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1.  Mild Cognitive Impairment 
Continuum : Lifelong Learning in Neurology  2013;19(2 Dementia):411-424.
Purpose of Review: The term mild cognitive impairment (MCI) is used to describe older subjects with demonstrable cognitive impairment who have not crossed the threshold for dementia. Because patients with MCI have an increased risk of developing dementia, especially Alzheimer disease (AD), there is significant interest in the clinical characterization of these subjects and in understanding the pathophysiology of the transition from MCI to AD.
Recent Findings: The MCI syndrome, as an expression of an incipient disorder that may lead to dementia, is extremely heterogeneous and may coexist with systemic, neurologic, or psychiatric disorders that can cause cognitive deficits. Recent clinical criteria were designed to take into account the different forms of clinical presentation of the syndrome, and introduced the possible contribution of biomarkers to the clinical diagnosis. Bedside diagnosis of MCI can be difficult, since patients who report having cognitive problems may have normal scores in global cognitive scales or in brief neuropsychological instruments.
Summary: This article presents the evolution of the clinical concept of MCI, the operationalization of its current definitions, the development of biomarkers that can help to identify an underlying neurodegenerative process as the etiology of the syndrome, and its proposed treatments.
PMCID: PMC3915547  PMID: 23558486
2.  Patterns of Compensation and Vulnerability in Normal Subjects at Risk of Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S427-S438.
Alzheimer’s disease (AD) is the most frequent form of dementia in elderly individuals and its incidence and prevalence increases with age. This risk of AD is increased in the presence of genetic and demographic factors including apolipoprotein E 4 allele, lower education, and family history of AD. There are medical risk modifiers including systemic hypertension, diabetes mellitus, cardiovascular disease, and cerebrovascular disease that increase the vulnerability for AD. By contrast, there are lifestyle risk modifiers that reduce the effects of AD risk factors include diet and physical and cognitive activity. Our research has consistently shown that it is the interactions among these risk factors with the pathobiological cascade of AD that determine the likelihood of a clinical expression of AD—either as dementia or mild cognitive impairment. However, the association between “vulnerability” and “protective” factors varies with age, since the effects of these factors on the risk for AD may differ in younger (age < 80) versus older (age > 80) individuals. The understanding of the dynamic of these factors at different age periods will be essential for the implementation of primary prevention treatments for AD.
PMCID: PMC3951098  PMID: 22669014
Alzheimer’s disease; cardiovascular disease; cerebrovascular disease; mild cognitive impairment
3.  Evolution of the diagnostic criteria for degenerative and cognitive disorders 
Current Opinion in Neurology  2011;24(6):532-541.
Purpose of review
This review describes the evolution of the clinical criteria for Alzheimer’s disease over the past 25 years, with special emphasis on those recently published that have incorporated the use of biomarkers.
Recent findings
One of the most important advances in the knowledge of Alzheimer’s disease was the development of cerebrospinal fluid, PET and MRI biomarkers. These have shown that the Alzheimer’s disease is present in cognitively normal individuals, suggesting that there is a long incubation process that precedes the onset of the symptoms. Although there are diagnostic criteria for Alzheimer’s disease, the National Institute on Aging and the Alzheimer’s Association has proposed a set of diagnostic criteria oriented to provide a unified vision of the pathological process from preclinical, to mild cognitive impairment, and to full-blown dementia. These new criteria take advantage of different biomarkers to support the clinical diagnosis of the different stages of the disease.
The new guidelines provide a definition of the dementia syndrome and core diagnostic features to be used in research and clinical practice, although they caution about the use of biomarkers, since they still require validation, and the longitudinal interaction and dynamics of these biomarkers in relationship to the manifestation of the symptoms are not fully understood.
PMCID: PMC3268228  PMID: 22071334
Alzheimer’s disease; dementia; diagnostic criteria; mild cognitive impairment; preclinical Alzheimer’s disease
4.  Abnormal Regional Cerebral Blood Flow in Cognitively Normal Elderly Subjects With Hypertension 
Background and Purpose
The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain.
rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups.
Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices
rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.
PMCID: PMC2701215  PMID: 18174483
CASL; cerebral blood flow; cognition; hypertension; MRI
5.  Effectiveness and Safety of Donepezil in Hispanic Patients with Alzheimer’s Disease: A 12-Week Open-Label Study 
Hispanics represent 10% of the U.S. population and are the fastest growing group. Studies show a higher prevalence and incidence of Alzheimer’s disease (AD) in Hispanics than in the non-Hispanic white population, with an earlier age of onset. Among the currently estimated 200,000 Hispanics with AD, a significant number remain undiagnosed and untreated, and Hispanic participation in AD clinical trials has been historically low. This study evaluated the efficacy and safety of donepezil hydrochloride (donepezil) in Hispanics with mild-to-moderate AD.
In this multicenter, open-label, 12-week study conducted in the United States, subjects were Hispanic men or women aged ≥50 years with a diagnosis of mild-to-moderate AD (DSMV-IV and NINCDS/ADRDA criteria), with Mini-Mental State Examination (MMSE) scores of 10–26 (inclusive) at screening. Subjects were treated with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for 6 weeks. Clinical evaluation was performed at baseline, week 6 and week 12. Cognitive improvement was measured using the MMSE, Fuld Object Memory Evaluation (FOME) and Symbol Digit Modality Test (SDMT). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI).
One-hundred-six patients with mild-to-moderate AD (mean age 68.6 years) were enrolled (intent to treat, n=97); most chose to have assessments conducted in Spanish. With 12 weeks of treatment, subjects showed statistically significant improvement from baseline on MMSE (P<0.0001), FOME retrieval (P=0.0042), FOME repeated retrieval (P=0.0020) and SDMT correct scores (P<0.0001). The NPI subdomain “apathy/indifference” showed statistically significant improvement (P=0.0010). The NPI Caregiver Distress scale (NPI-D) total score was statistically significantly improved (P=0.0500), suggesting a positive impact on relieving caregivers’ burden associated with patient behavior. Most patients tolerated the treatment well, with only 2 discontinuing because of adverse events. The most common (>5%) adverse events were insomnia (9.5%), dizziness (7.6%), diarrhea (5.7%) and nausea (5.7%).
The cognitive improvement and safety results from this study were consistent with those reported for donepezil in the general population. Increased awareness of AD in the Hispanic population will help more Hispanics with AD to benefit from early diagnosis and effective treatment.
PMCID: PMC2685180  PMID: 19024233
Alzheimer’s disease; drugs; Latinos
6.  Developing a national strategy to prevent dementia: Leon Thal Symposium 2009 
Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.
PMCID: PMC4298995  PMID: 20298968
Alzheimer's disease; Dementia; Mild cognitive impairment; Prevention; Biomarkers; Diagnosis; Screening; Clinical trials; MCI; Asymptomatic; Risk factors; Registry; Longitudinal studies; Database; PAD2020; Leon Thal Symposium; Treatment; Drug development; Health policy
7.  Hyperphosphorylated Tau is Elevated in Alzheimer's Disease with Psychosis 
Psychosis occurs in 40–60% of Alzheimer's disease (AD) subjects, is heritable, and indicates amore rapidly progressive disease phenotype. Neuroimaging and postmortem evidence support an exaggerated prefrontal cortical synaptic deficit in AD with psychosis. Microtubule-associated protein tau is a key mediator of amyloid-β-induced synaptotoxicity in AD, and differential mechanisms of progressive intraneuronal phospho-tau accumulation and interneuronal spread of tau aggregates have recently been described. We hypothesized that psychosis in AD would be associated with greater intraneuronal concentration of phospho-tau and greater spread of tau aggregates in prefrontal cortex. We therefore evaluated prefrontal cortex phospho-tau in a cohort of 45 AD cases with and without psychosis. Intraneuronal phospho-tau concentration was higher in subjects with psychosis, while a measure of phospho-tau spread, volume fraction, was not. Across groups both measures were associated with lower scores on the Mini-Mental State Examination and Digit Span Backwards test. These novel findings indicate that tau phosphorylation may be accelerated in AD with psychosis, indicating a more dynamic, exaggerated pathology in AD with psychosis.
