of the thalamus and provide important new insights on its possible role in the neurobehavioral comorbidities of childhood-onset epilepsy.
PMCID: PMC4259153  PMID: 24304435
6.  The Memory Fitness Program: Cognitive Effects of a Healthy Aging Intervention 
Age-related memory decline affects a large proportion of older adults. Cognitive training, physical exercise, and other lifestyle habits may help to minimize self-perception of memory loss and a decline in objective memory performance.
The purpose of this study was to determine whether a 6-week educational program on memory training, physical activity, stress reduction, and healthy diet led to improved memory performance in older adults.
A convenience sample of 115 participants (mean age: 80.9 [SD: 6.0 years]) was recruited from two continuing care retirement communities. The intervention consisted of 60-minute classes held twice weekly with 15–20 participants per class. Testing of both objective and subjective cognitive performance occurred at baseline, preintervention, and postintervention. Objective cognitive measures evaluated changes in five domains: immediate verbal memory, delayed verbal memory, retention of verbal information, memory recognition, and verbal fluency. A standardized metamemory instrument assessed four domains of memory self-awareness: frequency and severity of forgetting, retrospective functioning, and mnemonics use.
The intervention program resulted in significant improvements on objective measures of memory, including recognition of word pairs (t[114] = 3.62, p < 0.001) and retention of verbal information from list learning (t[114] = 2.98, p < 0.01). No improvement was found for verbal fluency. Regarding subjective memory measures, the retrospective functioning score increased significantly following the intervention (t[114] = 4.54, p < 0.0001), indicating perception of a better memory.
These findings indicate that a 6-week healthy lifestyle program can improve both encoding and recalling of new verbal information, as well as self-perception of memory ability in older adults residing in continuing care retirement communities.
PMCID: PMC4255461  PMID: 21765343
Community setting; healthy lifestyle; memory training; older adult
7.  Screening for Suicidal Ideation in Children with Epilepsy 
Epilepsy & behavior : E&B  2013;29(3):521-526.
Given the FDA’s warning regarding the potential connection between suicidal behavior and antiepileptic drugs, this study examined methods by which to detect suicidal ideation in children with epilepsy. It compared the sensitivity, specificity, and area under the curve for identifying children with suicidal behavior using the Child Behavior Checklist (CBCL) and a structured psychiatric interview. Parent completed CBCLs provided behavior problem scores on 177 children with epilepsy, aged 5–16 years. Psychiatric diagnoses were made based on separate child and parent structured psychiatric interviews about the child. Children answered questions on suicidal behaviors during the interview. The clinically elevated CBCL Total Problems scale and having more than one psychiatric diagnosis, irrespective of type of diagnosis, were significant predictors and correctly classified children with suicidal ideation in 79% of the cases based on the CBCL and 80% of the cases with more than one psychiatric diagnosis. These findings indicate that elevated CBCL Total Problems scores, a commonly used instrument, can screen and identify risk for suicidal behavior in children with epilepsy. Additionally, irrespective of diagnosis, if a child with epilepsy has more than one psychiatric diagnosis, further assessment of suicidal behavior is warranted. Importantly, the results underscore the utility of having parents complete a questionnaire in the waiting room in order to identify children with epilepsy at risk for suicidal behavior.
PMCID: PMC4079123  PMID: 24128934
pediatric epilepsy; suicide; psychiatric disorders; behavior problems
8.  Modifiable Risk Factors for Alzheimer Disease and Subjective Memory Impairment across Age Groups 
PLoS ONE  2014;9(6):e98630.
Previous research has identified modifiable risk factors for Alzheimer's disease (AD) in older adults. Research is limited on the potential link between these risk factors and subjective memory impairment (SMI), which may precede AD and other dementias. Examination of these potential relationships may help identify those at risk for AD at a stage when interventions may delay or prevent further memory problems. The objective of this study was to determine whether risk factors for AD are associated with SMI among different age groups.
