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1.  Whole genome sequences of two octogenarians with sustained cognitive abilities 
Neurobiology of aging  2014;36(3):1435-1438.
Although numerous genetic variants affecting aging and mortality have been identified, e.g. APOE ε4, the genetic component influencing cognitive aging has not been fully defined yet. A better knowledge of the genetics of aging will prove helpful in understanding the underlying biological processes. Here, we describe the whole genome sequences of two female octogenarians. We provide the repertoire of genomic variants that the two octogenarians have in common. We also describe the overlap with the previously reported genomes of two supercentenarians - individuals aged ≥ 110 years. We assessed the genetic disease propensities of the octogenarians and non-aged control genomes and could not find support for the hypothesis that long-lived healthy individuals might exhibit greater genetic fitness than the general population. Furthermore, there is no evidence for an accumulation of previously described variants promoting longevity in the two octogenarians. These findings suggest that genetic fitness, as currently defined, is not the sole factor enabling an increased lifespan. We identified a number of healthy-cognitive-aging candidate genetic loci awaiting confirmation in larger studies.
doi:10.1016/j.neurobiolaging.2014.11.003
PMCID: PMC4346472  PMID: 25618617
aging; APOEε4; genetics; cognition; next generation sequencing; personalized medicine
2.  Reward processing in neurodegenerative disease 
Neurocase  2014;21(1):120-133.
Representation of reward value involves a distributed network including cortical and subcortical structures. Because neurodegenerative illnesses target specific anatomic networks that partially overlap with the reward circuit they would be predicted to have distinct impairments in reward processing. This review presents the existing evidence of reward processing changes in neurodegenerative diseases including mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease, as well as in healthy aging. Carefully distinguishing the different aspects of reward processing (primary rewards, secondary rewards, reward-based learning, and reward-based decision-making) and using tasks that differentiate the stages of processing reward will lead to improved understanding of this fundamental process and clarify a contributing cause of behavioral change in these illnesses.
doi:10.1080/13554794.2013.873063
PMCID: PMC4301575  PMID: 24417286
reward; neurodegenerative disease; dementia
3.  NIH EXAMINER: Conceptualization and Development of an Executive Function Battery 
Executive functioning is widely targeted when human cognition is assessed, but there is little consensus on how it should be operationalized and measured. Recognizing the difficulties associated with establishing standard operational definitions of executive functioning, the National Institute of Neurological Disorders and Stroke entered into a contract with the University of California-San Francisco to develop psychometrically robust executive measurement tools that would be accepted by the neurology clinical trials and clinical research communities. This effort, entitled Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER), resulted in a series of tasks targeting working memory, inhibition, set shifting, fluency, insight, planning, social cognition and behavior. We describe battery conceptualization and development, data collection, scale construction based on item response theory, and lay the foundation for studying the battery’s utility and validity for specific assessment and research goals.
doi:10.1017/S1355617713001094
PMCID: PMC4474183  PMID: 24103232
working memory; cognitive control; fluency; planning; social cognition; item response theory
4.  Frontotemporal dementia: diagnosis, deficits and management 
Summary
Frontotemporal dementia (FTD) is a progressive neurologic syndrome with diverse clinical presentations and attendant underlying pathologies. Psychiatric prodrome, neuropsychiatric symptoms and language difficulties are common in FTD, but the diversity of presentation raises unique diagnostic challenges that can significantly impact patient care and counsel for caregivers regarding clinical status and prognosis. While neuropsychiatric symptom measures are helpful, more sensitive assessments delineating the specific behavioral and linguistic deficits accompanying FTD are needed. Comprehensive clinical assessment in combination with evaluation of language, socio-emotional functioning, cognition and neuroimaging aid in accurate and early diagnosis and treatment planning. In what follows, we review each of the FTD syndromes, highlight current research investigating the cognitive, behavioral and socio-emotional deficits observed with this disease, address common diagnostic challenges and summarize best practices associated with management of FTD.
