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1.  Dissociation of Neuropathologic Findings and Cognition 
Archives of Neurology  2007;64(8):1193-1196.
The apolipoprotein E (APOE) ε2 allele has been suggested as having a protective effect and delaying the age at onset of Alzheimer disease.
To describe a dissociation between findings neuropathologic with normal cognition in a woman with severe Alzheimer disease with the APOE ε2/ε2 genotype.
Case report from a community based prospective study of persons 90 years or older (The 90+ Study).
A 92-year-old woman without dementia with the APOE ε2/ε2 genotype who lived independently without significant cognitive or functional loss and was a participant in The 90+ Study. She died in December 2004, and postmortem examination of her brain was performed.
Neurologic examination and a battery of neuropsychological tests were performed 6 months and 1 month before death. Neuropathologic examination included Braak and Braak staging for senile plaques and neurofibrillary tangles.
Neuropathologic examination of the brain revealed advanced senile plaque and neurofibrillary tangle disease consistent with a high likelihood of Alzheimer disease. At clinical evaluation, the participant demonstrated no dementia and only mild cognitive deficits.
The APOE genotype may have contributed to maintenance of cognition despite advanced neuropathologic findings of Alzheimer disease. This case suggests that the APOE ε2 isoform may have a protective effect against cognitive decline in Alzheimer disease that may be independent from senile plaques and neurofibrillary tangles.
PMCID: PMC3378248  PMID: 17698712
2.  Three-Dimensional Gray Matter Atrophy Mapping in Mild Cognitive Impairment and Mild Alzheimer Disease 
Archives of neurology  2007;64(10):1489-1495.
Alzheimer disease (AD) is the most common form of dementia worldwide. Mild cognitive impairment (MCI) is the recent terminology for patients with cognitive deficiencies in the absence of functional decline. Most patients with MCI harbor the pathologic changes of AD and demonstrate transition to dementia at a rate of 10% to 15% per year. Patients with AD and MCI experience progressive brain atrophy.
To analyze the structural magnetic resonance imaging data for 24 patients with amnestic MCI and 25 patients with mild AD using an advanced 3-dimensional cortical mapping technique.
Cross-sectional cohort design.
We analyzed the structural magnetic resonance imaging data of 24 amnestic MCI (mean MMSE, 28.1; SD, 1.7) and 25 mild AD patients (all MMSE scores, >18; mean MMSE, 23.7; SD, 2.9) using an advanced 3-dimensional cortical mapping technique.
We observed significantly greater cortical atrophy in patients with mild AD. The entorhinal cortex, right more than left lateral temporal cortex, right parietal cortex, and bilateral precuneus showed 15% more atrophy and the remainder of the cortex primarily exhibited 10% to 15% more atrophy in patients with mild AD than in patients with amnestic MCI.
There are striking cortical differences between mild AD and the immediately preceding cognitive state of amnestic MCI. Cortical areas affected earlier in the disease process are more severely affected than those that are affected late. Our method may prove to be a reliable in vivo disease-tracking technique that can also be used for evaluating disease-modifying therapies in the future.
PMCID: PMC3197839  PMID: 17923632
3.  Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations 
Archives of neurology  2007;64(3):371-376.
Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families.
To determine whether there is a difference in the patterns of atrophy in cases with FTLD-U with and without a mutation in PGRN.
Case control study
Brain bank of a tertiary care medical center
All subjects that had screened positive for mutations in PGRN and had a volumetric MRI were identified (n=8, PGRN (+)). Subjects were then matched by clinical diagnosis to a group of eight subjects with a pathological diagnosis of FTLD-U that had screened negative for mutations in PGRN (PGRN (−)). All subjects were then age and gender-matched to a control subject.
Main outcome Measures
Voxel-based morphometry was used to assess the patterns of grey matter atrophy in the PGRN (+) and (−) groups compared to controls, and compared to each other.
The PGRN (+) group showed a widespread and severe pattern of grey matter loss predominantly affecting the frontal, temporal and parietal lobes. In comparison, the PGRN (−) group showed a less severe pattern of loss restricted mainly to the temporal and frontal lobes. On direct comparison the PGRN (+) group showed greater loss in the frontal and parietal lobes compared to the PGRN (−) group.
This study suggests that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.