PMCID: PMC4034758  PMID: 24270207
Alzheimer's disease; Braak stage; Mini-Mental State Examination; psychosis; tau
8.  Genetic determinants of disease progression in Alzheimer’s disease 
There is a strong genetic basis for late-onset of Alzheimer’s disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer’s Disease Research Center. Patients were classified as “rapid progressors” if the MMSE changed ≥3 points in 12 months and “slow progressors” if the MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between SNPs and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p=0.94) or APOE*2 (p=0.33) with AD progression, we found multiple nominally significant associations (p<0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2 and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ and ADAM19) at p<1E-05. Our data suggest that short-term clinical disease progression in AD has genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies.
PMCID: PMC4245313  PMID: 25114068
LOAD; GWAS; MMSE; AD progression
10.  Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults 
JAMA neurology  2014;71(5):562-568.
Recent studies show that cerebral β-amyloid (Aβ) deposition is associated with blood pressure and measures of arterial stiffness in nondemented individuals.
To examine the association between measures of arterial stiffness and change in Aβ deposition over time.
Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography using the Pittsburgh compound B twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer at the time closest to the second positron emission tomography scan. All measures were performed under standardized conditions. Pulse wave velocity (PWV) was measured in the central (carotid-femoral and heart-femoral PWV), peripheral (femoral-ankle PWV), and mixed (brachial-ankle PWV) vascular beds.
The change in Aβ deposition over 2 years was calculated from the 81 individuals with repeat Aβ-positron emission tomography.
The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time. Each standard deviation increase in central stiffness (carotid-femoral PWV, P = .001; heart-femoral PWV, P = .004) was linked with increases in Aβ deposition over 2 years.
This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.
PMCID: PMC4267249  PMID: 24687165
11.  A Rare Duplication on Chromosome 16p11.2 Is Identified in Patients with Psychosis in Alzheimer's Disease 
PLoS ONE  2014;9(11):e111462.
Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis.
PMCID: PMC4224411  PMID: 25379732
12.  Change in Inflammatory Markers and Cognitive Status among Oldest Old Women from the Study of Osteoporotic Fractures 
To determine the association between interleukin-6 (IL-6), IL-6 soluble receptor (sR) and tumor necrosis factor soluble receptor-1 (STNF-R1) and cognitive status among oldest old women.
20-year longitudinal cohort study.
Four clinical sites in the United States.
905 women from the Study of Osteoporotic Fractures (mean age 88.3±2.8 years at cognitive status adjudication).
At Year 20, cognitive status was adjudicated as normal, mild cognitive impairment (MCI), or dementia. Inflammatory markers were measured from blood serum at Years 10 and 16 in a random sample of women.
Over 10 years, 199 (22.0%) developed MCI, and 145 (16.0%) dementia. There were no significant associations between IL-6 or STNF-R1 and cognitive status. High IL-6 sR (≥37401.36pg/ml, high tertile) at Year 16 was significantly associated with decreased risk for dementia (OR=0.54; 95% CI: 0.30, 0.97), compared to women with lower levels (<37401.36 pg/ml, lower two tertiles). Women with high IL-6 sR at both time points (OR=0.39; 95% CI: 0.17, 0.89) or who transitioned to a high level (OR=0.35; 95% CI: 0.14, 0.88) had reduced risk of dementia.
In this cohort of white, high functioning oldest old women, a consistently high or an increasing level of IL-6 sR is associated with reduced risk of dementia. Compared to other studies of younger old adults, this suggests the effect of inflammation on dementia may differ in younger old and oldest old. Understanding these differences will be crucial in interpreting results from ongoing clinical trials and in targeting therapeutic strategies to the oldest old.