doi:10.2217/nmt.14.34
PMCID: PMC4824317  PMID: 25531687
differential diagnosis; frontotemporal dementia; neuropsychology; primary progressive aphasia; socio-emotional functioning
5.  RELATIONSHIP BETWEEN INSULIN-RESISTANCE PROCESSING SPEED AND SPECIFIC EXECUTIVE FUNCTION PROFILES IN NEUROLOGICALLY-INTACT OLDER ADULTS 
Objective
This study investigated the relationship between insulin-resistance and constituent components of executive function in a sample of neurologically-intact older adult subjects using the homeostasis model assessment (HOMA-IR) and latent factors of working memory, cognitive control and processing speed derived from confirmatory factor analysis. Low-density lipoprotein (LDL), mean arterial pressure (MAP), along with body mass index (BMI) and white matter hypointensity (WMH) were used to control for vascular risk factors, adiposity and cerebrovascular injury.
Methods
The study included 119 elderly subjects recruited from the University of California, San Francisco Memory and Aging Center. Subjects underwent neuropsychological assessment, fasting blood draw and brain magnetic resonance imaging (MRI). Partial correlations and linear regression models were used to examine the HOMA-IR-executive function relationship.
Results
Pearson correlation adjusting for age showed a significant relationship between HOMA-IR and working memory (rp=−.18, p=.047), a trend with cognitive control (rp=−.17, p=.068), and no relationship with processing speed (rp=.013, p=.892). Linear regression models adjusting for demographic factors (age, education and gender), LDL, MAP, BMI and WMH indicated that HOMA-IR was negatively associated with cognitive control (r=−.256; p=.026) and working memory (r=−.234; p=.054).
Conclusions
These results suggest a greater level of peripheral insulin-resistance is associated with decreased cognitive control and working memory. After controlling for demographic factors, vascular risk, adiposity and cerebrovascular injury, HOMA-IR remained significantly associated with cognitive control, with working memory showing a trend. These findings substantiate the insulin-resistance-executive function hypothesis and suggest a complex interaction, demonstrated by the differential impact of insulin-resistance on processing speed and specific aspects of executive function.
doi:10.1017/S1355617715000624
PMCID: PMC4764989  PMID: 26272269
Homeostatic Model Assessment; Insulin-Resistance; Confirmatory Factor Analysis; Executive Function; Working Memory; Cognitive Control; Processing Speed; White Matter Hypointensity
6.  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
7.  Neuropsychiatric Symptoms Predict Functional Status in Alzheimer’s Disease 
Background
Cognitive deficits are presumed to be the primary driver of functional impairment in Alzheimer’s disease (AD); however, functional impairment is likely multifactorially determined.
Objective
Our objective was to determine the relative contribution of neuropsychiatric symptoms in predicting ratings of functional status.
Methods
A total of 223 patients received routine neurological and neuropsychological evaluations and met criteria of probable AD dementia based on the McKhann criteria. Demographic, cognitive, and neuropsychiatric variables were entered in a hierarchical linear regression analysis to predict functional status as measured by the Functional Activities Questionnaire (FAQ).
Results
The total model explained 29.7% of the variance (p < 0.001) in FAQ. Importantly, neuropsychiatric variables explained 12.7% of the unique variance, with apathy and sleep as significant contributors.
Conclusion
Two neuropsychiatric variables, apathy and changes in sleep/nighttime behaviors, predicted ratings of functional status in AD patients independent of age, global cognition, memory and executive function measures, and depressive symptoms. These results highlight the importance of neuropsychiatric symptoms in understanding and potentially treating the functional limitations so prevalent in AD.
doi:10.3233/JAD-150018
PMCID: PMC4751056  PMID: 26402074
Alzheimer’s disease; apathy; neuropsychology; sleep disorders
8.  Plasma neurofilament light chain predicts progression in progressive supranuclear palsy 
Abstract
Objective
Blood‐based biomarkers for neurodegenerative conditions could improve diagnosis and treatment development. Neurofilament light chain (NfL), a marker of axonal injury, is elevated in cerebrospinal fluid (CSF) of patients with progressive supranuclear palsy (PSP). The goal of this study was to determine the diagnostic and prognostic value of plasma NfL in patients with PSP.
