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1.  Effects of Baseline CSF α-Synuclein on Regional Brain Atrophy Rates in Healthy Elders, Mild Cognitive Impairment and Alzheimer’s Disease 
PLoS ONE  2013;8(12):e85443.
Background
Cerebrospinal fluid (CSF) α-synuclein is reduced in synucleinopathies, including dementia with Lewy bodies, and some studies have found increased CSF α-synuclein in Alzheimer’s disease (AD). No study has explored effects of CSF α-synuclein on brain atrophy. Here we tested if baseline CSF α-synuclein affects brain atrophy rates and if these effects vary across brain regions, and across the cognitive spectrum from healthy elders (NL), to patients with mild cognitive impairment (MCI) and AD.
Methods
Baseline CSF α-synuclein measurements and longitudinal structural brain magnetic resonance imaging was performed in 74 NL, 118 MCI patients and 55 AD patients. Effects of baseline CSF α-synuclein on regional atrophy rates were tested in 1) four pre-hoc defined regions possibly associated with Lewy body and/or AD pathology (amygdala, caudate, hippocampus, brainstem), and 2) all available regions of interest. Differences across diagnoses were tested by assessing the interaction of CSF α-synuclein and diagnosis (testing NL versus MCI, and NL versus AD).
Results
The effects of CSF α-synuclein on longitudinal atrophy rates were not significant after correction for multiple comparisons. There were tendencies for effects in AD in caudate (higher atrophy rates in subjects with higher CSF α-synuclein, P=0.046) and brainstem (higher atrophy rates in subjects with lower CSF α-synuclein, P=0.063). CSF α-synuclein had significantly different effects on atrophy rates in NL and AD in brainstem (P=0.037) and caudate (P=0.006).
Discussion: With the possible exception of caudate and brainstem, the overall weak effects of CSF α-synuclein on atrophy rates in NL, MCI and AD argues against CSF α-synuclein as a biomarker related to longitudinal brain atrophy in these diagnostic groups. Any effects of CSF α-synuclein may be attenuated by possible simultaneous occurrence of AD-related neuronal injury and concomitant Lewy body pathology, which may elevate and reduce CSF α-synuclein levels, respectively.
doi:10.1371/journal.pone.0085443
PMCID: PMC3877372  PMID: 24392009
3.  Higher Education is Not Associated with Greater Cortical Thickness in Brain Areas Related to Literacy or Intelligence in Normal Aging or Mild Cognitive Impairment 
Education may reduce risk of dementia through passive reserve, by increasing neural substrate. We tested the hypotheses that education is associated with thicker cortex and reduced rates of atrophy in brain regions related to literacy and intellectual ability. Healthy older adults and those with mild cognitive impairment were categorized into High (≥18 yrs) and Low (≤13 yrs) education groups. Higher education was associated with thinner cortices in several areas, but one-year atrophy rates in these areas did not differ by education group. These results do not support a passive reserve model in which early life education protects against dementia by increasing cortical thickness. Connectivity and synaptic efficiency, or other lifestyle factors may more directly reflect cognitive reserve.
doi:10.1080/13803395.2012.702733
PMCID: PMC3488147  PMID: 22905705
Brain reserve; cortical thickness; education; hippocampal volume; literacy; Mild Cognitive Impairment (MCI); aging
4.  Biomarkers for Alzheimer's disease in plasma, serum and blood - conceptual and practical problems 
Substances produced throughout the body are detectable in the blood, which is the most common biological fluid used in clinical testing. Biomarkers for Alzheimer's disease (AD) have long been sought in the blood, but none has become an established or validated diagnostic test. Companion reviews in Alzheimer's Research & Therapy will review specific types of biomarkers or applications; in this overview, we cover key concepts related to AD blood biomarker studies in general. Reasons for the difficulty of detecting markers of a brain-specific disorder, such as AD, in the blood are outlined; these pose conceptual challenges for blood biomarker discovery and development. Applications of blood tests in AD go beyond screening and diagnostic testing; other potential uses are risk assessment, prognostication, and evaluation of treatment target engagement, toxicity, and outcome. Opportunities and questions that may surround these different uses are discussed. A systematic approach to biomarker discovery, detection, assay development and quality control, sample collection, handling and storage, and design and analysis of clinical studies needs to be implemented at every step of discovery and translation to identify an interpretable and useful biomarker.
