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1.  Mild cognitive impairment in clinical care 
Neurology  2010;75(5):425-431.
Objective:
To assess how neurologists view mild cognitive impairment (MCI) as a clinical diagnosis and how they treat patients with mild cognitive symptoms.
Methods:
Members of the American Academy of Neurology with an aging, dementia, or behavioral neurology practice focus were surveyed by self-administered questionnaire.
Results:
Survey respondents were 420 providers (response rate 48%), and 88% reported at least monthly encounters with patients experiencing mild cognitive symptoms. Most respondents recognize MCI as a clinical diagnosis (90%) and use its diagnostic code for billing purposes (70%). When seeing these patients, most respondents routinely provide counseling on physical (78%) and mental exercise (75%) and communicate about dementia risk (63%); fewer provide information on support services (27%) or a written summary of findings (15%). Most (70%) prescribe cholinesterase inhibitors at least sometimes for this population, with memantine (39%) and other agents (e.g., vitamin E) prescribed less frequently. Respondents endorsed several benefits of a diagnosis of MCI: 1) involving the patient in planning for the future (87%); 2) motivating risk reduction activities (85%); 3) helping with financial planning (72%); and 4) prescribing medications (65%). Some respondents noted drawbacks, including 1) too difficult to diagnose (23%); 2) better described as early Alzheimer disease (21%); and 3) diagnosis can cause unnecessary worry (20%).
Conclusions:
Patients with mild cognitive symptoms are commonly seen by neurologists, who view MCI as a useful diagnostic category. Information and treatments provided to patients with MCI vary significantly, suggesting a need for practice guidelines and further research on clinical decision-making with this population.
GLOSSARY
= age-associated memory impairment;
= American Academy of Neurology;
= Alzheimer disease;
= cognitive impairment, no dementia;
= Diagnostic and Statistical Manual of Mental Disorders, 5th edition;
= mild cognitive impairment;
= not otherwise specified.
doi:10.1212/WNL.0b013e3181eb5872
PMCID: PMC2918467  PMID: 20679636
2.  Discontinuous Fiber-reinforced Composites above Critical Length 
Journal of dental research  2005;84(4):365-370.
Micromechanical physics of critical fiber length, describing a minimum filament distance for resin impregnation and stress transfer, has not yet been applied in dental science. As a test of the hypothesis that 9-micron-diameter, 3-mm-long quartz fibers would increase mechanical strength over particulate-filled composites, photocure-resin-pre-impregnated discontinuous reinforcement was incorporated at 35 wt% into 3M Corporation Z100, Kerr Corporation HerculiteXRV, and an experimental photocure paste with increased radiopaque particulate. Fully articulated four-point bend testing per ASTM C 1161-94 for advanced ceramics and Izod impact testing according to a modified unnotched ASTM D 256-00 specification were then performed. All photocure-fiber-reinforced composites demonstrated significant improvements over particulate-filled compounds (p < 0.001) for flexural strength, modulus, work of fracture, strain at maximum load, and Izod toughness, with one exception for the moduli of Z100 and the experimental reinforced paste. The results indicate that inclusion of pre-impregnated fibers above the critical aspect ratio yields major advancements regarding the mechanical properties tested.
PMCID: PMC3989201  PMID: 15790745
critical length; critical aspect ratio; discontinuous
3.  The Apolipoprotein E Genotype Predicts Longitudinal Transitions to Mild Cognitive Impairment but Not to Alzheimer’s Dementia: Findings From a Nationally Representative Study 
Neuropsychology  2013;27(1):10.1037/a0030855.
Objective
The ε4 allele of the apolipoprotein E (APOE) genotype is the most widely accepted genetic risk factor for Alzheimer’s dementia (AD), but findings on whether it is a risk factor for the AD prodrome, mild cognitive impairment (MCI), have been inconsistent. In a prospective longitudinal design, we investigated (a) whether transitions to MCI and other forms of neurocognitive impairment without dementia (CIND) are more frequent among normal ε4 carriers than among noncarriers and (b) whether subsequent transitions to AD from MCI and from other forms of CIND are more frequent among ε4 carriers than among noncarriers.
Method
The frequency of the ε4 allele was studied in older adults (mean age > 70), who had participated in two or more waves of neuropsychological testing and diagnosis in the Aging, Demographics, and Memory Study (ADAMS) of the United States Department of Health and Human Services, National Institutes of Health, National Institute on Aging’s Health and Retirement Study, conducted by the University of Mchigan. The association between ε4 and longitudinal transitions to specific types of CIND and dementia can be determined with this data set.
