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author:("detsky, S.T.")
1.  Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study 
Neurology  2008;70(19):1664-1671.
Objectives
To examine the association between incident Alzheimer disease (AD), and plasma Aβ1-40 and Aβ1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study.
Methods
We determined the plasma Aβ1-40 and Aβ1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998 –1999 and repeated the measurements in 2002–2003. The mean age of the subjects at baseline was 79.3 ± 3.6 years. We examined the association between Aβ levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts.
Results
In an unadjusted prospective model in normal subjects, both Aβ1-40 and Aβ1-42 levels in 1998 –1999 were associated with incident AD (n = 55) in 2002–2003 (longitudinal analysis). In the fully adjusted multivariate model, neither Aβ1-42 nor Aβ1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for Aβ1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002–2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD.
Conclusions
Plasma Aβ levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, Aβ-40 and Aβ1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of Aβ do not seem to be useful biomarkers for AD.
doi:10.1212/01.wnl.0000306696.82017.66
PMCID: PMC2670993  PMID: 18401021
2.  Association of CLU and PICALM variants with Alzheimer's disease 
Neurobiology of Aging  2010;33(3):518-521.
Two recent large genome-wide association studies have reported significant associations in the CLU (APOJ), CR1 and PICALM genes. In order to replicate these findings, we examined 7 single nucleotide polymorphisms (SNPs) most significantly implicated by these studies in a large case-control sample comprising of 2,707 individuals. Principle components analysis revealed no population substructure in our sample. While no association was observed with CR1 SNPs (P=0.30–0.457), a trend of association was seen with the PICALM (P=0.071–0.086) and CLU (P=0.148–0.258) SNPs. A meta-analysis of three studies revealed significant associations with all three genes. Our data from an independent and large case-control sample suggest that these gene regions should be followed up by comprehensive resequencing to find functional variants.
doi:10.1016/j.neurobiolaging.2010.04.015
PMCID: PMC3010357  PMID: 20570404
Alzheimer's disease; Genetics; Association
3.  Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease 
Neurology  2011;77(1):39-47.
Objective:
This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD).
Methods:
Choline acetyltransferase (ChAT) activity, [3H]PiB binding, and soluble amyloid-β1–42 (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging–Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage.
Results:
Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [3H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [3H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology.
Conclusions:
Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.
doi:10.1212/WNL.0b013e3182231419
PMCID: PMC3127332  PMID: 21700583
4.  Determinants of vascular dementia in the Cardiovascular Health Cognition Study 
Neurology  2005;64(9):1548-1552.
Objective
The authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.
Methods
Incidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria.
Results
Approximately 44% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.
Conclusions
Vascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer’s Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.
doi:10.1212/01.WNL.0000160115.55756.DE
PMCID: PMC3378359  PMID: 15883315
5.  Replication Study of Genome-Wide Associated SNPs with Late-Onset Alzheimer’s Disease 
Late-onset Alzheimer’s disease (LOAD) is a multifactorial disease with the potential involvement of multiple genes. Four recent genome-wide association studies (GWAS) have found variants showing significant association with LOAD on chromosomes 6, 10, 11, 12, 14, 18, 19 and on the X chromosome. We examined a total of 12 significant SNPs from these studies to determine if the results could be replicated in an independent large case-control sample. We genotyped these 12 SNPs as well the E2/E3/E4 APOE polymorphisms in up to 993 Caucasian Americans with LOAD and up to 976 age-matched healthy Caucasian Americans. We found no statistically significant associations between the 12 SNPs and the risk of AD. Stratification by APOE*4 carrier status also failed to reveal statistically significant associations. Additional analyses were performed to examine potential associations between the 12 SNPs and age-at-onset (AAO) and disease duration among AD cases. Significant associations were observed between AAO and ZNF224/rs3746319 (p=0.002) and KCNMA1/rs16934131 (p=0.0066). KCNMA1/rs16934131 also demonstrated statistically significant association with disease duration (p=0.0002). Although we have been unable to replicate the reported GWAS association with AD risk in our sample, we have identified two new associations with AAO and disease duration that need to be confirmed in additional studies.
doi:10.1002/ajmg.b.31194
PMCID: PMC3082594  PMID: 21480501
Alzheimer’s disease; association; genome-wide association studies; replication; age-at-onset; disease duration
6.  Trends in American Board of Psychiatry and Neurology specialties and neurologic subspecialties 
Neurology  2010;75(12):1110-1117.