PMCID: PMC2752412  PMID: 17353379
Frontotemporal dementia; Voxel-based morphometry; Ubiquitin; Dentate; Progranulin
4.  Patterns of Atrophy differ among Specific Subtypes of Mild Cognitive Impairment 
Archives of neurology  2007;64(8):1130-1138.
To investigate patterns of cerebral atrophy associated with specific subtypes of mild cognitive impairment (MCI).
Case-control study
Community-based sample at a tertiary referral center
One hundred and forty-five subjects with MCI subjects and 145 age and gender-matched cognitively normal controls. MCI subjects were classified as amnestic single cognitive domain, amnestic multi-domain, non-amnestic single-domain and non-amnestic multi-domain MCI. The non-amnestic single-domain subjects were also divided into language, attention/executive, and visuospatial groups based on the specific cognitive impairment.
Main Outcome Measure
Patterns of grey matter loss in the MCI groups compared to controls assessed using voxel-based morphometry
The amnestic single and multi-domain groups both showed loss in the medial and inferior temporal lobes compared to controls, while the multi-domain group also showed involvement of the posterior temporal lobe, parietal association cortex and posterior cingulate. The non-amnestic single-domain subjects with language impairment showed loss in the left anterior inferior temporal lobe. The group with attention/executive deficits showed loss in the basal forebrain and hypothalamus. No coherent patterns of loss were observed in the other subgroups.
The pattern of atrophy in the amnestic groups is consistent with the concept that MCI in most of these subjects represents prodromal AD. However, the different patterns in the language and attention/executive groups suggest that these subjects may have a different underlying disorder.
PMCID: PMC2735186  PMID: 17698703
Archives of neurology  2007;64(6):873-877.
Frontotemporal dementia (FTD) is a clinical subtype of frontotemporal lobar degeneration in which patients show impairment of interpersonal conduct and social behavior. In vivo MRI structural analyses of FTD patients using voxel-based morphometry or conventional volumetric measures have confirmed gray matter (GM) loss in the frontal and temporal regions.
In this study, our goal was to compare deformation based maps of local anatomical size between FTD and healthy subjects, to identify regions of the brain involved in FTD.
Structural MRIs were obtained from 22 subjects with FTD and 22 cognitively normal (CN) age-matched controls. We applied deformation based morphometry and compared anatomy between groups using an ANCOVA model that included a categorical variable denoting group membership and covaried for head size.
FTD patients showed extensive, significant atrophy of the frontal lobes, affecting both GM and WM. Atrophy of similar magnitude but less significance was observed in the anterior temporal lobes. The subcortical and midbrain regions, particularly the thalamus, pons, and superior and inferior colliculi, showed strongly significant atrophy of smaller magnitude.
We confirmed frontal and anterior temporal GM atrophy in FTD. The observed WM loss, thalamic involvement, and midbrain atrophy are consistent with pathological findings in late stage FTD. Dysfunction of ventral frontal-brainstem circuitry may underlie some of the unique clinical features of FTD.
PMCID: PMC2733361  PMID: 17562936
6.  Disruptive Behavior as a Predictor in Alzheimer Disease 
Archives of neurology  2007;64(12):1755-1761.
Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality.
To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD.
Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a time-dependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use.
Five university-based AD centers in the United States and Europe (Predictors Study).
Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years.
Main Outcome Measures
Cognitive (Columbia Mini-Mental State Examination score, ≤ 20 of 57 [approximate Folstein Mini-Mental State Examination score, ≤ 10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, ≥ 10) ratings, institutionalization equivalent index, and death.
At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03–2.03]), functional decline (1.66 [95% CI, 1.17–2.36]), and institutionalization (1.47 [95% CI, 1.10–1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71–1.25]).
Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.
PMCID: PMC2690610  PMID: 18071039
7.  Hypertension and the Risk of Mild Cognitive Impairment 
Archives of neurology  2007;64(12):1734-1740.
Background and Objective
There are conflicting data relating hypertension to the risk of Alzheime's disease (AD). We sought to explore whether hypertension is associated with the risk of mild cognitive impairment (MCI), an intermediate stage to dementia.
Design and Setting
Prospective community-based cohort study conducted in northern Manhattan.