Methods
Plasma NfL was measured with ultrasensitive digital immunoassay‐based technology at baseline and 1‐year follow‐up in a pilot cohort of 15 PSP patients and 12 healthy controls, and a validation cohort of 147 PSP patients. Mixed linear models tested the ability of plasma NfL to predict neurological, cognitive and functional decline, and brain atrophy.
Results
Baseline mean plasma NfL levels were elevated in PSP patients (31 ± 4 pg/mL, vs. control, 17.5 ± 1 pg/mL, P < 0.05) and this difference persisted at follow‐up. A cutoff value of 20 pg/mL related to the diagnosis of PSP with a sensitivity of 0.80 and specificity of 0.83 (positive likelihood ratio = 4.7 and a negative likelihood radio of 0.24). Patients with higher NfL levels had more severe neurological (PSPRS, −36.9% vs. −28.9%, P = 0.04), functional (SEADL, −38.2% vs. −20%, P = 0.03), and neuropsychological (RBANS, −23.9% vs. −12.3%, P = 001) deterioration over 1 year. Higher baseline NfL predicted greater whole‐brain and superior cerebellar peduncle volume loss. Plasma and CSF NfL were significantly correlated (r = 0.74, P = 0.002).
Interpretation
Plasma NfL is elevated in PSP and could be of value as a biomarker both to assist clinical diagnosis and to monitor pharmacodynamic effects on the neurodegenerative process in clinical trials.
doi:10.1002/acn3.290
PMCID: PMC4774256  PMID: 27042681
9.  Loss of functional connectivity is greater outside the default mode network in non-familial early-onset Alzheimer’s disease variants 
Neurobiology of aging  2015;36(10):2678-2686.
The common and specific involvement of brain networks in clinical variants of Alzheimer’s disease (AD) is not well understood. We performed task-free (“resting-state”) functional imaging in 60 non-familial AD patients, including 20 early-onset AD (EOAD, age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (lvPPA, language deficits) and 16 posterior cortical atrophy patients (PCA, visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior and ventral) and four additional non-DMN networks: left and right executive-control, language and higher visual networks. Significant decreases in connectivity were found across AD variants compared with controls in the non-DMN networks. Within the DMN components, patients showed higher connectivity in the anterior DMN, in particular in lvPPA. No significant differences were found for the posterior and ventral DMN. Our findings suggest that loss of functional connectivity is greatest in networks outside the DMN in early-onset and non-amnestic AD variants, and may thus be a better biomarker in these patients.
doi:10.1016/j.neurobiolaging.2015.06.029
PMCID: PMC4698410  PMID: 26242705
Networks; intrinsic connectivity; functional magnetic resonance imaging; Alzheimer’s disease; posterior cortical atrophy; logopenic-variant primary progressive aphasia
10.  Sensitive measures of executive dysfunction in non-demented Parkinson’s disease 
Parkinsonism & related disorders  2014;20(12):1430-1433.
Background
We examined the sensitivity of different executive function measures for detecting deficits in Parkinson’s disease patients without dementia.
Methods
Twenty-one non-demented PD subjects and 21 neurologically healthy controls were administered widely used clinical executive functioning measures as well as the NIH EXAMINER battery, which produces Cognitive Control, Working Memory, and Verbal Fluency scores, along with an overall Executive Composite score, using psychometrically matched scales.
Results
No significant differences between groups were observed on widely used clinical measures. The PD patients scored lower than controls on the EXAMINER Executive Composite, Cognitive Control, and Working Memory Scores.