Objective: To review the current status and recent trends in the American Board of Psychiatry and Neurology (ABPN) specialties and neurologic subspecialties and discuss the implications of those trends for subspecialty viability.
Methods: Data on numbers of residency and fellowship programs and graduates and ABPN certification candidates and diplomates were drawn from several sources, including ABPN records, Web sites of the Accreditation Council for Graduate Medical Education and the American Medical Association, and the annual medical education issues of the Journal of the American Medical Association.
Results: About four-fifths of neurology graduates pursue fellowship training. While most recent neurology and child neurology graduates attempt to become certified by the ABPN, many clinical neurophysiologists elect not to do so. There appears to have been little interest in establishing fellowships in neurodevelopmental disabilities. The pass rate for fellowship graduates is equivalent to that for the “grandfathers” in clinical neurophysiology. Lower percentages of clinical neurophysiologists than specialists participate in maintenance of certification, and maintenance of certification pass rates are high.
Conclusion: The initial enthusiastic interest in training and certification in some of the ABPN neurologic subspecialties appears to have slowed, and the long-term viability of those subspecialties will depend upon the answers to a number of complicated social, economic, and political questions in the new health care era.
doi:10.1212/WNL.0b013e3181f39a41
PMCID: PMC3463033  PMID: 20855855
ABMS = American Board of Medical Specialties; ABPN = American Board of Psychiatry and Neurology; ACGME = Accreditation Council for Graduate Medical Education; MOC = maintenance of certification; RRC-N = Residency Review Committee in Neurology.
7.  Anti-Amyloid Effects of Small Molecule Aβ-Binding Agents in PS1/APP Mice 
Aims
One promising approach for treatment of Alzheimer’s disease (AD) is use of anti-amyloid therapies, based on the hypothesis that increases in amyloid-beta (Aβ) deposits in brain are a major cause of AD. Several groups have focused on Aβ immunotherapy with some success. Small molecules derivatives of Congo red have been shown to inhibit Aβ aggregation and protect against Aβ neurotoxicity in vitro. The agents described here are all small molecule Aβ-binding agents (SMAβBA’s) derivatives of Congo red.
Main Methods
Here, we have explored the anti-amyloid properties of these SMAβBA’s in mice doubly transgenic for human prensenilin-1 (PS1) and APP gene mutations that cause early-onset AD. Mice were treated with either methoxy-X04, X:EE:B34 and X:034-3-OMe1. After treatment, brains were examined for Aβ-deposition, using histochemistry, and soluble and insoluble Aβ levels were determined using ELISA.
Key Findings
A range of anti-amyloid activity was observed with these three compounds. PS1/APP mice treated with methoxy-X04 and X:EE:B34 showed decrease in total Aβ load, a decrease in Aβ fibril load, and a decrease in average plaque size. Treatment with methoxy-X04 also resulted in a decrease in insoluble Aβ levels. The structurally similar compound, X:034:3-OMe1, showed no significant effect on any of these measures. The effectiveness of the SMAβBA’s may be related to a combination of binding affinity for Aβ and entry into brain, but other factors appear to apply as well.
Significance
These data suggest that SMAβBA’s may significantly decrease amyloid burden in brain during the pathogenesis of AD and could be useful therapeutics alone, or in combination with immunotherapy.
doi:10.2174/157018009789057526
PMCID: PMC2812908  PMID: 20119496
Alzheimer’s Disease; amyloid β; Congo Red; Methoxy-X04; transgenic mice
8.  Cognitive trajectories associated with β-amyloid deposition in the oldest-old without dementia 
Neurology  2013;80(15):1378-1384.
Objective:
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.
Methods:
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.
Results:
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).
Conclusions:
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.
doi:10.1212/WNL.0b013e31828c2fc8
PMCID: PMC3662268  PMID: 23516317
9.  High-throughput sequencing of the paired human immunoglobulin heavy and light chain repertoire 
Nature biotechnology  2013;31(2):166-169.