Results
Epsilon 4 increased the rate of progression from normal functioning to MCI (58% of new diagnoses were carriers) but not to other forms of CIND. The rate of progression to AD from MCI or from other forms of CIND was not increased by ε 4.
Conclusions
The results support the hypothesis that ε4 is a risk factor for transitions from normal functioning to MCI but not for subsequent transitions to AD. In the ADAMS sample, the reason ε 4 is elevated in AD individuals is because it is already elevated in MCI individuals, who are the primary source of new AD diagnoses.
doi:10.1037/a0030855
PMCID: PMC3874553  PMID: 23356599
mild cognitive impairment; Alzheimer’s dementia; APOE genotype
4.  The incidence of MCI differs by subtype and is higher in men 
Neurology  2012;78(5):342-351.
Objective:
Although incidence rates for mild cognitive impairment (MCI) have been reported, few studies were specifically designed to measure the incidence of MCI and its subtypes using published criteria. We estimated the incidence of amnestic MCI (aMCI) and nonamnestic MCI (naMCI) in men and women separately.
Methods:
A population-based prospective cohort of Olmsted County, MN, residents ages 70–89 years on October 1, 2004, underwent baseline and 15-month interval evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychological testing. A panel of examiners blinded to previous diagnoses reviewed data at each serial evaluation to assess cognitive status according to published criteria.
Results:
Among 1,450 subjects who were cognitively normal at baseline, 296 developed MCI. The age- and sex-standardized incidence rate of MCI was 63.6 (per 1,000 person-years) overall, and was higher in men (72.4) than women (57.3) and for aMCI (37.7) than naMCI (14.7). The incidence rate of aMCI was higher for men (43.9) than women (33.3), and for subjects with ≤12 years of education (42.6) than higher education (32.5). The risk of naMCI was also higher for men (20.0) than women (10.9) and for subjects with ≤12 years of education (20.3) than higher education (10.2).
Conclusions:
The incidence rates for MCI are substantial. Differences in incidence rates by clinical subtype and by sex suggest that risk factors for MCI should be investigated separately for aMCI and naMCI, and in men and women.
doi:10.1212/WNL.0b013e3182452862
PMCID: PMC3280046  PMID: 22282647
5.  APOE modifies the association between Aβ load and cognition in cognitively normal older adults 
Neurology  2012;78(4):232-240.
Objective:
To determine the relationship between β-amyloid (Aβ) load as measured by [11C]–Pittsburgh compound B (PiB) PET and cognitive function in cognitively normal older adults.
Methods:
We studied 408 cognitively normal older adults who participated in the population-based Mayo Clinic Study of Aging (MCSA) from January 2009 through March 2011. The participants underwent PiB PET and neuropsychometric testing within 6 months. The association between PiB retention and cognitive function was measured by partial correlation and an interaction with APOE status was tested using linear regression after adjusting for age, sex, and education.
Results:
Higher PiB retention was associated with cognitive performance (Spearman partial r = −0.18; p < 0.01), specifically the memory, language, attention/executive, and visual-spatial processing domains in the whole group of participants. The association between PiB retention and cognition was modified by the APOE status on linear regression analysis even after controlling for the differences in the distribution of PiB values among APOE ϵ4 carriers and noncarriers (p = 0.02). Cognitive performance was associated with the Aβ deposition in the frontal, temporal, and parietal lobe association cortices in APOE ϵ4 carriers on SPM analysis (p < 0.001).
Conclusion:
There is a modest association between PiB retention and cognitive function in cognitively normal older adults and this relationship between Aβ load and cognitive function is modified by APOE status. Whereas Aβ load is associated with greater cognitive impairment in APOE ϵ4 carriers, the cognitive function in APOE ϵ4 noncarriers is influenced less by the Aβ load, suggesting that APOE isoforms modulate the harmful effects of Aβ on cognitive function. Neurology® 2012;78:232–240
doi:10.1212/WNL.0b013e31824365ab
PMCID: PMC3280056  PMID: 22189452
6.  TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers 
Neurology  2010;76(5):467-474.
Objectives:
To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression.
Methods:
We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD–TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls.
Results:
In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, pallelic = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected pallelic = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected precessive = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = −0.63, p = 7.7 × 10−5) and controls (r = −0.49, p = 2.2 × 10−10).
Conclusions:
In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.
doi:10.1212/WNL.0b013e31820a0e3b
PMCID: PMC3034409  PMID: 21178100
7.  Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN 
Neurology  2011;77(4):393-398.
