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1.  Longitudinal MRI and Cognitive Change in Healthy Elderly 
Neuropsychology  2007;21(4):412-418.
Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly.
doi:10.1037/0894-4105.21.4.412
PMCID: PMC2780018  PMID: 17605574
normal aging; memory; executive function; hippocampal volumes; white matter signal hyperintensity
2.  One-year test-retest reliability of intrinsic connectivity network fMRI in older adults 
NeuroImage  2012;61(4):1471-1483.
“Resting-state” or task-free fMRI can assess intrinsic connectivity network (ICN) integrity in health and disease, suggesting a potential for use of these methods as disease-monitoring biomarkers. Numerous analytical options are available, including model-driven ROI-based correlation analysis and model-free, independent component analysis (ICA). High test-retest reliability will be a necessary feature of a successful ICN biomarker, yet available reliability data remains limited. Here, we examined ICN fMRI test-retest reliability in 24 healthy older subjects scanned roughly one year apart. We focused on the salience network, a disease-relevant ICN not previously subjected to reliability analysis. Most ICN analytical methods proved reliable (intraclass coefficients > 0.4) and could be further improved by wavelet analysis. Seed-based ROI correlation analysis showed high map-wise reliability, whereas graph theoretical measures and temporal concatenation group ICA produced the most reliable individual unit-wise outcomes. Including global signal regression in ROI-based correlation analyses reduced reliability. Our study provides a direct comparison between the most commonly used ICN fMRI methods and potential guidelines for measuring intrinsic connectivity in aging control and patient populations over time.
doi:10.1016/j.neuroimage.2012.03.027
PMCID: PMC4226138  PMID: 22446491
3.  Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer's disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31828cc357.
Recently, Coppola and colleagues demonstrated that a rare MAPT sequence variant, c.454G>A (p.A152T), significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer's disease (AD) in a screen of 15,369 subjects1. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (PSP, n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (CBS, n=2); two patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathological correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
doi:10.1097/WAD.0b013e31828cc357
PMCID: PMC3796183  PMID: 23518664
All Cognitive Disorders/Dementia; Alzheimer's disease; Frontotemporal Dementia; Corticobasal degeneration; Progressive Supranuclear Palsy
4.  Antisaccade task reflects cortical involvement in mild cognitive impairment 
Neurology  2013;81(14):1235-1243.
Objective:
The aims of this study were to examine executive dysfunction using an antisaccade (AS) task in normal elderly (NE) and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) as well as to evaluate the relationship between AS performance and cortical thinning within AD-associated regions.
Methods:
We recorded eye movements in 182 subjects (NE: 118; MCI: 36; AD: 28) during an AS task. We also performed neuropsychological measures of executive function for comparison. Brain MRI scans were collected on most subjects, and cortical thickness was determined in 9 regions known to exhibit atrophy in AD dementia (“AD signature”). We investigated the relationships between AS and neuropsychological performance, as well as possible correlations between AS performance and cortical thickness.
Results:
AS performance in MCI resembled that in NE; subjects with AD were impaired relative to both MCI and NE. In all subjects, AS performance correlated with neuropsychological measures of executive function, even after controlling for disease severity. In the subjects with MCI but not in NE, cortical thickness in frontoparietal AD signature regions correlated with AS performance.
Conclusions:
The AS task is a useful measure of executive function across the AD spectrum. In MCI, AS performance may reflect disease burden within cortical brain regions involved in oculomotor control; however, AS impairments in NE may have etiologies other than incipient AD.
doi:10.1212/WNL.0b013e3182a6cbfe
PMCID: PMC3795604  PMID: 23986300
5.  Anterior temporal lobe degeneration produces widespread network-driven dysfunction 
Brain  2013;136(10):2979-2991.
The neural organization of semantic memory remains much debated. A ‘distributed-only’ view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality-selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain-specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.
doi:10.1093/brain/awt222
PMCID: PMC3857932  PMID: 24072486
anterior temporal lobe; semantic dementia; cognition; semantics; functional neuroimaging
6.  Life extension factor klotho enhances cognition 
Cell reports  2014;7(4):1065-1076.
