Relationships of Cerebral Perfusion With Gait Speed Across Systolic Blood Pressure Levels and Age: A Cohort Study.

BACKGROUND: This study aimed to examine if the association of cerebral perfusion with gait speed differs across systolic blood pressure (SBP) and age. METHODS: Cerebral perfusion was measured via arterial spin labeled (ASL)-MRI among community-dwelling adults aged 31-94 years in the population-based Mayo Clinic Study of Aging. Usual gait speed was assessed over 5.6 meters on an electronic mat. Sex- and body mass index (BMI)-adjusted linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP using 3-way and 2-way interaction terms between continuous age, SBP, and ASL. Results report estimated differences in gait speed per standard deviation (SD) lower ASL for exemplar SBPs and ages. RESULTS: Among 479 participants (mean age 67.6 years; 44% women; mean gait speed 1.17 m/s), ASL relations to gait speed varied by age (ASL-x-age interaction: p = .001) and SBP (ASL-x-SBP interaction: p = .009). At an SBP of 120 mmHg, each SD lower ASL was associated with a 0.04 m/s (95% confidence interval [CI]: 0.01, 0.07) slower gait speed at 65 years, 0.07 m/s (0.04, 0.10) at 75 years, and 0.09 m/s (0.05, 0.13) at 85 years. At an SBP of 140 mmHg, ASL associations with gait speed were attenuated to 0.01 (-0.01, 0.04), 0.04 (0.02, 0.06), and 0.06 (0.04, 0.09) m/s slower gait speed at ages 65, 75, and 85, respectively. CONCLUSION: Poorer cerebral perfusion is associated with clinically meaningful slower gait speeds, particularly with older age, while higher perfusion markedly attenuates age differences in gait speed.

Development, evaluation, and implementation of building downwash and plume rise enhancements in AERMOD.

Recent research has pointed out many reasons why the building downwash formulation in AERMOD needs to be updated due to: overly simplified equations for building wake development; equations that do not account for porous or streamlined structures; a discontinuity in the streamline equation; and over predictions when compared to field observations for buildings with a large footprint. Because of these issues, a research study was initiated in late 2016 with an overall objective of improving the building downwash algorithms in PRIME. The research study involved the use of wind tunnel modeling to develop a database of wind speed and turbulence intensity measurements downwind of various rectangular solids and streamlined (i.e., tanks and towers) structures. Based on those measurements, new equations (PRIME2) were developed to better describe the turbulence increase and velocity deficit in building wakes for these structure types. The PRIME2 building wake equations for turbulence intensity increase and velocity deficit were shown to agree better with wind tunnel observations than the current PRIME equations in AERMOD. The new equations were documented in a journal article and were added to AERMOD's PRIME subroutine. A new version of AERMOD was then compiled with the new enhanced turbulence and wind speed equations (PRIME2) for evaluation. The key feature of the PRIME2 equations is that building wake enhanced turbulence decays rapidly back to ambient levels above the top of the building versus the current PRIME theory that has constant enhanced turbulence extending up to the height of the wake. This paper provides details on the implementation of the PRIME2 code into AERMOD, PRIME plume rise enhancements, the field databases used to evaluate PRIME2, and the evaluation of PRIME2 against three field databases. The paper shows that AERMOD with the PRIME2 building downwash equations and other enhancements provides the overall best agreement with field observations.Implications: While AERMOD/PRIME is supposed to provide accurate and unbiased estimates (within a factor of two), recent research has identified several problems with the current building downwash theory in AERMOD and comparisons against field observations have shown significant under and overpredictions. One major problem is that the current theory has the wake effect extending well above the top of the building while new research shows that the wake effect decays rapidly above the top of the building. This could lead AERMOD to underpredict or overpredict ground-level concentrations. Based on recent wind tunnel tests, a new building downwash theory has been developed and documented in a Journal article. This theory has been added to the PRIME building downwash algorithm in AERMOD and is currently included as an Alpha option in AERMOD. This paper evaluates that new theory against field observations and demonstrates that the updated theory provides better agreement with field observations than the current AERMOD. This paper points out that research and development of model building downwash improvements should be an ongoing process to help ensure a "sustainable" future where these improvements can ultimately provide a model with unbiased performance and thereby allow for responsible industrial development. This study has shown that improvements can be made in a rather quick manner and be included as Alpha options in EPA model updates. The next challenge is to transition these options from Alpha to Beta options and then finally to a default status.