Each B-cell receptor consists of a pair of heavy and light chains. High-throughput sequencing can identify large numbers of heavy- and light-chain variable regions (VH and VL) in a given B-cell repertoire, but information about endogenous pairing of heavy and light chains is lost after bulk lysis of B-cell populations. Here we describe a way to retain this pairing information. In our approach, single B cells (>5 × 104 capacity per experiment) are deposited in a high-density microwell plate (125 pl/well) and lysed in situ. mRNA is then captured on magnetic beads, reverse transcribed and amplified by emulsion VH:VL linkage PCR. The linked transcripts are analyzed by Illumina high-throughput sequencing. We validated the fidelity of VH:VL pairs identified by this approach and used the method to sequence the repertoire of three human cell subsets—peripheral blood IgG+ B cells, peripheral plasmablasts isolated after tetanus toxoid immunization and memory B cells isolated after seasonal influenza vaccination.
doi:10.1038/nbt.2492
PMCID: PMC3910347  PMID: 23334449
10.  Phenotypic variability in three families with valosin-containing protein mutation 
Background and purpose
The phenotype of IBMPFD [inclusion body myopathy with Paget’s disease of the bone and frontotemporal dementia (FTD)] associated with valosin-containing protein(VCP) mutation is described in three families.
Methods
Probands were identified based on a pathological diagnosis of frontotemporal lobar degeneration with TDP-43-positive inclusions type IV. VCP sequencing was carried out. Clinical data on affected family members were reviewed.
Results
Ohio family: four subjects presented muscle weakness and wasting. (One subject had both neuropathic and myopathic findings and another subject showed only evidence of myopathy. The etiology of weakness could not be ascertained in the remaining two subjects.) Two individuals also showed Parkinsonism (with associated FTD in one of the two). The proband’s brain displayed FTLD-TDP type IV and Braak stage five Parkinson’s disease (PD). A VCP R191Q mutation was found. Pennsylvania family: 11 subjects developed IBMPFD. Parkinsonism was noted in two mutation carriers, whilst another subject presented with primary progressive aphasia (PPA). A novel VCP T262A mutation was found. Indiana family: three subjects developed IBMPFD. FTD was diagnosed in two individuals and suspected in the third one who also displayed muscle weakness. A VCP R159C mutation was found.
Conclusions
We identified three families with IBMPFD associated with VCP mutations. Clinical and pathological PD was documented for the first time in members of two families. A novel T262A mutation was found. One individual had PPA: an uncommon presentation of IBMPFD.
doi:10.1111/j.1468-1331.2012.03831.x
PMCID: PMC3734548  PMID: 22900631
frontotemporal dementia; genetic and inherited disorders; motor neuron disease; myopathies; neurodegenerative disorders (other than dementia); neuropathology; neuropsychology; Parkinson’s disease
11.  Association between performance on Neurology In-Training and Certification Examinations 
Neurology  2013;80(2):206-209.
Objective:
This study analyzed the relationship between performance on the American Academy of Neurology Residency In-Service Training Examination (RITE) and subsequent performance on the American Board of Psychiatry and Neurology (ABPN) Certification Examination.
Methods:
Pearson correlation coefficients were used to examine the relationship between performance on the RITE and the Certification Examination for 2 cohorts of adult neurologists and 2 cohorts of child neurologists. The 2 cohorts represented test takers for 2008 and 2009.
Results:
For adult neurologists, the correlation between the total RITE and the Certification Examination scores was 0.77 (p < 0.01) in 2008 and 0.65 (p < 0.01) in 2009. For child neurologists, it was 0.74 (p < 0.01) in 2008 and 0.56 (p < 0.01) in 2009.
Discussion:
For 2 consecutive years, there was a significant correlation between performance on the RITE and performance on the ABPN Certification Examination for both adult and child neurologists. The RITE is a self-assessment examination, and performance on the test is a positive predictor of future performance on the ABPN Certification Examination.
doi:10.1212/WNL.0b013e31827b92a3
PMCID: PMC3589193  PMID: 23296130
12.  Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study–Cognition Study 
Neurology  2012;79(15):1599-1606.
Objectives and Methods:
The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study–Cognition Study from 1998–1999 to 2010–2011.