Trained interviewers conducted daily telephone surveys (Gallup-Healthways) of a representative community sample of 18,614 U.S. respondents, including 4,425 younger (age 18 to 39 years), 6,365 middle-aged (40 to 59 years), and 7,824 older (60 to 99 years) adults. The surveyors collected data on demographics, lifestyles, and medical information. Less education, smoking, hypertension, diabetes, less exercise, obesity and depression, and interactions among them, were examined for associations with SMI. Weighted logistic regressions and chi-square tests were used to calculate odds ratios and confidence intervals for SMI with each risk factor and pairwise interactions across age groups.
Depression, less education, less exercise, and hypertension were significantly associated with SMI in all three age groups. Several interactions between risk factors were significant in younger and middle-aged adults and influenced their associations with SMI. Frequency of SMI increased with age and number of risk factors. Odds of having SMI increased significantly with just having one risk factor.
These results indicate that modifiable risk factors for AD are also associated with SMI, suggesting that these relationships occur in a broad range of ages and may be targeted to mitigate further memory problems. Whether modifying these risk factors reduces SMI and the eventual incidence of AD and other dementias later in life remains to be determined.
PMCID: PMC4045888  PMID: 24896243
9.  Psychological Well-Being and Regional Brain Amyloid and Tau in Mild Cognitive Impairment 
To determine whether psychological well-being in people with mild cognitive impairment (MCI), a risk state for Alzheimer disease (AD), is associated with in vivo measures of brain pathology.
Cross-sectional clinical assessments and positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile (FDDNP), a molecule that binds to plaques and tangles, were performed on middle-aged and older adults at a university research institute. Volunteers were aged 40–85 years with MCI (N = 35) or normal cognition (N = 29) without depression or anxiety. Statistical analyses included general linear models, using regional FDDNP-PET binding values as dependent variables and the Vigor-Activity subscale of the Profile of Mood States (POMS) as the independent variable, covarying for age. The POMS is a self-rated inventory of 65 adjectives that describe positive and negative feelings.
Scores on the POMS Vigor-Activity subscale were inversely associated with degree of FDDNP binding in the posterior cingulate cortex (r = −0.35, p = 0.04) in the MCI group but not in the control group.
Psychological well-being, as indicated by self-reports of greater vigor and activity, is associated with lower FDDNP-PET binding in the posterior cingulate cortex, a region involved in emotional regulation, in individuals with MCI but not in those with normal cognition. These findings are consistent with previous work indicating that deposition of brain amyloid plaques and tau tangles may result in noncognitive and cognitive symptoms in persons at risk for AD.
PMCID: PMC3883933  PMID: 23567426
Aging; FDDNP; positron emission tomography; POMS; well-being
10.  Vascular Burden and Cognitive Functioning in Depressed Older Adults 
Vascular burden is known to contribute to geriatric depression and cognitive impairment. The objective of our study was to evaluate the relationship between vascular burden and pattern of cognitive impairment in older adults with depression.
Ninety-four community-dwelling older adults (mean age = 70.8 years; SD = 7.63) diagnosed with major depression were recruited to participate in the tai chi complementary use study aimed to improve antidepressant response to an antidepressant medication. All participants received comprehensive evaluations of depression, apathy, and vascular risk factors, and completed a battery of cognitive measures of memory, cognitive control, verbal fluency, and attention.
The severity of vascular burden was significantly correlated with depression severity and impaired performance on measures of cognitive control (i.e., inhibition/mental flexibility), and attention, but not memory or verbal fluency. Neither the severity of comorbid apathy nor medical illness burden was related to cognitive impairment.
Vascular burden in older depressed adults contributes to cognitive impairment, particularly in domains of attention and cognitive control. Our findings suggest that aggressive treatment of vascular risk factors may reduce risk for further cognitive decline in depressed older adults.
PMCID: PMC3889859  PMID: 21857219
Cerebrovascular risk factors; cognitive impairment; geriatric depression; vascular disease
11.  Vascular Risk and FDDNP-PET Influence Cognitive Performance 
Journal of Alzheimer's disease : JAD  2013;35(1):10.3233/JAD-121903.