doi:10.1186/alzrt164
PMCID: PMC3706797  PMID: 23470193
5.  Early Visuospatial Deficits Predict the Occurrence of Visual Hallucinations in Autopsy-Confirmed Dementia with Lewy Bodies 
Objectives
The current study explored the value of visuospatial findings for predicting the occurrence of visual hallucinations (VH) in a sample of patients with Dementia with Lewy bodies (DLB) compared to patients with Alzheimer’s disease (AD).
Participants/Measurements
Retrospective analysis of 55 autopsy-confirmed DLB and 55 demographically-similar, autopsy-confirmed AD cases determined whether severe initial visuospatial deficits on the WISC-R Block Design subtest predicted the development of VH. Visuospatial deficits were considered severe if Block Design z-scores were 2.5 or more standard deviations below the mean of a well-characterized normal control group (Severe-VIS; DLB: n=35, AD: n=26) and otherwise were considered mild (Mild-VIS; DLB: n=20, AD: n=29).
Results
Forty percent of the Severe-VIS DLB group had baseline VH compared to 0% of Mild-VIS DLB patients. Only 8% of the Severe-VIS and 3% Mild-VIS AD patients had baseline VH. During the follow-up period (mean=5.0 years), an additional 61% of the Severe-VIS but only 11% of the Mild-VIS DLB patients developed VH. In that period, 38% of the Severe-VIS and 20% of the Mild-VIS AD patients developed VH. After considering initial MMSE score and rate of decline, logistic regression analyses found that performance on Block Design significantly predicted the presence of VH in the DLB group but not the AD group.
Conclusions
The presence of early, severe deficits on neuropsychological tests of visuospatial skill increases the likelihood that patients with suspected DLB will develop the prototypical DLB syndrome. The presence of such deficits may identify those DLB patients whose syndrome is driven by alpha-synuclein pathology rather than AD pathology and may inform treatment plans as well as future research.
doi:10.1097/JGP.0b013e31823033bc
PMCID: PMC3260388  PMID: 21997600
Lewy body disease; Hallucinations, visual; Alzheimer’s disease; Visuospatial cognition
6.  Potential Use of γ-Secretase Modulators in the Treatment of Alzheimer Disease 
Archives of neurology  2012;69(10):1255-1258.
Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent.
doi:10.1001/archneurol.2012.540
PMCID: PMC3747667  PMID: 22801784
7.  Temporal Sequence Learning in Healthy Aging and Amnestic Mild Cognitive Impairment 
Experimental aging research  2013;39(4):371-381.
Background/Study Context
Temporal sequence learning is a critical aspect of episodic memory that may be dependent on the temporal and frontal lobes. Since amnestic mild cognitive impairment (aMCI) and normal aging may result in changes within the temporal and frontal lobes, the present study investigated temporal sequence learning in patients with aMCI, cognitively normal older adults, and young adults.
Methods
On each trial of a temporal sequence task, circles appeared one at a time at the end of each arm of a computerized radial 8-arm maze. Participants were asked to reproduce the temporal sequence by placing numbered circles (1-8) on the arms of the 8-arm maze. Participants were presented with the same fixed sequence on each trial until the sequence was replicated without any errors, or until 15 trials were presented.
Results
Individuals with aMCI required significantly more trials to learn the temporal sequence compared to older adults (p <. 05). Older adults required significantly more trials to learn the sequence than young adults (p <. 05). Older adults and individuals with aMCI committed significantly more Trial 1 errors (p <. 05) than young adults; however, there were no significant differences between the aMCI and older adult groups on Trial 1.
Conclusion
The results suggest that temporal sequence learning deficits are detectable in aMCI. These deficits may disrupt a number of cognitive processes, such as episodic memory, that are important for the execution of daily activities. The results suggest that although temporal sequence learning declines with normal aging, this decline is greater in individuals who have a diagnosis of aMCI and are at higher risk for developing AD.
doi:10.1080/0361073X.2013.808122
PMCID: PMC3736698  PMID: 23875836
8.  Distinctive patterns of DNA methylation associated with Parkinson disease 
Epigenetics  2013;8(10):1030-1038.