Conclusions
The NIH EXAMINER Executive Composite and Cognitive Control Scores are sensitive measures of executive dysfunction in non-demented PD, and may be more sensitive than several widely used measures. Results highlight the importance of careful test selection when evaluating for mild cognitive impairment in PD.
doi:10.1016/j.parkreldis.2014.10.007
PMCID: PMC4314390  PMID: 25454318
Parkinson’s disease; Mild cognitive impairment; Executive function; Cognitive control; Working memory
11.  Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion 
Brain  2014;137(11):3047-3060.
Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.
doi:10.1093/brain/awu248
PMCID: PMC4208465  PMID: 25273996
frontotemporal dementia; functional connectivity; dementia; biomarkers; amyotrophic lateral sclerosis
12.  Longitudinal Inflammation, Cognitive Decline, and Alzheimer's Disease: A Mini-Review 
Introduction
The role of inflammation in cognitive decline has generated considerable interest, although few longitudinal evaluations have been conducted. A review of the literature yields mixed findings, but suggests that inflammatory dysregulation is evident and may be related to clinical outcomes. The directionality, magnitude, and progression of these associations remain unclear. Future studies employing multiple time points of inflammatory data along with Alzheimer’s disease biomarkers are critical for explication of longitudinal inflammation in cognitive decline.
doi:10.1038/clpt.2014.147
PMCID: PMC4224964  PMID: 25009982
13.  Brain Amyloid-β Burden Is Associated with Disruption of Intrinsic Functional Connectivity within the Medial Temporal Lobe in Cognitively Normal Elderly 
The Journal of Neuroscience  2015;35(7):3240-3247.
The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Aβ deposition in preclinical AD, but the pathological relationship between tau and Aβ remains unclear. We used task-free fMRI with a focus on the medical temporal lobe, together with Aβ PET imaging, in cognitively normal elderly human participants. We found that cortical Aβ load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Aβ load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss.
doi:10.1523/JNEUROSCI.2092-14.2015
PMCID: PMC4331637  PMID: 25698758
Alzheimer's disease; amyloid; hippocampus; perirhinal cortex
14.  The functional oculomotor network and saccadic cognitive control in healthy elders 
NeuroImage  2014;95:61-68.
Decline in executive function is the most common age-associated cognitive deficit and may be a risk factor for neurodegenerative disease. The antisaccade (AS) task involves inhibition of a prepotent visuomotor response and is a well-validated executive function test in aging and neurodegeneration. We investigated the functional connectivity of the cortical oculomotor network during successful AS performance in healthy elders. Elevated BOLD activity in the right lateral frontal eye field (rlatFEF), a region linked to volume loss in individuals with impaired AS performance, was associated with worse AS performance and weaker network efficiency. In contrast, hub integrity of the right dorsolateral prefrontal cortex (rDLPFC) and anterior cingulate cortex (rACC) was associated with better AS performance. These data suggest that while several right lateral frontal regions are central nodes in the oculomotor network, the rlatFEF demonstrates early neural aberrations and the rDLPFC and rACC continue to support inhibitory cognitive control in healthy elders. We conclude that alterations in AS task functional connectivity, quantified as hub and network efficiency, may be clinically-relevant biomarkers of cognitive decline in executive functioning.
doi:10.1016/j.neuroimage.2014.03.051
PMCID: PMC4043928  PMID: 24675647
executive function; graph theory; aging; fMRI; antisaccade
15.  The Chinese Verbal Learning Test Specifically Assesses Hippocampal State 
Background
Recently, the Chinese Verbal Learning Test (ChVLT) was developed to assess episodic memory in Chinese speakers. The goal of this analysis was to determine whether memory consolidation as measured by the ChVLT was specifically associated with hippocampal volume in patients with cognitive impairment.
Methods
We administered the ChVLT to 22 Chinese-speaking patients with mild cognitive impairment and 9 patients with dementia and obtained hippocampal and cortical volumes from T1-weighted magnetic resonance imaging.