Objective:
To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubule-associated protein tau (MAPT) gene mutations.
Methods:
In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline.
Results:
The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9–2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8–4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9–12], GRN = 6.5% [95% CI 1.7–11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p < 0.001).
Conclusions:
Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure.
doi:10.1212/WNL.0b013e318227047f
PMCID: PMC3140800  PMID: 21753165
8.  Age-related changes in the default mode network are more advanced in Alzheimer disease 
Neurology  2011;77(16):1524-1531.
Objective:
To investigate age-related default mode network (DMN) connectivity in a large cognitively normal elderly cohort and in patients with Alzheimer disease (AD) compared with age-, gender-, and education-matched controls.
Methods:
We analyzed task-free–fMRI data with both independent component analysis and seed-based analysis to identify anterior and posterior DMNs. We investigated age-related changes in connectivity in a sample of 341 cognitively normal subjects. We then compared 28 patients with AD with 56 cognitively normal noncarriers of the APOE ϵ4 allele matched for age, education, and gender.
Results:
The anterior DMN shows age-associated increases and decreases in fontal lobe connectivity, whereas the posterior DMN shows mainly age-associated declines in connectivity throughout. Relative to matched cognitively normal controls, subjects with AD display an accelerated pattern of the age-associated changes described above, except that the declines in frontal lobe connectivity did not reach statistical significance. These changes survive atrophy correction and are correlated with cognitive performance.
Conclusions:
The results of this study indicate that the DMN abnormalities observed in patients with AD represent an accelerated aging pattern of connectivity compared with matched controls.
doi:10.1212/WNL.0b013e318233b33d
PMCID: PMC3198977  PMID: 21975202
9.  Prevalence of mild cognitive impairment is higher in men 
Neurology  2010;75(10):889-897.
Objective:
We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria.
Methods:
We evaluated an age- and sex-stratified random sample of Olmsted County residents who were 70–89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria.
Results:
Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval [CI] 14.4–17.5) for any MCI, 11.1% (95% CI 9.8–12.3) for amnestic MCI, and 4.9% (95% CI 4.0–5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21–1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE ε3ε4 or ε4ε4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001).
Conclusions:
Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.
GLOSSARY
= Alzheimer disease;
= amnestic mild cognitive impairment;
= Clinical Dementia Rating scale;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= Functional Activities Questionnaire;
= mild cognitive impairment;
= nonamnestic mild cognitive impairment;
= odds ratio;
= Short Test of Mental Status;
= Telephone Interview for Cognitive Status-modified;
= Wechsler Adult Intelligence Scale-Revised.
doi:10.1212/WNL.0b013e3181f11d85
PMCID: PMC2938972  PMID: 20820000
10.  Magnetic resonance spectroscopy, β-amyloid load, and cognition in a population-based sample of cognitively normal older adults 
Neurology  2011;77(10):951-958.
Objective:
To determine the relationship between proton magnetic resonance spectroscopy (1H MRS) metabolites and β-amyloid (Aβ) load and the effects of Aβ load on the association between 1H MRS metabolites and cognitive function in cognitively normal older adults.
Methods:
We studied 311 cognitively normal older adults who participated in the population-based Mayo Clinic Study of Aging from January 2009 through September 2010. Participants underwent 11C-Pittsburgh compound B (PiB) PET, 1H MRS from the posterior cingulate gyri, and neuropsychometric testing to assess memory, attention/executive, language, and visual-spatial domain functions within 6 months. Partial Spearman rank order correlations were adjusted for age, sex, and education.
Results:
Higher PiB retention was associated with abnormal elevations in myoinositol (mI)/creatine (Cr) (partial rs = 0.17; p = 0.003) and choline (Cho)/Cr (partial rs = 0.13; p = 0.022) ratios. Higher Cho/Cr was associated with worse performance on Auditory Verbal Learning Test Delayed Recall (partial rs = −0.12; p = 0.04), Trail Making Test Part B (partial rs = 0.12; p = 0.04), Wechsler Adult Intelligence Scale–Revised (WAIS-R) Digit Symbol (partial rs = −0.18; p < 0.01), and WAIS-R Block Design (partial rs = −0.12; p = 0.03). Associations between 1H MRS metabolites and cognitive function were not different among participants with high vs low PiB retention.