Summary
Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a life span-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an NMDA receptor subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition at different life stages and counteract cognitive decline.
doi:10.1016/j.celrep.2014.03.076
PMCID: PMC4176932  PMID: 24813892
7.  Interleukin-6, Age, and Corpus Callosum Integrity 
PLoS ONE  2014;9(9):e106521.
The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.
doi:10.1371/journal.pone.0106521
PMCID: PMC4154691  PMID: 25188448
8.  TDP-43 Frontotemporal Lobar Degeneration and Autoimmune Disease 
Journal of neurology, neurosurgery, and psychiatry  2013;84(9):10.1136/jnnp-2012-304644.
Background
The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored.
Objective
To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls.
Design
Case control.
Setting
Academic medical centres.
Participants
129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels.
Outcome Measures
Chi-square comparison of autoimmune prevalence and follow up logistic regression.
Results
There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC.
Conclusions
svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.
doi:10.1136/jnnp-2012-304644
PMCID: PMC3840954  PMID: 23543794
9.  Rivastigmine is Associated with Restoration of Left Frontal Brain Activity in Parkinson’s Disease 
Objective
To investigate how acetylcholinesterase inhibitor (ChEI) treatment impacts brain function in Parkinson’s disease (PD).
Methods
Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after three months of ChEI treatment and were compared to 15 age and sex matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low frequency fluctuations.
Results
At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (e.g., caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (e.g., lateral prefrontal cortex), and episodic memory (e.g., precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased post-treatment compared to baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention.
Conclusions
PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared to controls, and rivastigmine is associated with performance-related normalization in left frontal cortex function.
doi:10.1002/mds.25575
PMCID: PMC4001926  PMID: 23847120
acetylcholine (D02.092.211.111); magnetic resonance imaging functional (E01.370.350.825.500); attention (F02.830.104.214); Acetylcholinesterase Inhibitors (D27.505.519.389.275) executive control (F02.463.217)
10.  Ecological Validity and Neuroantomical Correlates of the NIH EXAMINER Executive Composite Score 
Executive functions refer to a constellation of higher-level cognitive abilities that enable goal-oriented behavior. The NIH EXAMINER battery was designed to assess executive functions comprehensively and efficiently. Performance can be summarized by a single score, the ‘Executive Composite,’ which combines measures of inhibition, set-shifting, fluency, and working memory. We evaluated the ecological validity of the Executive Composite in a sample of 225 mixed neurological patients and controls using the Frontal Systems Behavior Scale (FrSBe), an informant-based measure of real-world executive behavior. In addition, we investigated the neuroanatomical correlates of the Executive Composite using voxel-based morphometry in a sample of 37 participants diagnosed with dementia, mild cognitive impairment, or as neurologically healthy. The Executive Composite accounted for 28% of the variance in FrSBe scores beyond age. Even after including two widely-used executive function tests (Trails B and Stroop) as covariates, the Executive Composite remained a significant predictor of real-world behavior. Anatomically, poorer scores on the Executive Composite were associated with smaller right and left dorsolateral prefrontal volumes, brain regions critical for good executive control. Taken together, these results suggest that the Executive Composite measures important aspects of executive function not captured by standard measures and reflects the integrity of frontal systems.
doi:10.1017/S1355617713000611
PMCID: PMC4059410  PMID: 23764015
executive function; magnetic resonance imaging; validity of results; neurological disorders; prefrontal cortex; neurodegenerative disorders
11.  CSF neurofilament concentration reflects disease severity in frontotemporal degeneration 
Annals of neurology  2014;75(1):116-126.
Objective
Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD.
Methods
CSF NfL, amyloid-β42 (Aβ42), tau and phosphorylated tau (ptau) concentrations were compared in 47 normal controls (NC), 8 asymptomatic gene carriers (NC2) of FTD-causing mutations, 79 FTD (45 behavioral variant frontotemporal dementia [bvFTD], 18 progressive nonfluent aphasia [PNFA], 16 semantic dementia [SD]), 22 progressive supranuclear palsy, 50 Alzheimer’s disease, 6 Parkinson’s disease and 17 corticobasal syndrome patients. Correlations between CSF analyte levels were performed with neuropsychological measures and the Clinical Dementia Rating scale sum of boxes (CDRsb). Voxel-based morphometry of structural MR images determined the relationship between brain volume and CSF NfL.