Parkinson disease (PD) is a multifactorial neurodegenerative disorder with high incidence in the elderly, where environmental and genetic factors are involved in etiology. In addition, epigenetic mechanisms, including deregulation of DNA methylation have been recently associated to PD. As accurate diagnosis cannot be achieved pre-mortem, identification of early pathological changes is crucial to enable therapeutic interventions before major neuropathological damage occurs. Here we investigated genome-wide DNA methylation in brain and blood samples from PD patients and observed a distinctive pattern of methylation involving many genes previously associated to PD, therefore supporting the role of epigenetic alterations as a molecular mechanism in neurodegeneration. Importantly, we identified concordant methylation alterations in brain and blood, suggesting that blood might hold promise as a surrogate for brain tissue to detect DNA methylation in PD and as a source for biomarker discovery.
doi:10.4161/epi.25865
PMCID: PMC3891683  PMID: 23907097
DNA methylation; Parkinson disease; brain; peripheral blood leukocytes; epigenetics; neurodegeneration; genome-wide methylation
9.  The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers 
Mattsson, Niklas | Andreasson, Ulf | Persson, Staffan | Arai, Hiroyuki | Batish, Sat Dev | Bernardini, Sergio | Bocchio-Chiavetto, Luisella | Blankenstein, Marinus A. | Carrillo, Maria C. | Chalbot, Sonia | Coart, Els | Chiasserini, Davide | Cutler, Neal | Dahlfors, Gunilla | Duller, Stefan | Fagan, Anne M. | Forlenza, Orestes | Frisoni, Giovanni B. | Galasko, Douglas | Galimberti, Daniela | Hampel, Harald | Handberg, Aase | Heneka, Michael T. | Herskovits, Adrianna Z. | Herukka, Sanna-Kaisa | Holtzman, David M. | Humpel, Christian | Hyman, Bradley T. | Iqbal, Khalid | Jucker, Mathias | Kaeser, Stephan A. | Kaiser, Elmar | Kapaki, Elisabeth | Kidd, Daniel | Klivenyi, Peter | Knudsen, Cindy S. | Kummer, Markus P. | Lui, James | Lladó, Albert | Lewczuk, Piotr | Li, Qiao-Xin | Martins, Ralph | Masters, Colin | McAuliffe, John | Mercken, Marc | Moghekar, Abhay | Molinuevo, José Luis | Montine, Thomas J. | Nowatzke, William | O’Brien, Richard | Otto, Markus | Paraskevas, George P. | Parnetti, Lucilla | Petersen, Ronald C. | Prvulovic, David | de Reus, Herman P. M. | Rissman, Robert A. | Scarpini, Elio | Stefani, Alessandro | Soininen, Hilkka | Schröder, Johannes | Shaw, Leslie M. | Skinningsrud, Anders | Skrogstad, Brith | Spreer, Annette | Talib, Leda | Teunissen, Charlotte | Trojanowski, John Q. | Tumani, Hayrettin | Umek, Robert M. | Van Broeck, Bianca | Vanderstichele, Hugo | Vecsei, Laszlo | Verbeek, Marcel M. | Windisch, Manfred | Zhang, Jing | Zetterberg, Henrik | Blennow, Kaj
Background
The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer’s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer’s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
Methods
The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.
Results
Forty laboratories participated. Twenty-six used INNOTESTenzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories.
Conclusions
Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.