Results:
Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13–142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 ± 1.8 years. Forty (20%) of the incident MCI cases had an “unstable” course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years).
Conclusions:
The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.
doi:10.1212/WNL.0b013e31826e25f0
PMCID: PMC3475628  PMID: 23019262
13.  Amyloid Imaging in Dementias With Atypical Presentation 
We explored the potential value of amyloid imaging in patients with atypical presentations of dementia. Twenty-eight patients with atypical dementia underwent PET imaging with the amyloid imaging tracer Pittsburgh Compound-B (PiB). Twenty-six had [18F]fluoro-2-deoxy-D-glucose (FDG) PET scans. After extensive clinical evaluation, this group of patients generated considerable diagnostic uncertainty and received working diagnoses that included possible AD (pAD), focal dementias [e.g. posterior cortical atrophy (PCA)], or cases in which no clear diagnostic category could be determined (dementia of uncertain etiology; DUE). Patients were classified as PiB-positive, -negative, or -intermediate based on objective criteria. Anterior-posterior (A-P) and left-right (L-R) indices of PiB and FDG uptake were calculated to examine differences in distribution of amyloid pathology and metabolic changes associated with clinical phenotype. Eleven patients (39%) were PiB-positive, 16 were PiB-negative (57%) and one (4%) was intermediate. By diagnostic category, 3/10 patients (30%) with DUE, 1/5 (20%) with primary progressive aphasia (PPA), 3/5 (60%) with posterior cortical atrophy (PCA), and 4/7 (57%) with pAD were PiB-positive. Brain metabolism of both PiB-positive and -negative patients were generally similar by phenotype, but differed from typical AD. PCA patients also appeared to differ in their relative distribution of PiB compared to typical AD, consistent with their atypical phenotype. AD pathology is frequently present in atypical presentations of dementia and can be identified by amyloid imaging. Clinical phenotype is more related to the pattern of cerebral hypometabolism than the presence/absence of amyloid pathology. These findings have diagnostic, prognostic, and therapeutic implications.
doi:10.1016/j.jalz.2011.07.003
PMCID: PMC3517915  PMID: 22285638
Amyloid imaging; PiB; PET; Alzheimer’s Disease; Posterior Cortical Atrophy; dementia; focal dementia
14.  Statins, Risk of Dementia and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study (GEMS) 
Goal
To examine whether lipid lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without Mild Cognitive Impairment (MCI) at baseline.
Methods
Longitudinal, observational study of 3,069 cognitively healthy elderly, ages 75 years and older, who were enrolled in the Ginkgo Evaluation of Memory Study. Primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). Secondary outcome measure was the change in global cognitive function over time measured by 3MSE and ADAS-cog scores.
Findings
Among participants without MCI at baseline current use of statins was consistently associated with a reduced risk of all cause dementia (HR 0. 79, 95% confidence interval, 0.65–0.96, p=0.021) and AD (HR 0.57, 95% confidence interval, 0.39–0.85, p= 0.005). In participants who initiated statin therapy lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast there was no significant association between LLM use (including statins), dementia onset or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline there was a trend for a neuroprotective effect of statins on cognitive decline.
Conclusions
Statins may slow the rate of cognitive decline and delay the onset of AD and all cause dementia in cognitively healthy elderly individuals whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.
doi:10.1016/j.jstrokecerebrovasdis.2010.11.002
PMCID: PMC3140577  PMID: 21236699
Cognitive function; 3HMG-ACoA reductase inhibitors; Mild Cognitive Impairment; dementia
15.  Genome-wide association analysis of age-at-onset in Alzheimer’s disease 
Molecular psychiatry  2011;17(12):1340-1346.
The risk of Alzheimer’s disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta analysis on 3 samples comprising a total of 2,222 AD cases. A total of ~2.5 million directly genotyped or imputed SNPs were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the APOE region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.
doi:10.1038/mp.2011.135
PMCID: PMC3262952  PMID: 22005931
Genome-wide association study; age-at-onset; Alzheimer’s disease; single-nucleotide polymorphisms; meta analysis
16.  Genome-wide Association Study of Alzheimer’s disease with Psychotic Symptoms 
Molecular psychiatry  2011;17(12):1316-1327.