The relationship of cerebrovascular risk and Alzheimer’s disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl{ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-β plaques and tau tangles). Here we report results of 75 healthy non-demented subjects (mean age, 63 years) who underwent neuropsychological testing, physical assessments, and FDDNP-PET scans. Controlling for AD family history, education, and APOE4 status in a general linear model, higher FSRP risk and global FDDNP-PET binding were each associated with poorer cognitive functioning. The interaction of FSRP and global FDDNP-PET binding was not significant in the model, indicating that stroke risk and plaque and tangle burden each contributed to worse cognitive performance. Within our healthy volunteers, age, blood pressure, and antihypertensive medication use were vascular risks that contributed significantly to the above findings. These findings suggest that even mild cerebrovascular risk may influence the extent of cognitive dysfunction in pre-dementia, along with amyloid-β and tau burden.
PMCID: PMC3874398  PMID: 23380994
Aging; Alzheimer’s disease; amyloid-µ plaques; FDDNP; Framingham stroke risk profile; mild cognitive impairment; older adults; positron emission tomography; tau tangles
12.  Prediction of Cognitive Decline Based on Hemispheric Cortical Surface Maps of FDDNP PET 
NeuroImage  2012;61(4):10.1016/j.neuroimage.2012.02.056.
A cross-sectional study to establish whether a subject’s cognitive state can be predicted based on regional values obtained from brain cortical maps of FDDNP Distribution Volume Ratio (DVR), which shows the pattern of beta amyloid and neurofibrillary binding, along with those of early summed FDDNP PET images (reflecting the pattern of perfusion) was performed.
Dynamic FDDNP PET studies were performed in a group of 23 subjects (8 control (NL), 8 Mild Cognitive Impairment (MCI) and 7 Alzheimer’s Disease (AD) subjects). FDDNP DVR images were mapped to the MR derived hemispheric cortical surface map warped into a common space. A set of Regions of Interest (ROI) values of FDDNP DVR and early summed FDDNP PET (0-6 min post tracer injection), were thus calculated for each subject which along with the MMSE score were used to construct a linear mathematical model relating ROI values to MMSE. After the MMSE prediction models were developed, the models’ predictive ability was tested in a non-overlapping set of 8 additional individuals, whose cognitive status was unknown to the investigators who constructed the predictive models.
Among all possible subsets of ROIs, we found that the standard deviation of the predicted MMSE was 1.8 by using only DVR values from medial and lateral temporal and prefrontal regions plus the early summed FDDNP value in the posterior cingulate gyrus. The root mean square prediction error for the eight new subjects was 1.6.
FDDNP scans reflect progressive neuropathology accumulation and can potentially be used to predict the cognitive state of an individual.
PMCID: PMC3839850  PMID: 22401755
cortical surface maps; MR; FDDNP PET; MMSE
13.  Executive Function Changes before Memory in Preclinical Alzheimer’s Pathology: A Prospective, Cross-Sectional, Case Control Study 
PLoS ONE  2013;8(11):e79378.
Early treatment of Alzheimer’s disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer’s disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology.
Methods and Findings
We recruited adults with probable Alzheimer’s disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer’s disease. We separated the asymptomatic group into those with (n = 34; preclinical Alzheimer’s disease) and without (n = 36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-ε genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR = 0.13, 95% CI = 0.04–0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study.
Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer’s disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach.
PMCID: PMC3832547  PMID: 24260210
14.  Influence of Alzheimer Disease Family History and Genetic Risk on Cognitive Performance in Healthy Middle-Aged and Older People 
Identification of risk factors for Alzheimer disease (AD) is critical for establishing effective diagnostic and therapeutic strategies. Carrying the ε4 allele of the apolipoprotein E gene (APOE4) and having a family history of the disease are two such factors, with family history risk reflecting additional yet unknown or rarely studied genetic and perhaps nongenetic risks. Our aim was to determine the influence of APOE genotype and family history status on cognitive performance in healthy individuals.
Longitudinal study.
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Seventy-two cognitively healthy middle-aged and older people (mean age ± SD: 62 ± 9 years).
Neuropsychological examinations at baseline and after 2 years.
Subjects with a family history of AD had lower baseline scores in processing speed, executive functioning, memory encoding, and delayed memory when compared with those without a family history. The family history risk factor did not influence degree of cognitive decline over time. By contrast, baseline cognitive performance did not vary according to APOE4 carrier status. Non-APOE4 carriers showed improved cognitive performance in the memory domains at follow-up, while performance of APOE4 carriers did not change.