doi:10.1016/j.jalz.2011.05.2243
PMCID: PMC3710290  PMID: 21784349
Alzheimer’s disease; Cerebrospinal fluid; Biomarkers; External assurance; External control; Proficiency testing
10.  The Influence of Chronic Stress on Dementia-Related Diagnostic Change in Older Adults 
Increased susceptibility of the aging brain to both chronic stress and incipient dementia-related neuropathology may accelerate cognitive decline. We investigated associations between chronic stress and diagnostic change in 62 individuals (mean age=78.7) participating in an Alzheimer’s disease research center longitudinal study. Subjects, diagnosed at baseline as cognitively normal (CN) or Mild Cognitive Impairment (MCI) were followed an average of 2.5 years. Senior neurologists, blind to detailed measures of stress and cognition, assigned diagnoses annually. Logistic regression analyses assessed accuracy with which measures of stress (event-based ratings, cortisol levels) predicted conversion to MCI and dementia. Eleven individuals with MCI at baseline received a dementia diagnosis during follow-up. Sixteen converted from CN to MCI. Prolonged, highly stressful experiences were associated with conversion from MCI to dementia. The cortisol awakening response, with age and education, was associated with diagnostic change to MCI. Cortisol measures were not associated with progression from MCI to dementia, and there was no association between stressful experiences and change to MCI. Mechanisms associated with the transition from normal cognition to MCI may differ from those associated with diagnostic change to dementia. These findings could facilitate identification of interventional strategies to reduce risk of decline at different stages of susceptibility.
doi:10.1097/WAD.0b013e3182389a9c
PMCID: PMC3290680  PMID: 22037597
chronic stress; aging; Alzheimer’s disease; mild cognitive impairment; dementia; diurnal rhythm; cortisol awakening response
11.  Antioxidants for Alzheimer Disease 
Archives of neurology  2012;69(7):836-841.
Objective
To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers.
Design
Double-blind, placebo-controlled clinical trial.
Setting
Academic medical centers.
Participants
Subjects with mild to moderate Alzheimer disease.
Intervention
Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo.
Main Outcome Measures
Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale).
Results
Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau181 levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups.
Conclusions
Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted.
Trial Registration
clinicaltrials.gov Identifier: NCT00117403
PMCID: PMC3661272  PMID: 22431837
12.  Incidence of New-Onset Seizures in Mild to Moderate Alzheimer Disease 
Archives of neurology  2012;69(3):368-372.
Objective
To estimate the incidence rate and predictors of seizures in patients with mild to moderate Alzheimer disease (AD).
Design
Cohort study of patients with mild to moderate AD in clinical trials. Risk factors for potential seizures were evaluated by stratified descriptive statistics and univariable and multivariable Cox proportional hazards regressions.
Setting
Pooled patient-level data from 10 Alzheimer Disease Cooperative Study clinical trials in mild to moderate AD from 1995 to 2010.
Patients
Three thousand seventy-eight subjects randomized to the treatment or placebo arms of 10 AD clinical trials. Screening Mini-Mental State Examination scores ranged between 10 and 28.
Results
Eighteen seizures were reported in 3078 randomized subjects, with an incidence rate of 484 per 100 000 person-years (95% CI, 287–764). Statistically significant independent risk factors for seizure were younger age (adjusted hazard ratio, 0.80; 95% CI, 0.69–0.93 per every 5 years of age), greater cognitive impairment at baseline (adjusted hazard ratio, 2.79; 95% CI, 1.06–7.33 for Mini-Mental State Examination scores <18 compared with Mini-Mental State Examination scores ≥18), and antipsychotic use at baseline (adjusted hazard ratio, 3.47; 95% CI, 1.33–9.08).
Conclusions
Seizure rates in patients with mild to moderate AD in clinical trials are similar to rates observed in longer observational cohort studies, but they are greater than expected in the general elderly population. Younger age, greater degree of cognitive impairment, and history of antipsychotic use were independent risk factors for new-onset seizures in AD.
doi:10.1001/archneurol.2011.830
PMCID: PMC3622046  PMID: 22410444
13.  Comparison of the Memory Performance Index With Standard Neuropsychological Measures of Cognition 
The Mild Cognitive Impairment Screen (MCIS) is a computer-based cognitive assessment designed for clinical and research use in detecting amnestic mild cognitive impairment (aMCI). Performance on the MCIS is reported as the Memory Performance Index (MPI). However, the comparability between the MPI and traditional neuropsychological tests in detecting aMCI, and in differentiating it from Alzheimer’s disease (AD) and normal aging has not been examined. A cross-sectional study was conducted to assess the validity of the MPI relative to standard neuropsychological measures. Participants included 12 individuals diagnosed with aMCI, 49 with mild AD, and 25 healthy elderly. The MCIS significantly discriminated among aMCI, AD, and healthy elderly controls. The MCIS is effective in detecting aMCI, and in discriminating it from cognitive changes observed in AD and normal aging. The MCIS may be a valuable tool in the identification of elderly at high risk for dementia due to its ease-of-use and brief administration time.
doi:10.1177/1533317511402316
PMCID: PMC3568924  PMID: 21406427
Mild Cognitive Impairment; Dementia; Alzheimer’s Disease; Screening; Memory
14.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis 
Lancet neurology  2008;7(5):409-416.