Psychotic symptoms occur in approximately 40% of subjects with Alzheimer’s disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD-P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD-P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0×10−7) and within VSNL1 (rs4038131, P=5.9×10−7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.
doi:10.1038/mp.2011.125
PMCID: PMC3272435  PMID: 22005930
Alzheimer’s disease; psychosis; behavioural symptoms; genome-wide association study; genetic
17.  Diuretic Use is Associated with Better Learning and Memory in Older Adults in the GEM Study 
Background
To investigate the association between diuretics, angiotensin-converting-enzyme inhibitors (ACE-I) and angiotensin 2 receptor blockers (AT2RB) and cognitive function.
Methods
This post-hoc analysis of the randomized controlled Ginkgo Evaluation of Memory Study trial focuses on 3069 non-demented community dwelling participants over the age of 75. At basline visit detailed information about medication use was collected and five cognitive domains were assessed. Multivariable linear regression analyses were used to assess cross-sectional associations between medication use and cognitive function.
Results
36% reported history of hypertension and 51% antihypertensive medication use, with 17% reporting diuretic, 11% ACE-I, and 2% AT2RB use. Potassium-sparing diuretic use (N=192) was associated with better verbal learning and memory measured by California Verbal Learning Test (CVLT), compared to no antihypertensive medication users (β=.068, P =.01; β =.094, P <.001) and other antihypertensive medication users (β=.080, P =.03; β=.153, P <.001). Use of ACE-I or AT2RB was not associated with better cognitive function.
Conclusion
Results warrant further investigation into possible protective effects of potassium-sparing diuretics and the role of potassium in mitigating cognitive decline.
doi:10.1016/j.jalz.2011.03.010
PMCID: PMC3341535  PMID: 22465175
Cognitive function; Diuretic; Angiotensin converting enzyme inhibitor; Angiotensin receptor blocker
18.  Toward the Treatment and Prevention of Alzheimer’s Disease: Rational Strategies and Recent Progress 
Annual review of medicine  2013;64:367-383.
Alzheimer’s disease (AD) is the major cause of late-life brain failure. In the past 25 years, autosomal dominant forms of AD were found to be primariy attributable to mutations in one of two presenilins, polytopic proteins that contain the catalytic site of the γ-secretase protease that releases the amyloid beta (Aβ) peptide. Some familial AD is also due to mutations in the amyloid precursor protein (APP), but recently a mutation in APP was discovered that reduces Aβ generation and is protective against AD, further implicating amyloid metabolism. Prion-like seeding of amyloid fibrils and neurofibrillary tangles has been invoked to explain the stereotypical spread of AD within the brain. Treatment trials with anti-Aβ antibodies have shown target engagement, if not significant treatment effects. Attention is increasingly focused on presymptomatic intervention, because Aβ mismetabolism begins up to 25 years before symptoms begin. AD trials deriving from new biological information involve extraordinary international collaboration and may hold the best hope for success in the fight against AD.
doi:10.1146/annurev-med-092611-084441
PMCID: PMC3625402  PMID: 23327526
dementia; neurodegeneration; cognitive decline; memory disorder; amyloidosis
19.  Anticipatory Grief in New Family Caregivers of Persons with Mild Cognitive Impairment and Dementia 
Anticipatory grief is the process of experiencing normal phases of bereavement in advance of the loss of a significant person. To date, anticipatory grief has been examined in family caregivers to individuals who have had Alzheimer’s Disease (AD) an average of 3 to 6 years. Whether such grief is manifested early in the disease trajectory (at diagnosis) is unknown. Using a cross-sectional design, we examined differences in the nature and extent of anticipatory grief between family caregivers of persons with a new diagnosis of mild cognitive impairment (MCI, n=43) or AD (n=30). We also determined whether anticipatory grief levels were associated with caregiver demographics, caregiving burden, depressive symptoms and marital quality. Mean anticipatory grief levels were high in the total sample, with AD caregivers endorsing significantly more anticipatory grief than MCI caregivers. In general, AD caregivers endorsed difficulty functioning whereas MCI caregivers focused on themes of “missing the person” they once knew. Being a female caregiver, reporting higher levels of objective caregiving burden and higher depression levels each bore independent, statistically significant relationships with anticipatory grief. Given these findings, family caregivers of individuals with mild cognitive deficits or a new AD diagnosis may benefit from interventions specifically addressing anticipatory grief.