Results
Mean CSF NfL concentrations were higher in bvFTD, SD and PNFA than other groups. NfL in NC2 was similar to NC. CSF NfL, but not other CSF measures, correlated with CDRsb and neuropsychological measures in FTD, and not in other diagnostic groups. Analyses in two independent FTD cohorts and a group of autopsy verified or biomarker enriched cases confirmed the larger group analysis. In FTD, gray and white matter volume negatively correlated with CSF NfL concentration, such that individuals with highest NfL levels exhibited the most atrophy.
Interpretation
CSF NfL is elevated in symptomatic FTD and correlates with disease severity. This measurement may be a useful surrogate endpoint of disease severity in FTD clinical trials. Longitudinal studies of CSF NfL in FTD are warranted.
doi:10.1002/ana.24052
PMCID: PMC4020786  PMID: 24242746
12.  Intrinsic connectivity network disruption in progressive supranuclear palsy 
Annals of neurology  2013;73(5):603-616.
Objective
Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP.
Methods
Using task-free fMRI, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region which shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity.
Results
Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletal, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within cortico-subcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores.
Interpretation
This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes.
doi:10.1002/ana.23844
PMCID: PMC3732833  PMID: 23536287
13.  Normative Data in Women Age 85 and Older: Verbal Fluency, Digit Span, and the CVLT-II Short Form 
The Clinical neuropsychologist  2012;26(1):18-30.
Individuals age 85 years and above (i.e., the oldest old) represent the fastest growing segment of the U.S. population and are at increased risk of developing dementia. This represents an important challenge for the clinical neuropsychologist, as the extant normative data on neuropsychological measures remains relatively limited for this age group. Therefore, the aim of the present study was to characterize the performance effects of age and education in a large, well-characterized sample of women between the ages of 85 and 95 years on the CVLT-II Short Form (Delis et al., 2000), verbal fluency tasks, and the WAIS-III Digit Span Test (Wechsler, 1997). In order to minimize the likelihood that women with an incipient neurodegenerative process were included in the final normative sample, we applied regression-based change scores to identify and exclude women who evidenced a statistically significant decline on a global cognitive screening measure over a 20 year interval. The results of our analysis indicate varying influence of age and education on these measures and we provide tables with descriptive statistics stratified by both age and education. Findings from the present normative study are discussed within the context of “robust” longitudinal normative data.
doi:10.1080/13854046.2011.639310
PMCID: PMC3927723  PMID: 22224509
oldest old; normative data; CVLT
14.  Dissociations in Hippocampal and Frontal Contributions to Episodic Memory Performance 
Neuropsychology  2005;19(6):799-805.
The hippocampus and frontal lobes both contribute to episodic memory performance. In the present study, the authors evaluated the relative contributions of hippocampus, frontal lobes, anterior temporal cortex, and posterior cortex to memory performance in neurodegenerative patients and normal older controls. Subjects (n = 42) were studied with structural MRI and a memory paradigm that measured delayed recall, semantic clustering during recall, recognition discriminability, and recognition response bias. Data were analyzed with multiple regression. Consistent with the authors’ hypotheses, hippocampal volumes were the best predictor of delayed recall and recognition discriminability, whereas frontal volumes were the best predictor of semantic clustering and response bias. Smaller frontal volumes were associated with less semantic clustering during recall and a more liberal response bias. Results indicate that hippocampal and frontal contributions to episodic memory can be dissociated, with the hippocampus more important for memory accuracy, and frontal structures more important for strategic processing and decision making.