PMCID: PMC4109652  PMID: 24697580
Dementia; mild cognitive impairment; inflammation; oldest old
13.  TAR DNA-binding protein 43 pathology in Alzheimer's disease with psychosis 
TAR DNA-binding protein 43 (TDP-43) has been identified as a major disease protein in frontotemporal lobar degeneration. More recently, TDP-43 proteinopathy has also been observed in Alzheimer's disease (AD) with a characteristic distribution of TDP-43 predominantly in the mesial temporal lobe, and to a lesser degree in the neocortical areas. AD subjects with psychotic symptoms (AD+P) represent a subgroup characterized by greater impairment of frontal cortex-dependent cognitive functions and more severe frontal cortical neuropathology. The aim of this study is to determine whether there is an association between TDP-43 pathology and AD+P. We hypothesized that TDP-43 pathology would be more frequent in AD+P than in AD without psychosis.
We studied the presence and distribution of TDP-43 pathology by immunohistochemistry in the dentate gyrus (DG) and prefrontal cortex (FC) of postmortem brain specimens from 68 subjects with a primary neuropathologic diagnosis of AD as determined by the Neuropathology Core of the University of Pittsburgh Alzheimer's Disease Research Center.
Forty-five (66%) subjects were classified as AD+P. Fourteen (20.6%) subjects had TDP-43 pathology in DG, eight (11.8%) had TDP-43 pathology in FC, and six (8.8%) had TDP-43 pathology in both regions. TDP-43 in DG was not significantly associated with AD+P. However, TDP-43 in FC demonstrated a trend toward reduced likelihood of psychosis (p = 0.068). TDP-43 pathology in DG, but not FC, was significantly associated with greater age at death and longer duration of illness.
Our findings indicate that there was no association between concomitant TDP-43 pathology in DG or FC and AD+P.
PMCID: PMC4157359  PMID: 24588894
TDP-43; Alzheimer's disease; psychosis
14.  Long-term Survival in Adults Aged 65 and Older With White Matter Hyperintensity: Association With Performance on the Digit Symbol Substitution Test 
Psychosomatic medicine  2013;75(7):10.1097/PSY.0b013e31829c1df2.
White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, ApoE4, neuroimaging, cardiometabolic, physiological and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test(DSST).
Cox-proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8years, 58%women, 84%white) with WMH (0–9 points), DSST (0–90 points), risk factor assessment in 1992–94 and data on mortality and incident stroke to 2009 (median follow-up [range]:14.2[0.5–18.1]years).
WMH predicted a 48% greater mortality risk (age-adjusted hazard ratio (HR)[95% confidence interval(CI)] for WMH>3 points=1.48[1.35–1.62]). This association was attenuated after adjustment for DSST (HR[CI]: 1.38[1.27–1.51]) or lacunar infarcts (HR[CI]: 1.37[1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p=0.011). In fully adjusted models stratified by WMH>3, participants with DSST>median had a 34% lower mortality risk among those with WMH>3 (n=532/1217) and a 28% lower mortality risk among those with WMH<3 (n=1364/2296), compared to participants with DSST
WMH is associated with increased long-term mortality risk in community-dwelling adults aged 65 and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.
PMCID: PMC3809761  PMID: 23886735
mortality; information processing; white matter hyperintensity
Nature  2013;505(7484):550-554.
Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1,2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low frequency coding variants with large effects on LOAD risk, we performed whole exome-sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large case-control datasets. A rare variant in PLD3 (phospholipase-D family, member 3, rs145999145; V232M) segregated with disease status in two independent families and doubled risk for AD in seven independent case-control series (V232M meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354 cases and controls of European-descent). Gene-based burden analyses in 4,387 cases and controls of European-descent and 302 African American cases and controls, with complete sequence data for PLD3, indicate that several variants in this gene increase risk for AD in both populations (EA: OR= 2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92; p=1.40×10-3). PLD3 is highly expressed in brain regions vulnerable to AD pathology, including hippocampus and cortex, and is expressed at lower levels in neurons from AD brains compared to control brains (p=8.10×10-10). Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may be used to identify rare variants with large effects on risk for disease or other complex traits.