Conclusion:
In cognitively normal older adults, the 1H MRS metabolite ratios mI/Cr and Cho/Cr are associated with the preclinical pathologic processes in the Alzheimer disease cascade. Higher Cho/Cr is associated with worse performance on domain-specific cognitive tests independent of Aβ load, suggesting that Cho/Cr elevation may also be dependent on other preclinical dementia pathologies characterized by Cho/Cr elevation such as Lewy body or ischemic vascular disease in addition to Aβ load. Neurology® 2011;77:951–958
doi:10.1212/WNL.0b013e31822dc7e1
PMCID: PMC3171960  PMID: 21865577
11.  The relative efficiency of time-to-threshold and rate of change in longitudinal data 
Contemporary clinical trials  2011;32(5):685-693.
Randomized, placebo-controlled trials often use time-to-event as the primary endpoint, even when a continuous measure of disease severity is available. We compare the power to detect a treatment effect using either rate of change, as estimated by linear models of longitudinal continuous data, or time-to-event estimated by Cox proportional hazards models. We propose an analytic inflation factor for comparing the two types of analyses assuming that the time-to-event can be expressed as a time-to-threshold of the continuous measure. We conduct simulations based on a publicly available Alzheimer's disease data set in which the time-to-event is algorithmically defined based on a battery of assessments. A Cox proportional hazards model of the time-to-event endpoint is compared to a linear model of a single assessment from the battery. The simulations also explore the impact of baseline covariates in either analysis.
doi:10.1016/j.cct.2011.04.007
PMCID: PMC3148349  PMID: 21554992
longitudinal data; survival analysis; linear mixed models; marginal linear models; power
12.  Altered functional connectivity in asymptomatic MAPT subjects 
Neurology  2011;77(9):866-874.
Objective:
To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD).
Methods:
In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest.
Results:
The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects.
Conclusions:
Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.
doi:10.1212/WNL.0b013e31822c61f2
PMCID: PMC3162637  PMID: 21849646
13.  Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies 
Neurology  2011;77(9):875-882.
Objective:
To determine whether adding REM sleep behavior disorder (RBD) to the dementia with Lewy bodies (DLB) diagnostic criteria improves classification accuracy of autopsy-confirmed DLB.
Methods:
We followed 234 consecutive patients with dementia until autopsy with a mean of 4 annual visits. Clinical diagnoses included DLB, Alzheimer disease (AD), corticobasal syndrome, and frontotemporal dementia. Pathologic diagnoses used the 2005 DLB consensus criteria and included no/low likelihood DLB (non-DLB; n = 136) and intermediate/high likelihood DLB (DLB; n = 98). Regression modeling and sensitivity/specificity analyses were used to evaluate the diagnostic role of RBD.
Results:
Each of the 3 core features increased the odds of autopsy-confirmed DLB up to 2-fold, and RBD increased the odds by 6-fold. When clinically probable DLB reflected dementia and 2 or more of the 3 core features, sensitivity was 85%, and specificity was 73%. When RBD was added and clinically probable DLB reflected 2 or more of 4 features, sensitivity improved to 88%. When dementia and RBD were also designated as probable DLB, sensitivity increased to 90% while specificity remained at 73%. The VH, parkinsonism, RBD model lowered sensitivity to 83%, but improved specificity to 85%.
Conclusions:
Inclusion of RBD as a core clinical feature improves the diagnostic accuracy of autopsy-confirmed DLB.
doi:10.1212/WNL.0b013e31822c9148
PMCID: PMC3162640  PMID: 21849645
14.  Diffusion tensor imaging and cognitive function in older adults with no dementia 
Neurology  2011;77(1):26-34.
Objective:
To determine the patterns of diffusivity associated with cognitive domain functions in older adults without dementia.
Methods:
We studied older adults without dementia (n = 220) who underwent neuropsychometric testing and a diffusion tensor imaging (DTI) examination at 3 T in a cross-sectional study. Memory, language, attention/executive function, and visual-spatial processing domains were assessed within 4 months of the MRI examination. A fluid-attenuated inversion recovery–based DTI sequence that enabled uncontaminated cortical diffusion measurements was performed. Associations between cortical mean diffusivity (MD) and cognitive function were tested using voxel-based regression analysis. Association between tract diffusivity and cognitive function was tested with regions of interest drawn on color-coded fractional anisotropy (FA) maps.