Our data highlight the unique contributions of each risk factor to cognitive performance in healthy people. Both factors should be modeled in neuropsychological assessments of people at risk for AD.
PMCID: PMC3816758  PMID: 21849821
Alzheimer disease; family history; APOE genotype
15.  Protein Binding in Patients With Late-Life Depression 
Archives of general psychiatry  2011;68(11):1143-1150.
Depression has been identified as a risk factor and a prodrome of dementia. Common neurobiological mechanisms may underlie this clinical and phenomenologic overlap.
To examine and compare protein (amyloid and tau) binding in critical brain regions in patients diagnosed as having late-life major depressive disorder (MDD) and healthy control individuals using 2-(1-{6-[(2-[18F]fluoroethyl) (methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([18F]FDDNP) positron emission tomography.
A cross-section neuroimaging study using positron emission tomography.
University of California, Los Angeles.
Our samples comprised 20 patients diagnosed as having MDD and 19 healthy control individuals of comparable age, sex, and educational level.
Main Outcome Measure
Relative distribution volume in regions of interest was used as the measure of [18F]FDDNP binding in all study participants.
When compared with controls, [18F]FDDNP binding was significantly higher overall and in the posterior cingulate and lateral temporal regions in the MDD group.
These findings suggest that neuronal injury associated with higher protein load in critical brain regions might provide a mechanism in the pathophysiologic manifestation of MDD in late life and have implications for the therapeutics of depression in elderly individuals.
PMCID: PMC3797600  PMID: 22065530
16.  A pilot study of the effects of meditation on regional brain metabolism in distressed dementia caregivers 
Aging health  2012;8(5):509-516.
Caregiver distress can affect mood and cognition. Meditation can be used to reduce stress. This pilot study explored whether yogic meditation could change regional cerebral metabolism in distressed caregivers.
Nine dementia caregivers were randomized to undergo meditation training compared with relaxation for 12 min per day for 8 weeks. Caregivers received neuropsychiatric assessments and brain FDG-PET scans at baseline and postintervention.
The groups did not differ on measures of mood, mental and physical health, and burden at baseline and follow-up. When comparing the regional cerebral metabolism between groups, significant differences over time were found in the bilateral cerebellum (p < 0.0005), right inferior lateral anterior temporal (p < 0.0005), right inferior frontal (p = 0.001), left superior frontal (p = 0.001), left associative visual (p = 0.002) and right posterior cingulate (p = 0.002) cortices.
Meditation practice in distressed caregivers resulted in different patterns of regional cerebral metabolism from relaxation. These pilot results should be replicated in a larger study.
PMCID: PMC3558935  PMID: 23378856
dementia caregiver; depression; Kirtan kriya; PET; regional brain metabolism; stress; yogic meditation
17.  White matter integrity, language, and childhood onset schizophrenia 
Schizophrenia Research  2012;138(2-3):150-156.
The heterogeneity of symptoms and cognitive deficits in schizophrenia can be explained by abnormal connectivity between brain regions. Childhood-onset schizophrenia (COS) is a particularly severe form of schizophrenia, with an onset during a key time period for both cerebral pruning and myelination.
Diffusion tensor images were acquired from 18 children and adolescents with COS and 25 controls. The COS group was divided into two sub-groups--one with linguistic impairment (LI) and the other without (NLI). The fractional anisotropy (FA), axial (AD), and radial diffusivity (RD) data from the two COS sub-groups were compared to each other and to the controls using tract-based spatial statistics (TBSS) analyses, which is a voxel-based method used to identify regions of white matter abnormalities.
TBSS identified several regions in the left hemisphere where the LI group had increased AD and RD relative to the NLI and the control groups. These areas primarily localized to linguistic tracts: left superior longitudinal fasciculus and left inferior longitudinal fasciculus/inferior fronto-occipital fasciculus. Regions of increased RD overlapped regions of increased AD, with the former showing more pronounced effects.