Results
Linear regression revealed that hippocampal volume explained 9.9% of the variance in delayed memory (P = .018) after controlling for the effects of age, education, immediate recall after the last learning trial, overall level of cognitive impairment, and volumes of other cortical regions.
conclusion
These results indicate that the ChVLT is specifically correlated with hippocampal volume, supporting its utility for detecting hippocampal disease and monitoring hippocampal state over time.
doi:10.1177/1533317514552667
PMCID: PMC4379122  PMID: 25270640
mild cognitive impairment; Alzheimer’s disease; memory; hippocampus; Chinese
16.  Anatomical correlates of reward-seeking behaviours in behavioural variant frontotemporal dementia 
Brain  2014;137(6):1621-1626.
Behavioural variant frontotemporal dementia is characterized by an increase in primary reward-seeking behaviours, including pursuit of food, drug, and sexual rewards. Perry et al. reveal that increased reward-seeking correlates with lower volume in the right ventral putamen and pallidum, which are known reward circuit structures.
Behavioural variant frontotemporal dementia is characterized by abnormal responses to primary reward stimuli such as food, sex and intoxicants, suggesting abnormal functioning of brain circuitry mediating reward processing. The goal of this analysis was to determine whether abnormalities in reward-seeking behaviour in behavioural variant frontotemporal dementia are correlated with atrophy in regions known to mediate reward processing. Review of case histories in 103 patients with behavioural variant frontotemporal dementia identified overeating or increased sweet food preference in 80 (78%), new or increased alcohol or drug use in 27 (26%), and hypersexuality in 17 (17%). For each patient, a primary reward-seeking score of 0–3 was created with 1 point given for each target behaviour (increased seeking of food, drugs, or sex). Voxel-based morphometry performed in 91 patients with available imaging revealed that right ventral putamen and pallidum atrophy correlated with higher reward-seeking scores. Each of the reward-related behaviours involved partially overlapping right hemisphere reward circuit regions including putamen, globus pallidus, insula and thalamus. These findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback.
doi:10.1093/brain/awu075
PMCID: PMC4032100  PMID: 24740987
frontotemporal dementia; reward processing; hypersexuality; overeating; alcohol
17.  QUANTITATIVE 7T PHASE IMAGING IN PREMOTOR HUNTINGTON DISEASE 
Background and Purpose
In vivo MRI and postmortem neuropathological studies have demonstrated elevated iron concentration and atrophy within the striatum of patients with Huntington disease (HD), implicating neuronal loss and iron accumulation in the pathogenesis of this neurodegenerative disorder. We used 7T MRI to determine whether quantitative phase, a putative marker of these endpoints, is altered in subjects with premotor HD.
Materials and Methods
Local field shift (LFS), calculated from 7T MR phase images, was quantified in 13 subjects with premotor HD and 13 age- and gender-matched controls. All participants underwent 3T and 7T MRI, including volumetric 3T T1 and 7T gradient-recalled echo sequences. LFS maps were created from 7T phase data and registered to caudate ROIs automatically parcellated from the 3T T1 images. HD-specific neurocognitive assessment was also performed and compared to LFS.
Results
Subjects with premotor HD had smaller caudate nuclear volume and higher LFS than controls. A significant correlation between these measurements was not detected, and prediction accuracy for disease state improved with inclusion of both variables. A positive correlation between LFS and genetic disease burden was also found, and there was a trend towards significant correlations between LFS and neurocognitive tests of working memory and executive function.
Conclusion
Subjects with premotor HD exhibit differences in 7T MRI phase within the caudate nuclei that correlate with genetic disease burden and trend with neurocognitive assessments. Ultra-high field MRI of quantitative phase may be a useful marker for monitoring neurodegeneration in premanifest HD.
doi:10.3174/ajnr.A3932
PMCID: PMC4425411  PMID: 24742810
18.  Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer’s disease 
BMC Neurology  2015;15:47.
Background
Heritability of Alzheimer’s disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in clinical presentation of AD, which is typically amnestic (AmnAD) but can less commonly involve visuospatial, language and/or dysexecutive syndromes (atypical or AtAD), further complicates genetic analyses. Taking a multi-locus approach may increase the ability to identify individuals at highest risk for any AD syndrome. In this study, we sought to develop and investigate the utility of a multi-variant genetic risk assessment on a cohort of phenotypically heterogeneous patients with sporadic AD clinical diagnoses.