doi:10.1097/WAD.0b013e31822f9051
PMCID: PMC3251637  PMID: 21946013
Anticipatory grief; dementia caregiving; mild cognitive impairment
20.  CR1 and the “Vanishing Amyloid” Hypothesis of Alzheimer’s Disease 
Biological psychiatry  2013;73(5):393-395.
doi:10.1016/j.biopsych.2013.01.013
PMCID: PMC3600375  PMID: 23399469
21.  Gray Matter Atrophy Associated with Extrapyramidal Signs in the Lewy Body Variant of Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2012;32(4):1043-1049.
Up to 60% of the patients with Alzheimer’s disease (AD) can have cortical or brainstem Lewy bodies (LB), and extrapyramidal signs (EPS) have been found to be associated with LB in AD patients. However, the relationship between EPS and brain volumes has not been studied in the LB variant of AD using structural magnetic resonance imaging (MRI). The purpose of this study was to determine the relationship between patterns of brain atrophy and clinical EPS in patients with pathologically confirmed AD. We compared gray matter structure using voxel-based morphometry in 29 Definite AD cases, 16 (55%) of whom also had LBs identified with α-synuclein immunohistochemistry. Multivariate models analyzed brain volume at a voxel level accounting for subject group, Mini-Mental State Examination (MMSE), EPS, total brain volume, and the time from MRI scan to death. There was no significant difference in gray matter volume in the Definite AD patients as a function of LB. There was a significant association between gray matter volumes and the MMSE in AD patients, both with and without LBs. There was a significant correlation between gray matter volume and EPS only in the group of AD patients with LBs, and not in those with pure AD. These findings suggest that that the etiology of EPS in patients with the LB variant of AD is associated with neuronal loss in the nigrostriatal tracts. By contrast, the source of the EPS in AD alone appears to be less well localized.
doi:10.3233/JAD-2012-121108
PMCID: PMC3589734  PMID: 22886020
Alzheimer’s disease; extrapyramidal signs; imaging; Lewy bodies; magnetic resonance imaging; voxel-based morphometry
22.  Early AD pathology in a [C-11]PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study 
Acta Neuropathologica  2012;123(3):433-447.
Amyloid-β (Aβ) deposits are detectable in the brain in vivo using positron emission tomography (PET) and [C-11]-labeled Pittsburgh Compound B ([C-11]PiB); however, the sensitivity of this technique is not well understood. In this study, we examined Aβ pathology in an individual who had clinical diagnoses of probable dementia with Lewy bodies and possible Alzheimer’s disease (AD) but with no detectable [C-11]PiB PET retention ([C-11]PiB(−)) when imaged 17 months prior to death. Brain samples were processed in parallel with region-matched samples from an individual with a clinical diagnosis of probable AD and a positive [C-11]PiB PET scan ([C-11]PiB(+)) when imaged 10 months prior to death. In the [C-11]PiB(−) case, Aβ plaques were sparse, occupying less than 2% cortical area, and were weakly labeled with 6-CN-PiB, a highly fluorescent derivative of PiB. In contrast, Aβ plaques occupied up to 12% cortical area in the [C-11]PiB(+) case, and were intensely labeled with 6-CN-PIB. The [C-11]PiB(−) case had low levels of [H-3]PiB binding (<100 pmol/g) and Aβ1–42 (<500 pmol/g) concentration except in the frontal cortex where Aβ1–42 values (788 pmol/g) approached cortical values in the [C-11]PiB(+) case (800–1,700 pmol/g). In several cortical regions of the [C-11]PiB(−) case, Aβ1–40 levels were within the range of cortical Aβ1–40 values in the [C-11]PiB(+) case. Antemortem [C-11]PiB DVR values correlated well with region-matched postmortem measures of Aβ1–42 and Aβ1–40 in the [C-11]PiB(+), and with Aβ1–42 only in the [C-11]PiB(−) case. The low ratios of [H-3]PiB binding levels to Aβ concentrations and 6-CN-PiB to Aβ plaque loads in the [C-11]PiB(−) case indicate that Aβ pathology in the brain may be associated with low or undetectable levels of [C-11]PiB retention. Studies in greater numbers of [C-11]PiB PET autopsy cases are needed to define the Aβ concentration and [H-3]PiB binding levels required to produce a positive [C-11]PiB PET signal.