Studies of adult-onset schizophrenia typically identify areas of higher RD but unchanged AD; however, normal development studies have shown that while RD decreases are pronounced over this age range, smaller decreases in AD can also be detected. The observed increases in both RD and AD suggest that developmental disturbances affecting the structural connectivity of these pathways are more severe in COS accompanied by severe linguistic impairments.
PMCID: PMC3372669  PMID: 22405729
Diffusion tensor imaging; Axial diffusivity; Radial diffusivity; Linguistic impairments; Neurodevelopment
18.  Prediction of Cognitive Decline by Positron Emission Tomography of Brain Amyloid and Tau 
Archives of neurology  2012;69(2):215-222.
To determine whether 2-(1-{6-[(2-fluorine18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) brain regional values in individuals without dementia predict and correlate with future cognitive change.
Two-year, longitudinal follow-up study.
A university research institute.
Volunteer sample of 43 middle-aged and older persons (median age, 64 years), including 21 with mild cognitive impairment (MCI) and 22 with normal aging.
Main Outcome Measures
Longitudinal [18F]FDDNP positron emission tomography (PET) binding values in the medial and lateral temporal, posterior cingulate, parietal, frontal, and global (mean) regions of interest; neuropsychological test battery measuring 5 cognitive domains, including memory, language, attention (and information-processing speed), executive functioning, and visuospatial ability.
For the entire study group (MCI and normal aging), increases in frontal, posterior cingulate, and global binding at follow-up correlated with progression of memory decline (r=−0.32 to −0.37, P=.03 to .01) after 2 years. Moreover, higher baseline [18F]FDDNP binding was associated with future decline in most cognitive domains, including language, attention, executive, and visuospatial abilities (r=−0.31 to −0.56, P=.05 to .002). For the MCI group, frontal and parietal [18F]FDDNP binding yielded the greatest diagnostic accuracy in identifying converters to Alzheimer disease vs nonconverters after 2 years, with an area under the receiver operating characteristic curve of 0.88 (95% CI, 0.72–1.00) compared with 0.68 (95% CI, 0.45–0.91) for medial temporal binding.
[18F]FDDNP PET regional binding patterns are consistent with known neuropathologic patterns of plaque and tangle brain accumulation, spreading from the medial temporal to other neocortical regions as disease progresses. Because binding patterns predict future cognitive decline and increase over time along with clinical decline, [18F]FDDNP PET scanning may have practical utility in identifying people at risk for future cognitive decline and in tracking the effectiveness of novel interventions designed to prevent or delay neurodegeneration and cognitive decline.
PMCID: PMC3623972  PMID: 22332188
19.  Proton Magnetic Resonance Spectroscopy and Thought Disorder in Childhood Schizophrenia 
Schizophrenia research  2011;133(1-3):82-90.
Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and thought disorder. This study examined this association in language-related brain regions using proton magnetic resonance spectroscopic imaging (1H MRSI).
MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5 T and short echo time (TR/TE=1500/30 ms). CSF-corrected “total NAA” (tNAA; N-acetyl-aspartate+N-acetyl-aspartyl-glutamate), glutamate+glutamine (Glx), creatine+phosphocreatine (Cr+PCr), choline compounds (Cho), and myo-inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter, and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder.
In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA in the left inferior frontal and superior temporal gyri and with Cr+PCr in left superior temporal gyrus.
Neurometabolite concentrations in language-related brain regions are associated with thought disorder in childhood-onset schizophrenia.
PMCID: PMC3229835  PMID: 21872444
Childhood-onset schizophrenia; Thought Disorder; Magnetic Resonance Spectroscopy; N-acetyl aspartate; Choline compounds
20.  Intelligence and Cortical Thickness in Children with Complex Partial Seizures 
NeuroImage  2011;57(2):337-345.
Prior studies on healthy children have demonstrated regional variations and a complex and dynamic relationship between intelligence and cerebral tissue. Yet, there is little information regarding the neuroanatomical correlates of general intelligence in children with epilepsy compared to healthy controls. In vivo imaging techniques, combined with methods for advanced image processing and analysis, offer the potential to examine quantitative mapping of brain development and its abnormalities in childhood epilepsy. A surface-based, computational high resolution 3-D magnetic resonance image analytic technique was used to compare the relationship of cortical thickness with age and intelligence quotient (IQ) in 65 children and adolescents with complex partial seizures (CPS) and 58 healthy controls, aged 6 -18 years. Children were grouped according to health status (epilepsy; controls) and IQ level (average and above; below average) and compared on age-related patterns of cortical thickness. Our cross-sectional findings suggest that disruption in normal age-related cortical thickness expression is associated with intelligence in pediatric CPS patients both with average and below average IQ scores.