doi:10.1037/0894-4105.19.6.799
PMCID: PMC1851935  PMID: 16351355
memory; hippocampus; frontal lobes; organization; response bias
15.  Patterns of striatal degeneration in frontotemporal dementia 
Behavioral variant frontotemporal dementia and semantic dementia have been associated with striatal degeneration, but few studies have delineated striatal subregion volumes in vivo or related them to clinical phenotype. We traced caudate, putamen, and nucleus accumbens on MR images to quantify volumes of these structures in behavioral variant frontotemporal dementia, semantic dementia, Alzheimer’s disease, and healthy controls (n = 12 per group). We further related these striatal volumes to clinical deficits and neuropathological findings in a subset of patients. Behavioral variant frontotemporal dementia and semantic dementia showed significant overall striatal atrophy compared with controls. Moreover, behavioral variant frontotemporal dementia showed panstriatal degeneration whereas semantic dementia featured a more focal pattern involving putamen and accumbens. Right-sided striatal atrophy, especially in the putamen, correlated with overall behavioral symptom severity and with specific behavioral domains. At autopsy, patients with behavioral variant frontotemporal dementia and semantic dementia showed striking and severe tau or TAR DNA-binding protein of 43 kDa pathology, especially in ventral parts of the striatum. These results demonstrate that ventral striatum degeneration is a prominent shared feature in behavioral variant frontotemporal dementia and semantic dementia and may contribute to social-emotional deficits common to both disorders.
doi:10.1097/WAD.0b013e31824a7df4
PMCID: PMC3389579  PMID: 22367382
16.  Neural correlates of cognitive intervention in persons at risk of developing Alzheimer’s disease 
Cognitive training is an emergent approach that has begun to receive increased attention in recent years as a non-pharmacological, cost-effective intervention for Alzheimer’s disease (AD). There has been increasing behavioral evidence regarding training-related improvement in cognitive performance in early stages of AD. Although these studies provide important insight about the efficacy of cognitive training, neuroimaging studies are crucial to pinpoint changes in brain structure and function associated with training and to examine their overlap with pathology in AD. In this study, we reviewed the existing neuroimaging studies on cognitive training in persons at risk of developing AD to provide an overview of the overlap between neural networks rehabilitated by the current training methods and those affected in AD. The data suggest a consistent training-related increase in brain activity in medial temporal, prefrontal, and posterior default mode networks, as well as increase in gray matter structure in frontoparietal and entorhinal regions. This pattern differs from the observed pattern in healthy older adults that shows a combination of increased and decreased activity in response to training. Detailed investigation of the data suggests that training in persons at risk of developing AD mainly improves compensatory mechanisms and partly restores the affected functions. While current neuroimaging studies are quite helpful in identifying the mechanisms underlying cognitive training, the data calls for future multi-modal neuroimaging studies with focus on multi-domain cognitive training, network level connectivity, and individual differences in response to training.
doi:10.3389/fnagi.2014.00231
PMCID: PMC4143724  PMID: 25206335
cognitive training; mild cognitive impairment (MCI); aging; plasticity; neuroimaging; cognitive stimulation; computerized training
17.  Before it is too late: professional responsibilities in late-onset Alzheimer’s research and pre-symptomatic prediction 
The development of a wide array of molecular and neuroscientific biomarkers can provide the possibility to visualize the course of Alzheimer’s disease (AD) at early stages. Many of these biomarkers are aimed at detecting not only a preclinical, but also a pre-symptomatic state. They are supposed to facilitate clinical trials aiming at treatments that attack the disease at its earliest stage or even prevent it. The increasing number of such biomarkers currently tested and now partly proposed for clinical implementation calls for critical reflection on their aims, social benefits, and risks. This position paper summarizes major challenges and responsibilities. Its focus is on the ethical and social problems involved in the organization and application of dementia research, as well as in healthcare provision from a cross-national point of view. The paper is based on a discussion of leading dementia experts from neuroscience, neurology, social sciences, and bioethics in the United States and Europe. It thus reflects a notable consensus across various disciplines and national backgrounds. We intend to initiate a debate on the need for actions within the researchers’ national and international communities.
doi:10.3389/fnhum.2014.00921
PMCID: PMC4238325  PMID: 25477802
late-onset Alzheimer’s dementia; medical ethics; recommendations; biomarker; public health policy; research participation; cultural diversity; public engagement
18.  Depressive Symptoms in Oldest-Old Women: Risk of Mild Cognitive Impairment and Dementia 
Objectives
Increasing evidence suggests that depression is a risk factor for cognitive impairment, but it is unclear if this is true among the oldest old. We determined whether elevated depressive symptoms predicted five-year incident mild cognitive impairment (MCI) or dementia, and neuropsychological test performance among oldest-old women.