PMCID: PMC4050701  PMID: 24336208
Our primary aim was to examine whether preclinical disability in performance of cognitively-focused instrumental activities of daily living (C-IADL) tasks can discriminate between older adults with normal cognitive function and those with Mild Cognitive Impairment (MCI). The secondary purpose was to determine the two tasks with the strongest psychometric properties and assess their discriminative ability. Our goal was to generate diagnosis-relevant information about cognitive changes associated with MCI and DSM-5 Mild Neurocognitive Disorder.
Secondary analyses of cross-sectional data from a cohort of individuals diagnosed with normal cognitive function or MCI.
Private home locations in Pittsburgh, PA.
Older adults with remitted major depression (N=157).
Diagnosis of cognitive status was made by the Alzheimer’s Disease Research Center at the University of Pittsburgh. Performance of 8 C-IADL was measured using the criterion-referenced, observation-based Performance Assessment of Self-Care Skills (PASS).
A total of 96 older adults with normal cognitive function (mean age=72.5, SD=5.9) and 61 older adults with MCI (mean age=75.5, SD=6.3) participated. The 8 C-IADL demonstrated 81% accuracy in discriminating cognitive status (area under curve 0.81, p<0.001). Two tasks (shopping and checkbook balancing) were the most discriminating (area under curve 0.80, p<0.001); they demonstrated similar ability, as the 8 C-IADL, to discriminate cognitive status. Assessing performance on these two C-IADL takes 10–15 minutes.
This is the first demonstration of the discriminative ability of preclinical disability in distinguishing MCI from cognitively normal older adults. These findings highlight potential tasks, when measured with the observation-based PASS, which demonstrate increased effort for individuals with MCI. These tasks may be considered when attempting to diagnose MCI or Mild Neurocognitive Disorder in clinical practice and research.
PMCID: PMC4107156  PMID: 24890517
Cognitive Function; Mild Cognitive Impairment; Mild Neurocognitive Disorder; Activities of Daily Living; Instrumental Activities of Daily Living
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
PMCID: PMC4055488  PMID: 24922517
Annals of neurology  2013;73(6):751-761.
This study examined amyloid-β (Aβ) deposition in 190 non-demented subjects aged 82 and older to determine the proportion of Aβ-positive scans and associations with cognition, APOE status, brain volume, and Ginko biloba (Gb) treatment.
Subjects who agreed to participate had a brain MRI and positron emission tomography scan with 11C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82, and the mean age of the subjects was 85.5 at the time of the scans;152 (80%) were cognitively normal and 38 (20%) were diagnosed with mild cognitive impairment (MCI)at the time of the PiB study.
A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB.
The data revealed a 55% prevalence of PiB-positivity in non-demented subjects age >80 and 85% PiB-positivity in the APOE*4 non-demented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition.
PMCID: PMC3725727  PMID: 23596051
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
PMCID: PMC3896259  PMID: 24162737
NeuroImage  2013;71:207-215.
An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aβ deposition from those in which Aβ deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(−)] subjects.
We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(−) subjects was not so distinct.
The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence.
The visual read and SKM methods, applied together, may optimize the identification of early Aβ deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.
PMCID: PMC3605888  PMID: 23353602
Amyloid; Positron Emission Tomography; Pittsburgh Compound B; Visual Read; Cluster analysis
The American journal of psychiatry  2013;170(9):1051-1058.
The authors sought to determine the effects of conventional and atypical antipsychotic use on time to nursing home admission and time to death in a group of outpatients with mild to moderate probable Alzheimer’s disease.