SUMMARY
BACKGROUND
TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
METHODS
TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identifi ed variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families.
FINDINGS
We identified two variants, p.Gly290Ala and p.Gly298Ser, in TARDBP in two familial ALS kindreds and we observed TDP-43 neuropathology in the CNS tissue available from one family. The variants are considered pathogenic mutations because they co-segregate with disease in both families, are absent in ethnically-matched controls, and are associated with TDP-43 neuropathology in several family members.
INTERPRETATION
The p.Gly290Ala and p.Gly298Ser mutations are located in the glycine-rich domain that regulates gene expression and mediates protein-protein interactions; in particular TDP-43 binds to heterogeneous ribonucleoproteins (hnRNPs) via this domain. We postulate that due to the varied and important cellular functions of TDP-43, these mutations may cause neurodegeneration through both gains and losses of function. The finding of TARDBP mutations implicates TDP-43 as an active mediator of neurodegeneration in a novel class of disorders, TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
doi:10.1016/S1474-4422(08)70071-1
PMCID: PMC3546119  PMID: 18396105
15.  Degree of Bilingualism Predicts Age of Diagnosis of Alzheimer’s Disease in Low-Education but not in Highly-Educated Hispanics 
Neuropsychologia  2011;49(14):3826-3830.
The current study investigated the relationship between bilingual language proficiency and onset of probable Alzheimer’s disease (AD) in 44 Spanish-English bilinguals at the UCSD Alzheimer’s Disease Research Center. Degree of bilingualism along a continuum was measured using Boston Naming Test (BNT) scores in each language. Higher degrees of bilingualism were associated with increasingly later age-of-diagnosis (and age of onset of symptoms), but this effect was driven by participants with low education level (a significant interaction between years of education and bilingualism) most of whom (73%) were also Spanish-dominant. Additionally, only objective measures (i.e., BNT scores), not self-reported degree of bilingualism, predicted age-of-diagnosis even though objective and self-reported measures were significantly correlated. These findings establish a specific connection between knowledge of two languages and delay of AD onset, and demonstrate that bilingual effects can be obscured by interactions between education and bilingualism, and by failure to obtain objective measures of bilingualism. More generally, these data support analogies between the effects of bilingualism and “cognitive reserve” and suggest an upper limit on the extent to which reserve can function to delay dementia.
doi:10.1016/j.neuropsychologia.2011.09.041
PMCID: PMC3223277  PMID: 22001315
16.  Recent Alzheimer's disease research highlights 
doi:10.1186/alzrt117
PMCID: PMC3506929  PMID: 22594696
17.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
doi:10.1093/brain/awr179
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
18.  Phosphorylated α-Synuclein in Parkinson’s Disease 
Science Translational Medicine  2012;4(121):121ra20.
Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson’s disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129, along withtotal α-synuclein, in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein CSF concentrations, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether PS-129 CSF concentrations will be useful for diagnosing PD and for monitoring PD severity and progression.
doi:10.1126/scitranslmed.3002566
PMCID: PMC3302662  PMID: 22344688
19.  PF-04494700, an Oral Inhibitor of Receptor For Advanced Glycation End Products (RAGE), in Alzheimer’s disease 
Objective
To evaluate the safety and tolerability of PF-04494700, an oral Inhibitor of receptor for advanced glycation end products (RAGE), in subjects with mild-to-moderate dementia of the Alzheimer’s type.
Methods
Subjects 50 years and older who met NINCDS-ADRDA criteria for AD with an MMSE score between 12–26 (inclusive) were randomized to 10-weeks of double-blind treatment with either a 10 mg “low dose” of PF-04494700 (after a 6-day loading dose of 30 mg/d to); or a 20 mg “high dose” of PF-04494700 (after a loading dose of 60 mg/d); or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead ECG.