Use of mild cognitive impairment and prodromal AD/MCI due to AD in clinical care: a European survey.

INTRODUCTION: The diagnosis of mild cognitive impairment (MCI) refers to cognitive impairment not meeting dementia criteria. A survey among members of the American Association of Neurology (AAN) showed that MCI was considered a useful diagnosis. Recently, research criteria have been proposed for the diagnosis of Alzheimer's disease (AD) in MCI based on AD biomarkers (prodromal AD/MCI due to AD). The aim of this study was to investigate the attitudes of clinicians in Europe on the clinical utility of MCI and prodromal AD/MCI due to AD criteria. We also investigated whether the prodromal AD/MCI due to AD criteria impacted management of MCI patients. METHODS: An online survey was performed in 2015 among 102 members of the European Academy of Neurology (EAN) and the European Alzheimer's Disease Consortium (EADC). Questions were asked on how often criteria were used, how they were operationalized, how they changed patient management, and what were considered advantages and limitations of MCI and prodromal AD/MCI due to AD. The questionnaire consisted of 47 questions scored on a Likert scale. RESULTS: Almost all respondents (92%) used the MCI diagnosis in clinical practice. Over 80% of the EAN/EADC respondents found a MCI diagnosis useful because it helped to label the cognitive problem, involve patients in planning for the future, and start risk reduction activities. These findings were similar to those reported in the AAN survey. Research criteria for prodromal AD/MCI due to AD were used by 68% of the EAN/EADC respondents. The most common reasons to use the criteria were increased certainty of diagnosis (86%), increased possibilities to provide counseling (51%), facilitation of follow-up planning (48%), start of medical intervention (49%), and response to patients' wish for a diagnosis (41%). Over 70% of the physicians considered that a diagnosis of prodromal AD/MCI due to AD had an added value over the MCI diagnosis. CONCLUSIONS: The diagnostic criteria of MCI and prodromal AD/MCI due to AD are commonly used among EAN/EADC members. The prodromal AD/MCI due to AD were considered clinically useful and impacted patient management and communication.

Critical review of the building downwash algorithms in AERMOD.

The only documentation on the building downwash algorithm in AERMOD (American Meteorological Society/U.S. Environmental Protection Agency Regulatory Model), referred to as PRIME (Plume Rise Model Enhancements), is found in the 2000 A&WMA journal article by Schulman, Strimaitis and Scire. Recent field and wind tunnel studies have shown that AERMOD can overpredict concentrations by factors of 2 to 8 for certain building configurations. While a wind tunnel equivalent building dimension study (EBD) can be conducted to approximately correct the overprediction bias, past field and wind tunnel studies indicate that there are notable flaws in the PRIME building downwash theory. A detailed review of the theory supported by CFD (Computational Fluid Dynamics) and wind tunnel simulations of flow over simple rectangular buildings revealed the following serious theoretical flaws: enhanced turbulence in the building wake starting at the wrong longitudinal location; constant enhanced turbulence extending up to the wake height; constant initial enhanced turbulence in the building wake (does not vary with roughness or stability); discontinuities in the streamline calculations; and no method to account for streamlined or porous structures. IMPLICATIONS: This paper documents theoretical and other problems in PRIME along with CFD simulations and wind tunnel observations that support these findings. Although AERMOD/PRIME may provide accurate and unbiased estimates (within a factor of 2) for some building configurations, a major review and update is needed so that accurate estimates can be obtained for other building configurations where significant overpredictions or underpredictions are common due to downwash effects. This will ensure that regulatory evaluations subject to dispersion modeling requirements can be based on an accurate model. Thus, it is imperative that the downwash theory in PRIME is corrected to improve model performance and ensure that the model better represents reality.

Impact of apolipoprotein E4-cerebrospinal fluid ß-amyloid interaction on hippocampal volume loss over 1 year in mild cognitive impairment.