Multivariate proportional hazards regression analyses, relating hypertension to incident all-cause MCI, amnestic MCI, and non-amnestic MCI in 918 persons without prevalent MCI at baseline followed for a mean of 4.7 years.
There were 334 cases of incident MCI, 160 cases of amnestic MCI and 174 cases of non-amnestic MCI during 4337 person years of follow-up. Hypertension was associated with an increased risk of all-cause MCI (HR 1.4, 95% CI 1.06-1.77, p=0.02) and non-amnestic MCI (HR 1.7, 95% CI 1.13-2.42, p=0.009) after adjusting for age and gender. Both associations were slightly attenuated in models additionally adjusting for stroke and other vascular risk factors. There was no association between hypertension and the risk of amnestic MCI (HR 1.1, 95% CI 0.79-1.63, p=0.49). Consistent with this association, hypertension was related with the slope of change in an executive ability score, but not with memory or language scores. There was no effect modification of the association between hypertension and MCI by APOEε4 genotype or use of antihypertensive medication.
A history of hypertension is related to a higher risk of MCI. The association seems to be stronger with the non-amnestic than the amnestic component of MCI. These findings suggest that prevention and treatment of hypertension may have an important impact in lowering the risk of cognitive impairment.
PMCID: PMC2672564  PMID: 18071036
blood pressure; hypertension; mild cognitive impairment
8.  The Association Between Genetic Variants in SORL1 and Alzheimer’s Disease in an Urban, Multiethnic, Community-Based Cohort 
Archives of neurology  2007;64(4):501-506.
Variants in 3′ and 5′ regions of SORL1, the neuronal sorting protein-related receptor, were recently found to be associated with late onset familial and sporadic Alzheimer’s disease in several datasets that were selected for familial aggregation or were ethnically diverse or clinic-based selected series.
To investigate the association between Alzheimer’s disease and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic community-based population.
Design & Setting
We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan.
There were 296 patients with probable Alzheimer’s disease and 428 healthy elderly controls. The participants were of African American (34%), Caribbean Hispanic (51%) or non-Hispanic whites (15%).
Main Outcome Measures
We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods which included APOE genotype as a covariate.
Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with Alzheimer’s disease. SNP 12 near the 5′ region was associated with AD in African-Americans and Hispanics. Two SNPs in the 3′ region were also associated with AD in African-Americans (SNP 26) and Whites (SNP 20). A single haplotype in the 3′ region was associated with AD in Hispanics. However, several different haplotypes were associated with AD in the African-Americans and Whites, including the “TTC” haplotypes at SNPs 23–25 (p=0.035) that was significantly associated with AD in the North European Whites in the previous report.
This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these datasets overlap with those previously reported, the finding of novel SNP and haplotype associations suggest that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
PMCID: PMC2639214  PMID: 17420311
SORL1; Alzheimer’s disease; sporadic; African American; Caribbean Hispanic
9.  The New Neurobiology of Autism 
Archives of neurology  2007;64(7):945-950.
This review covers a fraction of the new research developments in autism but establishes the basic elements of the new neurobiologic understanding of autism. Autism is a polygenetic developmental neurobiologic disorder with multiorgan system involvement, though it predominantly involves central nervous system dysfunction. The evidence supports autism as a disorder of the association cortex, both its neurons and their projections. In particular, it is a disorder of connectivity, which appears, from current evidence, to primarily involve intrahemispheric connectivity. The focus of connectivity studies thus far has been on white matter, but alterations in functional magnetic resonance imaging activation suggest that intracortical connectivity is also likely to be disturbed. Furthermore, the disorder has a broad impact on cognitive and neurologic functioning. Deficits in high-functioning individuals occur in processing that places high demands on integration of information and coordination of multiple neural systems. Intact or enhanced abilities share a dependence on low information-processing demands and local neural connections. This multidomain model with shared characteristics predicts an underlying pathophysiologic mechanism that impacts the brain broadly, according to a common neurobiologic principle. The multiorgan system involvement and diversity of central nervous system findings suggest an epigenetic mechanism.
PMCID: PMC2597785  PMID: 17620483
10.  Elevated plasma amyloid β-peptide Aβ42, incident dementia and mortality in Down syndrome 
Archives of neurology  2007;64(7):1007-1013.