Results
27 subjects received PF-04494700 30/10 mg (female, 63%; mean age, 74.6 years; mean MMSE, 21.1), 28 subjects received PF-04494700 60/20 mg (female, 57%; mean age, 76.6 years; mean MMSE, 21.6), and 12 subjects received placebo (female, 67%; mean age, 74.1 years; mean MMSE, 19.2). A higher proportion of subjects completed 10 weeks of double-blind treatment on both the “low dose” regimen of PF-04494700 (88.9%) and the “high dose” regimen (85.7%) than completed on placebo (66.7%). Discontinuation due to adverse events, and incidence of severe adverse events, respectively, were lower on the “low dose” regimen (7.4%,11.1%) and the “high dose” regimen (3.6%,10.7%) compared to placebo (25.0%,16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean ECG parameters in subjects treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of Aβ, inflammatory biomarkers, or secondary cognitive outcomes.
Conclusions
Ten weeks of treatment with PF-04494700 was safe and well-tolerated in subjects with mild-to-moderate AD, indicating the feasibility of a larger long-term efficacy trial.
doi:10.1097/WAD.0b013e318204b550
PMCID: PMC3346183  PMID: 21192237
Alzheimer’s disease; randomized clinical trial; RAGE
20.  Antemortem Pulse Pressure Elevation Predicts Cerebrovascular Disease in Autopsy-Confirmed Alzheimer’s Disease 
Journal of Alzheimer's Disease  2012;30(3):595-603.
Elevated pulse pressure (PP) is associated with cognitive decline and increased risk of Alzheimer’s disease (AD) in older adults, although the mechanisms behind these associations remain unclear. To address this question, we examined whether antemortem late-life PP elevation predicted vascular or AD pathology in autopsy-confirmed AD patients. Sixty-five elderly patients (mean age 74.2 years) clinically diagnosed with possible or probable AD underwent neuropsychological testing and blood pressure examinations. Postmortem histopathological measures of cerebrovascular disease (CVD) and AD neuropathology were later obtained on these same patients. We expected that antemortem PP elevation, but not standard blood pressure measures such as systolic or diastolic blood pressure, would predict the autopsy-based presence of CVD, and possibly AD pathology, in elderly AD patients. Results demonstrated that antemortem PP elevation was associated with the presence and severity of CVD at autopsy. For every 5 mmHg increase in antemortem PP there was an estimated 36% increase in the odds of having CVD at autopsy. Additionally, PP accounted for 12% of variance in CVD severity. No significant associations were present for cerebral amyloid angiopathy or Braak and Braak staging of the severity of AD pathology. Other standard blood pressure measures also did not significantly predict neuropathology. The association between antemortem PP and CVD at autopsy suggests that in older adults with AD, PP elevation may increase the risk of CVD. These findings may have treatment implications since some antihypertensive medications specifically address the pulsatile component of blood pressure (e.g., renin-angiotensin system inhibitors, calcium channel blockers).
doi:10.3233/JAD-2012-111697
PMCID: PMC3370943  PMID: 22451309
Alzheimer’s disease; blood pressure; cerebrovascular disease; pulse pressure
21.  Cerebrospinal Fluid Biomarkers for Parkinson Disease Diagnosis and Progression 
Annals of neurology  2011;69(3):570-580.
Background
There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or α-synuclein in the cerebrospinal fluid (CSF) is a potential index for PD diagnosis, but not for PD severity.
Methods
Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (Aβ1-42), Flt3 ligand and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these five markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and α-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally.
Findings
The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/Aβ1-42 that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples.
Interpretation
We have demonstrated that this panel of seven CSF proteins could aid in PD diagnosis, differential diagnosis, and correlation with disease severity and progression.
doi:10.1002/ana.22311
PMCID: PMC3117674  PMID: 21400565
22.  Increased Cerebrospinal Fluid F2-Isoprostanes are Associated with Aging and Latent Alzheimer’s Disease as Identified by Biomarkers 
Neuromolecular medicine  2010;13(1):37-43.