Results:
Memory function was associated with the medial temporal lobe cortical MD on voxel-based analysis (p < 0.001, corrected for multiple comparisons), and inferior longitudinal fasciculus and posterior and anterior cingulum FA on tract-based analysis (p < 0.001). Language function was associated with the left temporal lobe cortical MD (p < 0.001, corrected for multiple comparisons), inferior longitudinal fasciculus, fornix, and posterior cingulum FA (p < 0.05). Attention and executive function was associated with the posterior and anterior cingulum FA, and visual-spatial function was associated with posterior cingulum FA (p < 0.01).
Conclusion:
Specific cognitive domain functions are associated with distinct patterns of cortical and white matter diffusivity in elderly with no dementia. Posterior cingulum tract FA was associated with all 4 cognitive domain functions, in agreement with the hypothesis that the posterior cingulate cortex is the main connectivity hub for cognitive brain networks. Microstructural changes identified on DTI may be associated with neurodegenerative pathologies underlying cognitive changes in older adults without dementia.
doi:10.1212/WNL.0b013e31822313dc
PMCID: PMC3127333  PMID: 21593440
15.  MRS in presymptomatic MAPT mutation carriers 
Neurology  2010;75(9):771-778.
Objective:
To determine the proton magnetic resonance spectroscopy (1H MRS) changes in carriers of microtubule-associated protein (MAPT) mutations in a case-control study.
Methods:
Patients with MAPT mutations (N279K, V337M, R406W, IVS9-10G>T, P301L) from 5 different families (n = 24) underwent MRI and single voxel 1H MRS from the posterior cingulate gyrus inferior precuneus at 3 T. Ten of the patients were symptomatic with median Clinical Dementia Rating sum of boxes score (CDR-SOB) of 6.5 and 14 patients were presymptomatic with CDR-SOB of 0. Age- and sex-matched controls (n = 24) were recruited.
Results:
Symptomatic MAPT mutation carriers were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) ratio, an index of neuronal integrity, increased myoinositol (mI)/Cr ratio, a possible marker for glial activity, decreased NAA/mI, and hippocampal atrophy (p < 0.001). Whereas presymptomatic MAPT mutation carriers had elevated mI/Cr and decreased NAA/mI (p < 0.001), NAA/Cr levels and hippocampal volumes were not different from controls. Decrease in NAA/Cr (R2 = 0. 22; p = 0.021) and hippocampal volumes (R2 = 0.46; p < 0.001) were associated with proximity to the expected or actual age at symptom onset in MAPT mutation carriers.
Conclusion:
1H MRS metabolite abnormalities characterized by an elevated mI/Cr and decreased NAA/mI are present several years before the onset of symptoms in MAPT mutation carriers. The data suggest an ordered sequencing of the 1H MRS and MRI biomarkers. MI/Cr, a possible index of glial proliferation, precedes the decrease in neuronal integrity marker NAA/Cr and hippocampal atrophy. 1H MRS may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies.
GLOSSARY
= automated anatomic labeling;
= Alzheimer disease;
= Clinical Dementia Rating sum of boxes score;
= creatine;
= frontotemporal dementia;
= frontotemporal lobar degeneration;
= gray matter;
= myoinositol;
= Montreal Neurological Institute;
= magnetic resonance;
= magnetic resonance spectroscopy;
= N-acetylaspartate;
= region of interest;
= statistical parametric mapping;
= single voxel;
= white matter.
doi:10.1212/WNL.0b013e3181f073c7
PMCID: PMC2938968  PMID: 20805522
16.  Association and heterogeneity at the GAPDH locus in Alzheimer’s disease 
Neurobiology of aging  2010;33(1):203.e25-203.e33.
Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogues were implicated in late-onset Alzheimer’s disease (LOAD), although the strength and direction of association have not been consistent. We genotyped three previously reported SNPs (rs3741916-GAPDH 5’UTR, rs2029721-pGAPD and rs4806173-GAPDHS) in three case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p=0.003). The minor allele of rs3741916 showed a protective effect in our combined series (OR=0.87, 95% confidence interval (CI)=0.79–0.96). This is consistent with results from the two published follow-up studies and in opposite direction of the original report. Meta-analysis of the published series with ours suggests presence of heterogeneity (Breslow-Day p<0.0001). Meta-analysis of only the follow-up series including ours revealed a significant protective effect for the minor allele of rs3741916 (OR=0.85, 95% CI=0.76–0.96, p=0.009). Our results support the presence of LOAD variants and heterogeneity at the GAPDH locus. The most promising rs3741916 variant is unlikely to be functional given opposing effects in different series. Identification of functional variant(s) in this region likely awaits deep sequencing.
doi:10.1016/j.neurobiolaging.2010.08.002
PMCID: PMC3017231  PMID: 20864222
Alzheimer's disease; Association studies in genetics; Case control studies
17.  Report of the task force on designing clinical trials in early (predementia) AD 
Neurology  2010;76(3):280-286.