PMCID: PMC3117889  PMID: 21586333
Cortical morphometry; IQ; complex partial seizures; cortical thickness; development; childhood
International Psychogeriatrics / Ipa  2012;24(7):1076-1084.
Whether perceived changes in memory parallel changes in brain pathology is uncertain. Positron emission tomography (PET) scans using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) can measure levels of amyloid plaques and tau neurofibrillary tangles in vivo. Here we investigate whether degree of self-reported memory impairment is associated with FDDNP-PET binding levels in persons without dementia.
57 middle-aged and older adults without dementia (mean age [±SD] = 66.3±10.6 years), including 25 with normal aging and 32 with mild cognitive impairment (MCI), were assessed. The outcome measures were the four factor scores of the Memory Functioning Questionnaire (MFQ) (frequency of forgetting, seriousness of forgetting, retrospective functioning, and mnemonics use) and FDDNP-PET binding levels in medial temporal, lateral temporal, posterior cingulate, parietal, frontal, and global (overall average) regions of interest.
After controlling for age, higher reported frequency of forgetting was associated with greater medial temporal (r = −0.29, p = 0.05), parietal (r = −0.30, p =.03), frontal (r = −0.35, p = 0.01) and global FDDNP-PET binding levels (r = −0.33, p = .02). The remaining MFQ factor scores were not significantly associated with FDDNP-PET binding levels, and no significant differences were found between normal aging and MCI subjects. Item analysis of the frequency of forgetting factor revealed 5 questions that yielded similar results as the full 32 question scale (r = −0.52, p = .0002).
These findings suggest that some forms of memory self-awareness, in particular the reported frequency of forgetting, may reflect extent of cerebral amyloid and tau brain pathology.
PMCID: PMC3350563  PMID: 22335970
aging; neuroimaging; cognitive testing; MCI; subjective cognitive impairment; beta-amyloid plaques; tau neurofibrillary tangles; FDDNP
22.  Deformation-based morphometry of prospective neurodevelopmental changes in new onset paediatric epilepsy 
Brain  2011;134(4):1003-1014.
Epilepsy is a prevalent childhood neurological disorder, but there are few prospective quantitative magnetic resonance imaging studies examining patterns of brain development compared to healthy controls. Controlled prospective investigations initiated at or near epilepsy onset would best characterize the nature, timing and course of neuroimaging abnormalities in paediatric epilepsy. In this study, we report the results of a deformation-based morphometry technique to examine baseline and 2-year prospective neurodevelopmental brain changes in children with new and recent onset localization-related epilepsies (n = 24) and idiopathic generalized epilepsies (n = 20) compared to healthy controls (n = 36). Children with epilepsy demonstrated differences from controls in baseline grey and white matter volumes suggesting antecedent anomalies in brain development, as well as abnormal patterns of prospective brain development that involved not only slowed white matter expansion, but also abnormalities of cortical grey matter development involving both greater and lesser volume changes compared to controls. Furthermore, abnormal neurodevelopmental changes extended outside the cortex affecting several subcortical structures including thalamus, cerebellum, brainstem and pons. Finally, there were significant differences between the epilepsy syndromes (localization-related epilepsies and idiopathic generalized epilepsies) with the idiopathic generalized epilepsies group showing a more disrupted pattern of brain structure both at baseline and over the 2-year interval.
PMCID: PMC3069702  PMID: 21398377
MRI; prospective neurodevelopment changes; deformation-based morphometry; new and recent onset epilepsy; localization-related epilepsy; idiopathic generalized epilepsy
23.  Positron Emission Tomography of Brain β-Amyloid and Tau Levels in Adults With Down Syndrome 
Archives of Neurology  2011;68(6):768-774.