The authors examined time to nursing home admission and time to death in 957 patients with the diagnosis of probable Alzheimer’s disease who had at least one follow-up evaluation (mean follow-up time, 4.3 years [SD=2.7]; range, 0.78–18.0 years) using Cox proportional hazard models adjusted for age, gender, education level, dementia severity, hypertension, diabetes mellitus, heart disease, extrapyramidal signs, depression, psychosis, aggression, agitation, and dementia medication use.
A total of 241 patients (25%) were exposed to antipsychotics at some time during follow-up (conventional, N=138; atypical, N=95; both, N=8). Nursing home admission (63% compared with 23%) and death (69% compared with 34%) were more frequent in individuals taking conventional than atypical antipsychotics. In amodel that included demographic and cognitive variables, hypertension, diabetes mellitus, heart disease, incident strokes, and extrapyramidal signs, only conventional antipsychotic use was associated with time to nursing home admission. However, the association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with nursing home admission and time to death, but neither conventional nor atypical antipsychotics were associated with time to death.
The use of antipsychotic medications, both conventional and atypical, was not associated with either time to nursing home admission or time to death after adjustment for relevant covariates. Rather, it was the presence of psychiatric symptoms, including psychosis and agitation, that was linked to increased risk of institutionalization and death after adjustment for exposure to antipsychotics.
PMCID: PMC3990263  PMID: 23896958
Neurology  2013;80(15):1378-1384.
To determine whether a high prevalence (55%) of Aβ deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging.
A total of 194 participants (mean age 85.5 years, range 82–95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B–PET imaging. We examined cross-sectional associations between Aβ status and performance on a broad neuropsychological test battery completed at GEMS entry 7–9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models.
At GEMS screening (2000–2002), participants who were Aβ-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aβ-positive relative to Aβ-negative participants (ps < 0.05).
Highly prevalent Aβ deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7–9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aβ-status groups may be detectable 7–9 years before neuroimaging.
PMCID: PMC3662268  PMID: 23516317
Journal of Aging Research  2014;2014:897671.
Background. Dementia and cardiovascular disease (CVD) are frequently comorbid. The presence of dementia may have an effect on how CVD is treated. Objective. To examine the effect of dementia on the use of four medications recommended for secondary prevention of ischemic heart disease (IHD): angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering medications, and antiplatelet medications. Design. Retrospective analysis of data from the Cardiovascular Health Study: Cognition Study. Setting and Subjects. 1,087 older adults in four US states who had or developed IHD between 1989 and 1998. Methods. Generalized estimating equations to explore the association between dementia and the use of guideline-recommended medications for the secondary prevention of IHD. Results. The length of follow-up for the cohort was 8.7 years and 265 (24%) had or developed dementia during the study. Use of medications for the secondary prevention of IHD for patients with and without dementia increased during the study period. In models, subjects with dementia were not less likely to use any one particular class of medication but were less likely to use two or more classes of medications as a group (OR, 0.60; 95% CI, 0.36–0.99). Conclusions. Subjects with dementia used fewer guideline-recommended medications for the secondary prevention of IHD than those without dementia.
PMCID: PMC3955600  PMID: 24719764
JAMA neurology  2013;70(2):223-228.
To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy.
Genetic case-control association study.
Academic research.
Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269).
Main Outcome Measure
The APOE allele frequencies.
The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ42=185.25; P=5.56×10−39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, ε4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4–15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1–19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5–10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7–5.6).
The APOE ε4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ε4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ε4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
PMCID: PMC3580799  PMID: 23407718
PLoS ONE  2014;9(1):e86141.
Background and Aims
The Australian National University AD Risk Index (ANU-ADRI, is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.
This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.
For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596–0·678), for the KP study it was 0·740 (0·712–0·768) and for the CVHS it was 0·733 (0·691–0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650–0.727), 0.666 (0.628–0.704) and 0.734 (0.707–0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427–0.554) to 0.595 (0.565–0.625).
A composite risk score derived from the ANU-ADRI weights including 8–10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.
PMCID: PMC3900468  PMID: 24465922

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