Background:
A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia.
Method:
An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.
Results:
General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.
Conclusion:
A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.
doi:10.1212/WNL.0b013e318207b1b9
PMCID: PMC3034393  PMID: 21178097
18.  Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort 
Neurology  2010;76(1):69-79.
Objectives:
CSF levels of Aβ1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42).
Methods:
A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p < 0.01 (uncorrected p < 3.10 × 10−8) and secondarily examined SNPs with uncorrected p values less than 10−5 to identify potential candidates.
Results:
Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates.
Conclusions:
In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.
doi:10.1212/WNL.0b013e318204a397
PMCID: PMC3030225  PMID: 21123754
19.  Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects(e–Pub ahead of print) 
Neurology  2010;75(22):1976-1981.
Objective:
To determine whether elderly normal APOE E2 (APOE2) carriers exhibit slower rates of hippocampal atrophy and memory decline compared to APOE3/3 carriers. We also determined whether APOE2 carriers have less Alzheimer pathology as reflected by CSF biomarkers.
Methods:
We included longitudinal data from 134 cognitively normal individuals (27 APOE2/2 or E2/3, 107 APOE3/3) from the Alzheimer's Disease Neuroimaging Initiative, a prospective cohort study. A linear mixed-effects model was used to determine how APOE2 affected rates of hippocampal atrophy and cognitive change over time. In a subsample of 72 individuals who also underwent CSF analysis, an ordinary least-squares regression was used to determine whether CSF β-amyloid (Aβ), total tau, and phosphorylated tau-181 (p-tau) differed by APOE2 status.
Results:
APOE2 carriers demonstrated slower rates of hippocampal atrophy (p = 0.004). The mean rate of hippocampal atrophy among APOE2 carriers was −33 mm3/year (95% confidence interval −65 to +0.4), or −0.5%/year, compared to −86 mm3/year (95% confidence interval −102 to −71), or −1.3%/year, in the APOE3/3 group. No differences in the rates of episodic memory (p = 0.23) or overall cognitive change (p = 0.90) were detected. In the CSF subsample, APOE2 carriers had higher levels of CSF Aβ (p = 0.01), lower p-tau (p = 0.02), and marginally lower tau (p = 0.12).
Conclusion:
A slower rate of hippocampal atrophy in normal APOE2 carriers is consistent with the lower risk of Alzheimer disease in these individuals. We hypothesize that the slower atrophy rate is related to decreased preclinical Alzheimer pathology.
GLOSSARY
= β-amyloid;
= Alzheimer disease;
= Alzheimer's Disease Assessment Scale Cognitive Subscale;
= Alzheimer's Disease Neuroimaging Initiative;
= mild cognitive impairment;
= magnetization-prepared rapid gradient echo;
= phosphorylated tau-181;
= Wechsler Memory Scale–Revised.
doi:10.1212/WNL.0b013e3181ffe4d1
PMCID: PMC3014234  PMID: 20980669
20.  Imaging correlates of pathology in corticobasal syndrome(Podcast) 
Neurology  2010;75(21):1879-1887.
Background:
Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS.
Methods:
This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls.
Results:
All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD.
Conclusions:
Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology.
GLOSSARY
= automated anatomic labeling;
= Alzheimer disease;
= corticobasal degeneration;
= corticobasal syndrome;
= Clinical Dementia Rating sum of boxes;
= false discovery rate;
= frontotemporal lobar degeneration;
= Mini-Mental State Examination;
= progressive supranuclear palsy;
= region of interest;
= supplemental motor area;
= TDP-43 immunoreactivity;
= total intracranial volume;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e3181feb2e8
PMCID: PMC2995388  PMID: 21098403
21.  Impact of APOE4-CSF Aβ interaction on hippocampal volume loss over 1 year in MCI 
Background
The majority of studies relating amyloid pathology with brain volumes have been cross-sectional. Apolipoprotein E4 (APOE4), a genetic risk factor for Alzheimer’s disease (AD), is also associated with hippocampal volume loss. No studies have considered the effects of amyloid pathology and APOE4 together on longitudinal volume loss.