Deposition of the amyloid beta peptide, Aβ42, is thought to be an important initial step in the pathogenesis of Alzheimer’s disease. Individuals with Down syndrome have both increased levels of Aβ peptides and increased risk for Alzheimer’s disease.
To examine the relation of plasma levels of Aβ42 and Aβ40 to risk of dementia in nondemented participants and to all-cause mortality in adults with Down syndrome.
Prospective, community-based longitudinal cohort study.
State and voluntary service providers in New York State
Adults with Down syndrome (N=204).
Plasma Aβ42 and Aβ40 levels were measured at initial examination. Participants were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, health and vital status at 14–18 month intervals over four cycles of data collection.
Among participants who were nondemented at baseline, those in the middle and highest tertiles of plasma Aβ42 levels were over 2 times as likely to develop AD as those in the lowest tertile. Compared with participants without AD, participants with prevalent AD had higher levels of plasma Aβ42 but not Aβ40. Among all participants, those in the highest tertile of plasma Aβ42 level at baseline were over twice as likely to die over the study period as those in the lowest tertile, while there was no difference in risk of death between those in the middle and lowest tertile of plasma Aβ42 level.
Elevations in plasma Aβ42 peptide are associated with earlier onset of AD and increased risk of death.
PMCID: PMC2587094  PMID: 17620492
Beta amyloid 1–42; Down syndrome; Alzheimer’s disease; blood plasma
11.  Patterns of White Matter Atrophy in Frontotemporal Lobar Degeneration 
Archives of neurology  2007;64(11):1619-1624.
Structural magnetic resonance imaging (MRI) has been used to investigate the in vivo pathology of frontotemporal lobar degeneration. However, few neuroimaging studies have focused on white matter (WM) alterations in this disease.
To use volumetric MRI techniques to identify the patterns of WM atrophy in vivo in 2 clinical variants of frontotemporal lobar degeneration—fronto-temporal dementia (FTD) and semantic dementia—and to compare the patterns of WM atrophy with those of gray matter (GM) atrophy in these diseases.
Structural MRIs were obtained from patients with FTD (n=12) and semantic dementia (n=13) and in cognitively healthy age-matched controls (n=24). Regional GM and WM were classified automatically from high-resolution T1-, T2-, and proton density-weighted MRIs with Expectation-Maximization Segmentation and compared between the groups using a multivariate analysis of covariance model that included age and WM lesion volumes as covariates.
Patients with FTD had frontal WM atrophy and frontal, parietal, and temporal GM atrophy compared with controls, who had none. Patients with semantic dementia had temporal WM and GM atrophy and patients with FTD had frontal GM atrophy. Adding temporal WM volume to temporal GM volume significantly improved the discrimination between semantic dementia and FTD.
These results show that patients with frontotemporal lobar degeneration who are in relatively early stages of the disease (Clinical Dementia Rating score, 1.0-1.2) have WM atrophy that largely parallels the pattern of GM atrophy typically associated with these disorders.
PMCID: PMC2443735  PMID: 17998444
12.  Measures of adiposity and dementia risk in the elderly 
Archives of neurology  2007;64(3):392-398.
Studies relating adiposity to dementia are conflicting. We explored the associations of body mass index (BMI) waist circumference (WC), and weight change to dementia, probable Alzheimer’s disease (AD), and dementia associated with stroke (DAS).
Persons without dementia were followed for 5 years; 893 persons had BMI, 907 persons had WC, and 709 persons had a second weight measurement. Dementia was ascertained using standard methods. Cox regression was used for analyses using follow-up as time-to-event, adjusting for demographics, and APOE-ɛ4.
Compared to persons in the first quartile of BMI, persons in the third quartile had a lower dementia and AD risk, and persons in the second quartile had a lower DAS risk. The association between BMI and dementia resembled a U-shape in those < 76 years, while dementia risk decreased with higher BMI in those ≥ 76 years. The 4th quartile of WC was related to a higher DAS risk in the whole sample, and to dementia and AD in persons < 76 years. Weight loss was related to a higher dementia and DAS risk, and weight gain was related to a higher DAS risk only.
The prospective association between adiposity and dementia differs depending on the anthropometric measure used and is modified by age. This may explain previous conflicting reports.
PMCID: PMC1821350  PMID: 17353383

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