To determine the neuropathological load in the living brain of nondemented adults with Down syndrome using positron emission tomography with 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) and to assess the influence of age and cognitive and behavioral functioning. For reference, [18F]FDDNP binding values and patterns were compared with those from patients with Alzheimer disease and cognitively intact control participants.
Cross-sectional clinical study.
Volunteer sample of 19 persons with Down syndrome without dementia (mean age, 36.7 years), 10 patients with Alzheimer disease (mean age, 66.5 years), and 10 controls (mean age, 43.8 years).
Main Outcome Measures
Binding of [18F]FDDNP in brain regions of interest, including the parietal, medial temporal, lateral temporal, and frontal lobes and posterior cingulate gyrus, and the average of all regions (global binding).
The [18F]FDDNP binding values were higher in all brain regions in the Down syndrome group than in controls. Compared with the Alzheimer disease group, the Down syndrome group had higher [18F]FDDNP binding values in the parietal and frontal regions, whereas binding levels in other regions were comparable. Within the Down syndrome group, age correlated with [18F]FDDNP binding values in all regions except the posterior cingulate, and several measures of behavioral dysfunction showed positive correlations with global, frontal, parietal, and posterior cingulate [18F]FDDNP binding.
Consistent with neuropathological findings from postmortem studies, [18F]FDDNP positron emission tomography shows high binding levels in Down syndrome comparable to Alzheimer disease and greater levels than in members of a control group. The positive associations between [18F]FDDNP binding levels and age as well as behavioral dysfunction in Down syndrome are consistent with the age-related progression of Alzheimer-type neuropathological findings in this population.
PMCID: PMC3261613  PMID: 21670401
24.  Reduced Hippocampal CA2, 3, and Dentate Gyrus Activity in Asymptomatic People At Genetic Risk for Alzheimer’s Disease 
Neuroimage  2009;53(3):1077-1084.
Previous functional magnetic resonance imaging (MRI) studies in healthy subjects with the apolipoprotein E 4 (APOE-4) genetic risk for Alzheimer’s disease have shown increased activation during memory task performance in broadly distributed cortical regions. These findings have been hypothesized to reflect compensatory recruitment of intact brain regions that presumably result from subtle neural dysfunction reflecting incipient disease. In this study, we used high-resolution functional MRI in APOE-4 carriers and non-carriers to measure activity in hippocampal subregions (CA fields 1, 2, 3; dentate gyrus [DG], and subiculum) and adjacent medial temporal lobe (parahippocampal and entorhinal) subregions. We found reduced left CA2, 3 and dentate gyrus (CA23DG) activity in cognitively intact APOE-4 carriers. These results suggest that reduced neural activity in hippocampal subregions may underlie the compensatory increase in extra hippocampal activity in people with a genetic risk for Alzheimer’s disease prior to the onset of cognitive deficits.
PMCID: PMC3260048  PMID: 20005961
Alzheimer’s Disease; ApoE; Hippocampus; MRI; fMRI; high-resolution imaging
25.  Plaque and tangle imaging and cognition in normal aging and Alzheimer’s disease 
Neurobiology of aging  2008;31(10):1669-1678.
Amyloid plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer’s disease (AD), begin accumulating in the healthy human brain decades before clinical dementia symptoms can be detected. There is great interest in how this pathology spreads in the living brain and its association with cognitive deterioration. Using MRI-derived cortical surface models and four-dimensional animation techniques, we related cognitive ability to positron emission tomography (PET) signal from 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP), a molecular imaging probe for plaques and tangles. We examined this relationship at each cortical surface point in 23 older adults (10 cognitively intact, 6 with amnestic mild cognitive impairment, 7 with AD). [18F]FDDNP-PET signal was highly correlated with cognitive performance, even in cognitively intact subjects. Animations of [18F]FDDNP signal growth with decreased cognition across all subjects ( mirrored the classic Braak and Braak trajectory in lateral temporal, parietal, and frontal cortices. Regions in which cognitive performance was significantly correlated with [18F]FDDNP signal include those that deteriorate earliest in AD, suggesting the potential utility of [18F]FDDNP for early diagnosis.
PMCID: PMC2891885  PMID: 19004525
Amyloid; Cerebral cortex; Cognitive aging; Memory; PET

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