BACKGROUND: The majority of studies relating amyloid pathology with brain volumes have been cross-sectional. Apolipoprotein ɛ4 (APOE ɛ4), a genetic risk factor for Alzheimer's disease, is also known to be associated with hippocampal volume loss. No studies have considered the effects of amyloid pathology and APOE ɛ4 together on longitudinal volume loss. METHODS: We evaluated whether an abnormal level of cerebrospinal fluid beta-amyloid (CSF Aß) and APOE ɛ4 carrier status were independently associated with greater hippocampal volume loss over 1 year. We then assessed whether APOE ɛ4 status and CSF Aß acted synergistically, testing the significance of an interaction term in the regression analysis. We included 297 participants: 77 cognitively normal, 144 with mild cognitive impairment (MCI), and 76 with Alzheimer's disease. RESULTS: An abnormal CSF Aß level was found to be associated with greater hippocampal volume loss over 1 year in each group. APOE ɛ4 was associated with hippocampal volume loss only in the cognitively normal and MCI groups. APOE ɛ4 carriers with abnormal CSF Aß in the MCI group acted synergistically to produce disproportionately greater volume loss than noncarriers. CONCLUSION: Baseline CSF Aß predicts progression of hippocampal volume loss. APOE ɛ4 carrier status amplifies the degree of neurodegeneration in MCI. Understanding the effect of interactions between genetic risk and amyloid pathology will be important in clinical trials and our understanding of the disease process.

Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis.

For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1(st), 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 "top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.

Evidence for an association between KIBRA and late-onset Alzheimer's disease.

We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P<0.010, corrected) in a study of laser-capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (P=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.

Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative.

BACKGROUND: The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. METHODS: We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). FINDINGS: Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. INTERPRETATION: Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.

Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.

National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.

BACKGROUND AND PURPOSE: One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. METHODS: The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. RESULTS: The results of these discussions are reported herein. CONCLUSIONS: The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

Subtype of mild cognitive impairment and progression to dementia and death.

BACKGROUND: Mild cognitive impairment (MCI) represents a common cognitive state between normal cognitive aging and dementia. There is limited information about the heterogeneity of MCI and how this heterogeneity may influence the clinical course of MCI. We determined the longitudinal course of subtypes of MCI and assessed the rate of progression to dementia and to death. METHODS: As part of the Alzheimer's Disease Research Centers of California, we studied 327 patients with MCI (250 with amnestic MCI, 34 with single nonmemory MCI, and 43 with multiple domain MCI) who were followed longitudinally. We determined if subtype of MCI was independently associated with time to dementia diagnosis and time to death using Cox proportional hazard models, and type of dementia using Fisher's exact test. RESULTS: Mean age of the patients with MCI was 72.9 +/- 9.3 years and mean Mini-Mental State Examination score was 25.7 +/- 4.3. After a mean follow-up of 3.1 years, 199 (65%) progressed to dementia and 80 (24%) died. After multivariate adjustment, compared to those with amnestic MCI, patients with single nonmemory or multiple subtype MCI were less likely to receive a diagnosis of dementia (HR = 0.60; 95% CI 0.35-1.05 and HR = 0.71; 95% CI 0.44-1.14) but more likely to die (HR = 2.57; 95% CI 1.13-5.84 and HR = 1.73; 95% CI 0.72-4.18), but these results were of borderline statistical significance. There were significant differences in the type of dementia diagnosed across MCI subtypes (p = 0.006). Among the patients who progressed to Alzheimer's disease, 76% had prior amnestic MCI; of the patients who progressed to vascular dementia, 50% had prior amnestic MCI; all patients who progressed to a frontal dementia syndrome had single nonmemory MCI previously. CONCLUSIONS: The majority of patients with MCI progressed to dementia and a significant proportion died. Subtype of MCI may influence rates of progression to death and to dementia and has a major influence on subsequent type of dementia diagnosis.

CHMP2B mutations are not a common cause of frontotemporal lobar degeneration.

It was reported in 1995 that a large Danish family with familial frontotemporal dementia (FTD) was linked to the pericentromeric region of chromosome 3. It has since been claimed that a mutation in the splice acceptor site of exon 6 of CHMP2B is the pathogenic variant in this family. In order to determine whether CHMP2B mutations are a common cause of disease in patients with frontotemporal lobar degeneration (FTLD) we sequenced all exons and flanking regions of CHMP2B in 141 familial FTLD probands from the USA and UK. We failed to find a single pathogenic variant in any case. Polymorphisms were detected but were present in control samples. We conclude that mutations in CHMP2B are a rare cause of familial FTLD and may be specific to the Danish pedigree.