Methods
We evaluated whether an abnormal level of cerebrospinal fluid beta-amyloid (CSF Aβ) and APOE4 carrier status were independently associated with greater hippocampal volume loss over 1 year. We then assessed whether APOE4 status and CSF Aβ acted synergistically, testing the significance of an interaction term in the regression analysis. We included 297 participants: 77 cognitively normal (NC), 144 with mild cognitive impairment (MCI), and 76 with AD.
Results
An abnormal CSF Aβ level was found to be associated with greater hippocampal volume loss over 1 year in each group. APOE4 was associated with hippocampal volume loss only in the NC and MCI groups. APOE4 carriers with abnormal CSF Aβ in the MCI group acted synergistically to produce disproportionately greater volume loss than noncarriers.
Conclusion
Baseline CSF Aβ predicts progression of hippocampal volume loss. APOE4 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.
doi:10.1016/j.jalz.2010.12.010
PMCID: PMC3177162  PMID: 21889115
apolipoprotein E4; hippocampal atrophy; beta-amyloid; biomarker; MRI
22.  Comparing predictors of conversion and decline in mild cognitive impairment(Podcast)(e–Pub ahead of print) 
Neurology  2010;75(3):230-238.
Objective:
A variety of measurements have been individually linked to decline in mild cognitive impairment (MCI), but the identification of optimal markers for predicting disease progression remains unresolved. The goal of this study was to evaluate the prognostic ability of genetic, CSF, neuroimaging, and cognitive measurements obtained in the same participants.
Methods:
APOE ε4 allele frequency, CSF proteins (Aβ1-42, total tau, hyperphosphorylated tau [p-tau181p]), glucose metabolism (FDG-PET), hippocampal volume, and episodic memory performance were evaluated at baseline in patients with amnestic MCI (n = 85), using data from a large multisite study (Alzheimer's Disease Neuroimaging Initiative). Patients were classified as normal or abnormal on each predictor variable based on externally derived cutoffs, and then variables were evaluated as predictors of subsequent conversion to Alzheimer disease (AD) and cognitive decline (Alzheimer's Disease Assessment Scale–Cognitive Subscale) during a variable follow-up period (1.9 ± 0.4 years).
Results:
Patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7 times more likely to convert to AD than subjects who had normal results on both measures (p ≤ 0.02). In addition, the CSF ratio p-tau181p/Aβ1-42 (β = 1.10 ± 0.53; p = 0.04) and, marginally, FDG-PET predicted cognitive decline.
Conclusions:
Baseline FDG-PET and episodic memory predict conversion to AD, whereas p-tau181p/Aβ1-42 and, marginally, FDG-PET predict longitudinal cognitive decline. Complementary information provided by these biomarkers may aid in future selection of patients for clinical trials or identification of patients likely to benefit from a therapeutic intervention.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Assessment Scale–Cognitive Subscale;
= Alzheimer's Disease Neuroimaging Initiative;
= Auditory Verbal Learning Test;
= Clinical Dementia Rating;
= confidence interval;
= [18F]fluorodeoxyglucose;
= mild cognitive impairment;
= Montreal Neurological Institute;
= hyperphosphorylated tau;
= receiver operating characteristic;
= total tau.
doi:10.1212/WNL.0b013e3181e8e8b8
PMCID: PMC2906178  PMID: 20592257
23.  Serial MRI and CSF biomarkers in normal aging, MCI, and AD 
Neurology  2010;75(2):143-151.
Objective:
To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials.
Methods:
We used data from the Alzheimer's Disease Neuroimaging Initiative study consisting of CN, aMCI, and AD cohorts with both baseline and 12-month follow-up CSF and MRI. The annual change in CSF (total-tau [t-tau], Aβ1-42) and MRI (change in ventricular volume) was obtained in 312 subjects (92 CN, 149 aMCI, 71 AD).
Results:
There was no significant average annual change in either CSF biomarker in any clinical group except t-tau in CN; moreover, the annual change did not differ by clinical group in pairwise comparisons. In contrast, annual increase in ventricular volume increased in the following order, AD > aMCI > CN, and differences were significant between all clinical groups in pairwise comparisons. Ventricular volume increase correlated with concurrent worsening on cognitive/functional indices in aMCI and AD whereas evidence of a similar correlation with change in CSF measures was unclear. The annual changes in MRI differed by APOE ε4 status overall and among aMCI while annual changes in CSF biomarkers did not. Estimated sample sizes for clinical trials are notably less for MRI than the CSF or clinical measures.