Design
Prospective
Setting
Three study sites
Participants
302 women ≥85 years (mean, 87 ±2)
Measurements
Depressive symptoms were measured with the 15-item Geriatric Depression Scale (GDS); scores ≥6 indicated elevated symptoms. Five years later, participants completed neuropsychological testing and clinical cognitive status was adjudicated.
Results
In analyses of MCI vs. normal cognition, 70% of women with GDS ≥6 at baseline developed MCI vs. 37% with GDS <6. After adjustment for age, education, alcohol and benzodiazepine use, and study site, GDS ≥6 remained independently associated with much greater likelihood of developing MCI (multivariable odds ratio (MOR) = 3.71, 95% confidence interval (CI) 1.30, 10.59). In analyses of dementia vs. normal cognition, 65% of women with GDS ≥6 developed dementia compared to 37% of those with GDS <6 (MOR = 3.15, 95% CI 1.03, 9.65). Only 19% of women with GDS ≥6 had normal cognitive status five years later, compared to 46% of those with GDS <6 (MOR = 0.28, 95% CI 0.11, 0.73). Women with elevated depressive symptoms had worse scores on tests of global cognition and working memory.
Conclusion
Elevated depressive symptoms are an important risk factor for cognitive disorders and lower cognitive performance among women living to their ninth and tenth decades.
doi:10.1097/JGP.0b013e318235b611
PMCID: PMC3326212  PMID: 22015706
oldest-old; women; depression; mild cognitive impairment; dementia
19.  Body Mass and White Matter Integrity: The Influence of Vascular and Inflammatory Markers 
PLoS ONE  2013;8(10):e77741.
High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001). Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [β=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [β=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability.
doi:10.1371/journal.pone.0077741
PMCID: PMC3797689  PMID: 24147070
20.  Memantine in frontotemporal lobar degeneration: A multicenter, randomised, double-blind, placebo-controlled trial 
Lancet neurology  2013;12(2):149-156.
Background
Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI).
Methods
We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974
Findings
100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group.
Interpretation
There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD.
Funding
Forest Research Institute
doi:10.1016/S1474-4422(12)70320-4
PMCID: PMC3756890  PMID: 23290598
21.  Anti-saccade performance predicts executive function and brain structure in normal elders 
Objective
To assess the neuropsychological and anatomical correlates of anti-saccade (AS) task performance in normal elders.
Background
The AS task correlates with neuropsychological measures of executive function and frontal lobe volume in neurological diseases, but has not been studied in a well-characterized normal elderly population. Because executive dysfunction can indicate an increased risk for cognitive decline in cognitively normal elders, we hypothesized that AS performance might be a sensitive test of age-related processes that impair cognition.
Method
The percentage of correct AS responses was evaluated in forty-eight normal elderly subjects and compared with neuropsychological test performance using linear regression analysis and gray matter volume measured on MRI scans using voxel-based morphometry.
Results
The percentage of correct AS responses was associated with measures of executive function, including modified trails, design fluency, Stroop inhibition, abstraction, and backward digit span, and correlated with gray matter volume in two brain regions involved in inhibitory control: the left inferior frontal junction and the right supplementary eye field. The association of AS correct responses with neuropsychological measures of executive function was strongest in individuals with fewer years of education.
