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issn:0003-99.2
1.  Antioxidants for Alzheimer Disease 
Archives of neurology  2012;69(7):836-841.
Objective
To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers.
Design
Double-blind, placebo-controlled clinical trial.
Setting
Academic medical centers.
Participants
Subjects with mild to moderate Alzheimer disease.
Intervention
Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo.
Main Outcome Measures
Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale).
Results
Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau181 levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups.
Conclusions
Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted.
Trial Registration
clinicaltrials.gov Identifier: NCT00117403
PMCID: PMC3661272  PMID: 22431837
2.  Ecology of aging human brain 
Archives of neurology  2011;68(8):1049-1056.
OBJECTIVE
Alzheimer’s disease (AD), cerebral vascular brain injury (VBI), and isocortical Lewy body (LB) disease (LBD) are the major contributors to dementia in community- or population-based studies: Adult Changes in Thought (ACT) study, Honolulu-Asia Aging Study (HAAS), Nun Study (NS), and Oregon Brain Aging Study (OBAS). However, the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults is less clear.
DESIGN and SETTING
We evaluated 1672 brain autopsies from ACT, HAAS, NS, and OBAS of which 424 met criteria for CN.
MAIN OUTCOME MEASURES
Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque (NP) density, Braak stage for neurofibrillary tangles (NFTs), Lewy body (LB) distribution, and number of cerebral microinfarcts (CMIs).
RESULTS
47% of CN cases had moderate or frequent NP density; of these 6% also had Braak stage V or VI for NFTs. 15% of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any CMIs was identified in 33% and high level CMIs in 10% of CN individuals. Overall burden of lesions in each individual and their co-morbidity varied widely within each study but were similar among studies.
CONCLUSIONS
These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker or neuroimaging studies as well as clinical trials that focus on community- or population-based cohorts.
doi:10.1001/archneurol.2011.157
PMCID: PMC3218566  PMID: 21825242
Alzheimer’s disease; vascular brain injury; Lewy body disease; cognitive aging
3.  Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment 
Archives of neurology  2011;68(6):743-752.
Objective
To compare the effects of a 4-week high–saturated fat/high–glycemic index (HIGH) diet with a low–saturated fat/low–glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI).
Design
Randomized controlled trial.
Setting
Veterans Affairs Medical Center clinical research unit.
Participants
Forty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years).
Intervention
Participants received the HIGH diet (fat, 45% [saturated fat, >25%]; carbohydrates, 35%–40% [glycemic index, >70]; and protein, 15%–20%) or the LOW diet (fat, 25%; [saturated fat, <7%]; carbohydrates, 55%–60% [glycemic index, <5]; and protein, 15%–20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet.
Main Outcome Measures
The CSF concentrations of β-amyloid (Aβ42 and Aβ40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition.
Results
For the aMCI group, the LOW diet increased CSF Aβ42 concentrations, contrary to the pathologic pattern of lowered CSF Aβ42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Aβ42, whereas the HIGH diet increased CSF Aβ42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet.
Conclusion
Our results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of Aβ42, lipoproteins, oxidative stress, and insulin.
doi:10.1001/archneurol.2011.125
PMCID: PMC3175115  PMID: 21670398
4.  Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment 
Archives of Neurology  2011;69(1):29-38.
Objective
To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).
Design
Randomized, double-blind, placebo-controlled trial.
Setting
Clinical research unit of a Veterans Affairs medical center.
Participants
The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40).
Intervention
Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).
Main Outcome Measures
Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease’s Assessment Scale–cognitive subscale (ADAS-cog) score and the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.
Results
Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein–to–Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.
Conclusions
These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD.
doi:10.1001/archneurol.2011.233
PMCID: PMC3260944  PMID: 21911655
5.  Meta-Analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes 
Archives of neurology  2010;67(12):1473-1484.
Objectives
To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.
Design
Association study of AD and CLU, PICALM, CR1 and APOE genotypes.
Setting
Academic research institutions in the United States, Canada, and Israel.
Participants
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Results
Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.
Conclusions
We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.
doi:10.1001/archneurol.2010.201
PMCID: PMC3048805  PMID: 20697030
6.  The Spectrum of Mutations in Progranulin 
Archives of neurology  2010;67(2):161-170.
Background
Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations.
Objectives
To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants.
Design
Case-control study.
Setting
Clinical and neuropathology dementia research studies at 8 academic centers.
Participants
Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease.
Main Outcome Measures
Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays.
Results
We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history.
Conclusions
Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.
doi:10.1001/archneurol.2009.328
PMCID: PMC2901991  PMID: 20142524
7.  Different Patterns of Cerebral Injury in Dementia with or Without Diabetes 
Archives of neurology  2009;66(3):315-322.
Background
Diabetes mellitus (DM) increases the risk of dementia in the elderly. However the underlying mechanisms, its connection with Alzheimer's disease (AD) and vascular cognitive impairment (VCI), and effects of therapy remain unclear.
Objective
To test the hypothesis that DM promotes specific neuropathologic processes that contribute to dementia and that these processes may be suppressed by antidiabetic therapy.
Design
A comprehensive neuropathologic assessment of all cases from a community-based study of incident dementia (Adult Changes in Thought study) that underwent autopsies (n=259) and had information on DM status (n=196). Biochemical analysis was conducted on a subset of these cases with rapidly frozen brain tissue (n=57).
Participants
Autopsy cases were divided into four groups: no DM/no dementia (DM−/dementia−), DM/no dementia (DM+/dementia−), no DM/dementia (DM−/dementia+), and DM/dementia (DM+/ dementia+). Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of dementia was assigned through a consensus of experts following biennial cognitive and physical evaluations. Diabetes was diagnosed based on information obtained from participants’ extensive medical records.
Results
In cases without dementia (n=125), neuropathologic or biochemical endpoints did not differ significantly by DM status. However, we observed 2 patterns of injury in patients with dementia (n=71) by their DM status. Individuals without DM, but with dementia (DM−/dementia+) had greater Aβ peptide load and increased F2-isoprostanes in the cerebral cortex, while DM+/dementia+ patients had more microvascular infarcts (MVI) and an increased cortical IL-6 (interleukin 6) concentration. The number of microvascular infarcts was greater in deep cerebral structures in patients with dementia whose diabetes was treated, whereas amyloid plaque load tended to be greater for untreated diabetic patients with dementia.
Conclusions
These novel characterizations of 2 different patterns of cerebral injury in patients with dementia depending on DM status may have etiologic and therapeutic implications.
doi:10.1001/archneurol.2008.579
PMCID: PMC2766529  PMID: 19139294
8.  Lewy Body Pathology in Familial Alzheimer Disease 
Archives of neurology  2006;63(3):370-376.
Background
The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood.
Objective
To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes.
Methods
Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using α-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions.
Results
The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP.
Conclusion
These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.
doi:10.1001/archneur.63.3.370
PMCID: PMC1892620  PMID: 16533963

Results 1-8 (8)