Methods
We genotyped 75 variants in our cohort and, using a two-staged study design, we developed a 17-marker AD risk score in a Discovery cohort (n = 59 cases, n = 133 controls) then assessed its utility in a second Validation cohort (n = 126 cases, n = 150 controls). We also performed a data-driven decision tree analysis to identify genetic and/or demographic criteria that are most useful for accurately differentiating all AD cases from controls.
Results
We confirmed APOE ε4 as a strong risk factor for AD. A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P < 0.00001) in the Discovery cohort, but not in the Validation cohort. In decision tree analyses, we found that APOE best differentiated cases from controls only in AmnAD but not AtAD. In AtAD, HFE SNP rs1799945 was the strongest predictor of disease; variation in HFE has previously been implicated in AD risk in non-ε4 carriers.
Conclusions
Our study suggests that APOE ε4 remains the best predictor of broad AD risk when compared to multiple other genetic factors with modest effects, that phenotypic heterogeneity in broad AD can complicate simple polygenic risk modeling, and supports the association between HFE and AD risk in individuals without APOE ε4.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0304-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12883-015-0304-6
PMCID: PMC4459447  PMID: 25880661
Alzheimer’s disease; Genetics; Decision tree analysis
19.  Executive Functions in Premanifest Huntington’s Disease 
Objective
We investigated the viability of psychometrically robust executive function measures as markers for premanifest Huntington’s disease (HD).
Methods
Fifteen premanifest HD subjects and 42 controls were compared on the NIH EXAMINER executive function battery. This battery yields an overall Executive Composite score, plus Working Memory, Cognitive Control, and Fluency Scores that are measured on psychometrically matched scales. The scores were correlated with two disease markers, disease burden and striatal volumes, in the premanifest HD subjects.
Results
The premanifest HD subjects scored significantly lower on the Working Memory Score. The Executive Composite positively correlated with striatal volumes, and Working Memory Score negatively correlated with disease burden. The Cognitive Control and Fluency Scores did not differ between the groups or correlate significantly with the disease markers.
Conclusions
The NIH EXAMINER Executive Composite and Working Memory Score are sensitive markers of cognitive dysfunction, striatal volume, and disease burden in premanifest HD.
doi:10.1002/mds.25762
PMCID: PMC4029327  PMID: 24375511
Huntington’s disease; Executive function; Working memory; Striatal volume; Disease burden
20.  Memory consolidation in aging and MCI after 1 week 
Neuropsychology  2013;28(2):273-280.
Objective
To assess consolidation in amnestic mild cognitive (aMCI) impairment, controlling for differences in initial learning and using a protracted delay period for recall.
Methods
Fifteen individuals with MCI were compared to fifteen healthy older adult controls on a story learning task. Subjects were trained to criteria to equalize initial learning across subjects. Recall was tested at both the 30-minute typically used delay and a 1-week delay used to target consolidation.
Results
Using repeated measures ANOVAs adjusted for age, we found group × time point interactions across the entire task between the final trial and 30-minute delay, and again between the 30-minute and 1-week delay periods, with MCI having greater declines in recall as compared to controls. Significant group main effects were also found, with MCI recalling less than controls.
Conclusion
Consolidation was impaired in aMCI as compared to controls. Our findings indicate that MCI-related performance typically measured at 30 minutes underestimates MCI-associated memory deficits. This is the first study to isolate consolidation by controlling for initial learning differences and using a protracted delay period to target consolidation in an MCI sample.
doi:10.1037/neu0000013
PMCID: PMC4211844  PMID: 24219610
consolidation; episodic learning; amnestic mild cognitive impairment; memory; cognitive aging
21.  Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and Progressive Supranuclear Palsy 
Background
Elevated CSF tau is considered a biomarker of neuronal injury in newly developed Alzheimer’s disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of tau species in other primary tauopathies. We assessed CSF tau protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterized by deposition of four microtubule binding repeat (4R) tau with minimal Aβ pathology.