Conclusions
The AS task is sensitive to executive dysfunction and frontal lobe structural alterations in normal elders.
doi:10.1097/WNN.0b013e318223f6c6
PMCID: PMC3775477  PMID: 21697711
anti-saccade; normal aging; executive function; frontal lobe; cognitive reserve
22.  Validating the Chinese version of the Verbal Learning Test for screening Alzheimer’s disease 
Episodic memory tasks are one of the most sensitive tools to discriminate Alzheimer’s disease (AD). This study aimed to validate a shorter version verbal memory test that will efficiently assess Chinese elderly with memory complaints. One hundred and eighty-five elderly with normal cognition (NC) and 217 AD patients were evaluated. Each participant received the Chinese Version Verbal Learning Test (CVVLT) consisting of 9 two-character nouns with 4 learning trials, 2 delayed recalls in 30 seconds and 10 minutes, and a word recognition test. In the NC elderly, age and sex had significant effects on recall scores in CVVLT, while education level showed an inverse correlation with 3 different patterns of errors made during the learning, recall, and recognition trials. AD patients had lower scores across all recall tests. In those with lower educational level, NC elderly had higher perseveration errors than AD patients. The cutoff value between the AD and NC groups in the 10-minute recall was 4/5 for those aged >75 years and 5/6 for those aged <75 years. This study has good validity in discriminating AD participants and the data here can help in diagnosing AD and mild cognitive impairment using the CVVLT.
doi:10.1017/S1355617709991184
PMCID: PMC3767760  PMID: 20003579
Chinese Verbal Learning Test; education; memory; dementia; cutoff value; validation
23.  Inflammation and clinical presentation in neurodegenerative disease: a volatile relationship 
Neurocase  2012;19(2):182-200.
A proposed immune mechanism that potentially modifies or exacerbates neurodegenerative disease presentation in older adults has received considerable attention in the past decade, with recent studies demonstrating a strong link between pro-inflammatory markers and neurodegeneration. The overarching aim of the following review is to synthesize recent research that supports a possible relationship between inflammation and clinical features of neurodegenerative diseases, including risk of development, cognitive and clinical correlates, and progression of the specified diseases. Specific emphasis is placed on providing a temporal context for the association between inflammation and neurodegeneration.
doi:10.1080/13554794.2011.654227
PMCID: PMC3733377  PMID: 22515699
Inflammation; Cognition; Neuropsychology; Neurodegenerative disease; Alzheimer’s
24.  Neuropsychological correlates of dominance, warmth, and extraversion in neurodegenerative disease 
Introduction
Changes in personality differ qualitatively and quantitatively between patients with different neurodegenerative diseases, likely due to divergent patterns of regional neurodegeneration. Regional damage to circuits underlying various cognitive and emotional functions have been associated with interpersonal traits like dominance, extraversion, and warmth in patients with neurodegenerative diseases, suggesting that personality may in part be mediated by these more basic neuropsychological functions. In this study, we hypothesized that different combinations of cognitive, neuropsychiatric, and emotional measures would predict different interpersonal traits in patients with neurodegenerative diseases.
Methods
A battery of cognitive, neuropsychiatric, and emotional measures was administered to 286 patients with various neurodegenerative diseases such as Alzheimer’s disease, behavioral variant frontotemporal dementia, semantic dementia, and progressive supranuclear palsy, and informants described patients’ dominance, extraversion, and warmth using the Interpersonal Adjective Scales (IAS) personality questionnaire. Regression modeling was performed to identify which neuropsychological factors uniquely predicted current personality, controlling for age, gender, and premorbid personality.
Results
Social dominance covaried with patients’ capacity for cognitive control and verbal fluency. Conversely, warmth did not rely on these executive or verbal skills, but covaried primarily with patients’ capacity for emotional responsiveness. Extraversion, representing a blend of dominance and warmth, demonstrated an intermediate degree of relationship to both executive/verbal and emotional functions.
Conclusions
These findings suggest that different personality traits are partly subserved by specific cognitive and emotional functions in neurodegenerative disease patients. While this study was performed in the context of brain damage, the results raise the question of whether individual differences in these neuropsychological abilities may also underlie variability in normal personality.
doi:10.1016/j.cortex.2011.03.001
PMCID: PMC3132224  PMID: 21470601
personality; neurodegenerative disease; cognition; emotion
25.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
doi:10.1038/ng.2466
PMCID: PMC3510344  PMID: 23143602

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