doi:10.1007/s00401-012-0943-2
PMCID: PMC3383058  PMID: 22271153
Alzheimer’s disease; Brain amyloidosis; Pittsburgh Compound B; Plaques; Imaging
23.  Acute Blast Injury Reduces Brain Abeta in Two Rodent Species 
Blast-induced traumatic brain injury (TBI) has been a major cause of morbidity and mortality in the conflicts in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. In particular, it is unclear whether blast injures the brain through mechanisms similar to those found in non-blast closed impact injuries (nbTBI). The β-amyloid (Aβ) peptide associated with the development of Alzheimer’s disease is elevated acutely following TBI in humans as well as in experimental animal models of nbTBI. We examined levels of brain Aβ following experimental blast injury using enzyme-linked immunosorbent assays for Aβ 40 and 42. In both rat and mouse models of blast injury, rather than being increased, endogenous rodent brain Aβ levels were decreased acutely following injury. Levels of the amyloid precursor protein (APP) were increased following blast exposure although there was no evidence of axonal pathology based on APP immunohistochemical staining. Unlike the findings in nbTBI animal models, levels of the β-secretase, β-site APP cleaving enzyme 1, and the γ-secretase component presenilin-1 were unchanged following blast exposure. These studies have implications for understanding the nature of blast injury to the brain. They also suggest that strategies aimed at lowering Aβ production may not be effective for treating acute blast injury to the brain.
doi:10.3389/fneur.2012.00177
PMCID: PMC3527696  PMID: 23267342
abeta; amyloid precursor protein; β-site APP cleaving enzyme 1; blast; mouse; presenilin-1; rat; traumatic brain injury
24.  Genome-wide Association Study of Alzheimer’s disease with Psychotic Symptoms 
Molecular psychiatry  2011;17(12):1316-1327.
Psychotic symptoms occur in approximately 40% of subjects with Alzheimer’s disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD−P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD−P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD−P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0×10−7) and within VSNL1 (rs4038131, P=5.9×10−7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.
doi:10.1038/mp.2011.125
PMCID: PMC3272435  PMID: 22005930
Alzheimer’s disease; psychosis; behavioural symptoms; genome-wide association study; genetic
25.  Incidence and Predictors of Advance Care Planning Among Persons with Cognitive Impairment 
Objective
Persons with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are at heightened risk for future decisional incapacity. We sought to characterize advance care planning (ACP) rates over time in individuals who had no advance directives (living will or durable power of attorney) in place when they initially presented for a cognitive evaluation.
Design
Retrospective analysis of data that had been prospectively collected.
Setting
Alzheimer’s Disease Research Center memory disorders clinic.
Participants
Persons (N=127) with a diagnosis of MCI or early AD (n = 72) or moderate to severe AD (n = 55) and no advance directives upon initial presentation for a cognitive evaluation.
Measurements
Extraction of responses to items pertaining to advance care planning assessed during annual semi-structured interviews.
Results
By 5 years of follow-up, 39% of the sample had initiated ACP, with little difference by baseline diagnosis. Younger subjects (under 65 years old) were significantly more likely to initiate advance directives (43%) than were older subjects (37%). This age effect was more pronounced in men than women as well as in married subjects, those with a family history of dementia, no depressive disorder, and subjects with moderate to severe AD (versus those with MCI or early AD) at baseline.
Conclusion
Only a minority of subjects initiated ACPs. The findings suggest the need for interventions aimed at enhancing ACP completion rates, particularly among older adults with cognitive impairment since these individuals may have a timed-limited opportunity to plan for future medical, financial, and other major life decisions.
doi:10.1097/JGP.0b013e3181faebef
PMCID: PMC3145957  PMID: 21785291
mild cognitive impairment; Alzheimer’s disease; durable power of attorney; living will

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