Methods
26 normal control (NC), 37 AD, and 24 PSP patients participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total tau, and ptau181. Additional, novel ELISAs targeting different N-terminal and central tau epitopes were developed to examine CSF tau components and to investigate interactions between diagnostic group, demographics, and genetic variables.
Results
PSP had lower CSF N-terminal and C-terminal tau concentrations than NC and AD measured with both the novel tau ELISAs and the standard AlzBio3 tau and ptau assays. AD had higher total tau and ptau levels than NC and PSP. There was a gender by diagnosis interaction in both AD and PSP for most tau species, with lower concentrations for male compared to female patients.
Conclusions
CSF tau fragment concentrations are different in PSP compared with AD despite the presence of severe tau pathology and neuronal injury in both disorders. CSF tau concentration likely reflects multiple factors in addition to the degree of neuronal injury.
doi:10.1136/jnnp-2014-308004
PMCID: PMC4256124  PMID: 24899730
Alzheimer’s disease; Progressive supranuclear palsy; CSF; Tau
22.  Variation in longevity gene KLOTHO is associated with greater cortical volumes 
Objective
Identifying genetic variation associated with brain structures in aging may elucidate new biologic mechanisms underlying resilience to cognitive decline. We investigated whether carrying one copy of the protective haplotype “KL-VS” in longevity gene KLOTHO (KL) is associated with greater gray matter volume in healthy human aging compared to carrying no copies.
Methods
We performed unbiased whole-brain analysis in cognitively normal older adults from two independent cohorts to assess the relationship between KL-VS and gray matter volume using voxel-based morphometry.
Results
We found that KL-VS heterozygosity was associated with greater volume in right dorsolateral prefrontal cortex (rDLPFC). Because rDLPFC is important for executive function, we analyzed working memory and processing speed in individuals. KL-VS heterozygosity was associated with enhanced executive function. Larger rDLPFC volume correlated with better executive function across the lifespan examined. Statistical analysis suggested that volume partially mediates the effect of genotype on cognition.
Interpretation
These results suggest that variation in KL is associated with bigger brain volume and better function.
doi:10.1002/acn3.161
PMCID: PMC4369272  PMID: 25815349
23.  Practical utility of amyloid and FDG-PET in an academic dementia center 
Neurology  2014;82(3):230-238.
Objective:
To evaluate the effect of amyloid imaging on clinical decision making.
Methods:
We conducted a retrospective analysis of 140 cognitively impaired patients (mean age 65.0 years, 46% primary β-amyloid (Aβ) diagnosis, mean Mini-Mental State Examination 22.3) who underwent amyloid (Pittsburgh compound B [PiB]) PET as part of observational research studies and were evaluated clinically before and after the scan. One hundred thirty-four concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed for changes between the pre- and post-PET clinical diagnosis (from Aβ to non-Aβ diagnosis or vice versa) and Alzheimer disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Postmortem diagnosis was available for 24 patients (17%).
Results:
Concordance between scan results and baseline diagnosis was high (PiB 84%, FDG 82%). The primary diagnosis changed after PET in 13/140 patients (9%) overall but in 5/13 (38%) patients considered pre-PET diagnostic dilemmas. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (unadjusted p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (adjusted p = 0.00013). Changes in treatment were associated with discordant PiB in patients with non-Aβ diagnoses (adjusted p = 0.028), while FDG had no effect on therapy. Both PiB (96%) and FDG (91%) showed high agreement with autopsy diagnosis.
Conclusions:
PET had a moderate effect on clinical outcomes. Discordant PiB had a greater effect than discordant FDG, and influence on diagnosis was greater than on treatment. Prospective studies are needed to better characterize the clinical role of amyloid PET.
doi:10.1212/WNL.0000000000000032
PMCID: PMC3902757  PMID: 24353340
24.  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
25.  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

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