Conclusions:
Unlike the CSF biomarkers evaluated, changes in serial structural MRI are correlated with concurrent change on general cognitive and functional indices in impaired subjects, track with clinical disease stage, and are influenced by APOE genotype.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Assessment Scale–cognitive subscale;
= Alzheimer's Disease Neuroimaging Initiative;
= amnestic mild cognitive impairment;
= area under the receiver operator characteristic curve;
= boundary shift integral;
= Clinical Dementia Rating–sum of boxes;
= cognitively normal;
= Mini-Mental State Examination;
= neurofibrillary tangle;
= neuropil thread;
= Pittsburgh compound B;
= total-tau.
doi:10.1212/WNL.0b013e3181e7ca82
PMCID: PMC2905929  PMID: 20625167
24.  Outcomes of mild cognitive impairment depend on definition: a population study 
Archives of neurology  2011;68(6):761-767.
Objective
To determine the one-year outcomes of individuals classified as having mild cognitive impairment (MCI) by different definitions at the population level.
Design
Inception cohort, one-year followup. Participants classified as MCI using the following definitions operationalized for this study: Amnestic MCI by Mayo criteria, Expanded MCI by International Working Group criteria, Clinical Dementia Rating (CDR)=0.5, and a purely cognitive classification into Amnestic and Non-amnestic MCI.
Setting
General community.
Participants
Stratified random population-based sample of 1982 individuals aged 65+ years.
Main Outcome Measures
For each MCI definition, three outcomes: worsening ( progression to dementia (CDR≥1) or severe cognitive impairment); improvement (reversion to CDR=0 or normal cognition); and stability (unchanged CDR or cognitive status).
Results
Regardless of MCI definition, over one year, a small proportion progressed to CDR ≥ 1 (range 0–3%) or severe cognitive impairment (0–20%) at rates higher than their cognitively normal peers. Somewhat larger proportions improved or reverted to normal (6–53%). The majority remained stable (29–88%). Where definitions focused on memory impairment, and on multiple cognitive domains, higher proportions progressed and lower proportions reverted on CDR.
Conclusion
MCI as ascertained by several operational definitions is a heterogeneous entity at the population level but progresses to dementia at rates higher than in normal elderly. Proportions progressing to dementia are lower, and proportions reverting to normal are higher, than in clinical populations. Memory impairments and impairments in multiple domains lead to greater progression and lesser improvement. Research criteria may benefit from validation at the community level before incorporation into clinical practice.
doi:10.1001/archneurol.2011.101
PMCID: PMC3135309  PMID: 21670400
aging; community; population; epidemiology; MCI; dementia
25.  Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration? 
Neurology  2010;75(24):2212-2220.
Objective:
To determine whether TDP-43 type is associated with distinct patterns of brain atrophy on MRI in subjects with pathologically confirmed frontotemporal lobar degeneration (FTLD).
Methods:
In this case-control study, we identified all subjects with a pathologic diagnosis of FTLD with TDP-43 immunoreactive inclusions (FTLD-TDP) and at least one volumetric head MRI scan (n = 42). In each case we applied published criteria for subclassification of FTLD-TDP into FTLD-TDP types 1-3. Voxel-based morphometry was used to compare subjects with each of the different FTLD-TDP types to age- and gender-matched normal controls (n = 30). We also assessed different pathologic and genetic variants within, and across, the different types.
Results:
Twenty-two subjects were classified as FTLD-TDP type 1, 9 as type 2, and 11 as type 3. We identified different patterns of atrophy across the types with type 1 showing frontotemporal and parietal atrophy, type 2 predominantly anterior temporal lobe atrophy, and type 3 predominantly posterior frontal atrophy. Within the FTLD-TDP type 1 group, those with a progranulin mutation had significantly more lateral temporal lobe atrophy than those without. All type 2 subjects were diagnosed with semantic dementia. Subjects with a pathologic diagnosis of FTLD with motor neuron degeneration had a similar pattern of atrophy, regardless of whether they were type 1 or type 3.
Conclusions:
Although there are different patterns of atrophy across the different FTLD-TDP types, it appears that genetic and pathologic factors may also affect the patterns of atrophy.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Research Center;
= behavioral variant frontotemporal dementia;
= corticobasal syndrome;
= Clinical Dementia Rating scale sum of boxes;
= frontotemporal lobar degeneration;
= frontotemporal lobar degeneration with motor neuron degeneration;
= frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions;
= Mini-Mental State Examination;
= neuronal cytoplasmic inclusion;
= progressive nonfluent aphasia;
= semantic dementia;
= Short Test of Mental Status;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e31820203c2
PMCID: PMC3013590  PMID: 21172844

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