Alzheimer’s disease (AD) is a common age-related chronic illness with latent, prodrome, and fully symptomatic dementia stages. Increased free radical injury to regions of brain is one feature of prodrome and dementia stages of AD; however, it also is associated with advancing age. This raises the possibility that age-related free radical injury to brain might be caused in part or in full by latent AD. We quantified free radical injury in the central nervous system with cerebrospinal fluid (CSF) F2-isoprostanes (IsoPs) in 421 clinically normal individuals and observed a significant increase over the adult human lifespan (P < 0.001). Using CSF amyloid (A) β42 and tau, we defined normality using results from 28 clinically normal individuals < 50 years old, and then stratified 74 clinically normal subjects ≥ 60 years into those with CSF that had normal CSF Aβ42 and tau (n=37); abnormal CSF Aβ42 and tau, the biomarker signature of AD (n=24); decreased Aβ42 only (n=4); or increased tau only (n=9). Increased CSF F2-IsoPs were present in clinically normal subjects with the biomarker signature of AD (P < 0.05) and those subjects with increased CSF tau (P < 0.001). Finally, we analyzed the relationship between age and CSF F2-IsoPs for those clinically normal adults with normal CSF (n=37) and those with abnormal CSF Aβ42 and/or tau (n=37); only those with normal CSF demonstrated a significant increase with age (P < 0.01). These results show that CSF F2-IsoPs increased across the human lifespan and that this age-related increase in free radical injury to brain persisted after culling those with laboratory evidence of latent AD.
doi:10.1007/s12017-010-8126-6
PMCID: PMC3000441  PMID: 20632131
Alzheimer’s disease; cerebrospinal fluid; biomarkers; Aβ42; tau; F2-isoprostanes
23.  The aging systemic milieu negatively regulates neurogenesis and cognitive function 
Nature  2011;477(7362):90-94.
Summary
In the central nervous system (CNS), aging results in a precipitous decline in adult neural stem/progenitor cells (NPCs) and neurogenesis, with concomitant impairments in cognitive functions1. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise1. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age dependent fashion in mice. Accordingly, exposing a young animal to an old systemic environment, or to plasma from old mice, decreased synaptic plasticity and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines - including CCL11/Eotaxin – whose plasma levels correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and whose levels are increased in plasma and cerebral spinal fluid of healthy aging humans. Finally, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis, and cognitive impairments, observed during aging can be in part attributed to changes in blood-borne factors.
doi:10.1038/nature10357
PMCID: PMC3170097  PMID: 21886162
24.  Neuropathology of Dementia with Lewy Bodies in Advanced Age: a comparison with Alzheimer Disease 
Neuroscience letters  2010;485(3):222-227.
Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α–synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70–79, 80–89 and ≥90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80–89 and ≥90 year cases compared to 70–79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70–79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group.
doi:10.1016/j.neulet.2010.09.016
PMCID: PMC2987680  PMID: 20849919
Cognition; Neuropsychological assessment
25.  CSF Aβ42 and tau in Parkinson’s disease with cognitive impairment 
We tested the hypothesis that the CSF biomarker signature associated with Alzheimer’s disease (AD) is present in a subset of individuals with Parkinson’s disease and Dementia (PD-D) or with PD and Cognitive Impairment, Not Dementia (PD-CIND). We quantified CSF Aβ42, total tau (T-tau), and phospho-tau (P181-Tau) using commercially available kits. Samples were from 345 individuals in seven groups (n): Controls ≤ 50 years (35), Controls > 50 years (115), amnestic Mild Cognitive Impairment (aMCI) (24), AD (49), PD (49), PD-CIND (62), and PD-D (11). We observed expected changes in AD or aMCI compared with age-matched or younger controls. CSF Aβ42 was reduced in PD-CIND (P < 0.05) and PD-D (P < 0.01) while average CSF T-Tau and P181-Tau were unchanged or decreased. One-third of PD-CIND and one-half of PD-D patients had the biomarker signature of AD. Abnormal metabolism of Aβ42 may be a common feature of PD-CIND and PD-D.
doi:10.1002/mds.23287
PMCID: PMC2978754  PMID: 20818673
Parkinson’s disease; cognitive impairment; CSF biomarkers; Aβ42; tau

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