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1.  LDL Phenotype in Subjects with Mild Cognitive Impairment and Alzheimer’s Disease 
Background
Centenarians with normal cognitive function have a “longevity phenotype” characterized by large low-density lipoproteins (LDL) and high-density lipoproteins (HDL) and low incidence of metabolic syndrome, hypertension, and cognitive impairment. Alzheimer’s disease (AD) is associated with a number of cardiovascular risk factors, but it is not known if they have or lack the “longevity phenotype”.
Objective
The study was designed to determine LDL size and body fat content and distribution in subjects with mild cognitive impairment (MCI) and AD.
Results
Fifty-eight persons with MCI or AD (cases) and 42 control subjects of similar age had measurement of LDL size and lipoprotein lipids after a 12 h fast and analysis of body composition by dual x-ray absorptiometry. Cases had small LDL size more often than controls (73% versus 66%) associated with significantly higher triglycerides, lower HDL cholesterol, and higher triglyceride/HDL cholesterol ratio (p ≤ 0.02). Cases with large LDL had a better lipoprotein profile than those with small LDL. Cases and controls had similar percent body fat, fat index, and lean mass index. Forty-seven percent of cases and 39% of controls were obese.
Conclusion
The prevalence of small LDL phenotype in MCI and AD cases contrasts with the “longevity phenotype” reported for centenarians with preserved cognitive function. The small LDL phenotype is an atherogenic lipoprotein profile found in metabolic syndrome, type 2 diabetes, and insulin resistance. It is now also reported in persons with MCI and AD.
doi:10.3233/JAD-130443
PMCID: PMC4082186  PMID: 23635406
Atherogenic dyslipidemia; longevity phenotype; small LDL
2.  Leptin and Cognition 
Background
Leptin has been reported to have positive effects on cognition but has not been studied in a population-based sample or stratified by race or gender.
Methods
Leptin and fat mass were measured in 2731 subjects, including 50% African Americans. Eight years later, subjects completed a cognitive assessment. Demographic factors and baseline measures, including leptin deficient or in excess of what was predicted by fat, were investigated to see which predicted cognitive performance.
Results
There was a statistical trend for lower leptin levels to be associated with higher cognitive scores. Once stratified by race and gender, excessive leptin was associated with lower scores and word recall for black men but white men demonstrated an opposite effect.
Conclusion
Excess leptin appears to have differential effects on recall in black and white men.
doi:10.1159/000339956
PMCID: PMC3732374  PMID: 22814193
3.  Lipids and Adipokines as Risk Factors for Alzheimer’s Disease 
To determine if measures of adipokines and other blood lipids differentiate between normal controls (NC) and persons with Alzheimer’s disease (AD), we examined levels of leptin, adiponectin, total cholesterol, high density lipoproteins (HDL), calculated low density lipoproteins (LDL), triglycerides and apolipoprotein E allele status in 196 early AD subjects and 198 normal controls. We were unable to demonstrate a significant difference between leptin and adiponectin levels between NC and AD subjects. We were able to confirm observations of others of lower HDL and higher LDL cholesterol concentration in AD subjects than in controls. As expected, the presence of the apolipoprotein E4 allele distinguished between the two groups.
doi:10.3233/JAD-2012-111385
PMCID: PMC3732377  PMID: 22232009
Cholesterol; Leptin; Adiponectin; Alzheimer’s Disease
4.  Videoconference Diagnosis and Management of Choctaw Indian Dementia Patients 
Background
To report a 5-year experience using videoconference (VC) technology to diagnose and treat adult members of the Choctaw Nation with symptoms or complaints of cognitive impairment.
Methods
Patients were given the option of VC or face-to-face clinic. Prior to their VC session, patients underwent neuropsychological testing, Clinical Dementia Rating, Geriatric Depression Scale and Neuropsychiatric Inventory, brain CT, and routine blood tests.
Physical observations made by VC included eyesight, hearing, facial expression, gait and station, coordination, tremor, rapid alternating movements, psychomotor activity, and motor tests of executive function. Cogwheeling and rigidity were tested by our on-site nurse, who also obtains vital signs as indicated.
Results
From January 2005 to March 2010 there 47 clinics, 171 visits, and 85 unique patients. There were 52 new evaluations and 119 follow-up visits. The number of visits ranged from 1–8; length of follow-up ranged from 1 month to 4.5 years. The no-show rate for all VC sessions in 2009 was 3%, and only 2 subjects in 5 years refused further VC visits.
Conclusion
Once cultural barriers are dealt with, VC-based diagnosis and treatment of adults with cognitive disorders who live in remote areas is feasible and well accepted by patients and families.
doi:10.1016/j.jalz.2011.02.006
PMCID: PMC3210436  PMID: 22055972
Videoconferencing; dementia
5.  Plasma 24S-hydroxycholesterol and other oxysterols in acute closed head injury 
Brain Injury  2008;22(7-8):611-615.
Primary objective
To determine if plasma levels of 24S-hydroxycholesterol, the primary catabolite of brain cholesterol, provide a measure of axonal damage in acute brain trauma.
Research design
Determination of plasma 24S-hydroxycholesterol in a series of persons admitted to an intensive care unit for treatment of closed head injury.
Methods and procedures
Levels of 24-S-hydroxycholesterol, 27-hydroxycholesterol, lathosterol and total cholesterol were measured in peripheral blood from 38 persons from 14–55 years of age treated by craniotomy and ventriculostomy for intractable intracerebral hypertension. Severity of brain injury was estimated by the Glasgow Coma Scale (range = 3–13, median = 6 points) and overall injury by the Injury Severity Scale (range = 10–48, median = 29). All subjects were intubated and anaesthetized with intravenous propofol. Plasma sterol levels were compared with those of age-matched control subjects.
Outcomes and results
There was no significant increase in plasma 24-S-hydroxycholesterol in subjects with head injury, but measures of peripheral cholesterol synthesis were markedly reduced as compared with values for age-matched normal control subjects.
Conclusion
Plasma 24S-hydroxycholesterol levels do not change with severe closed head injury.
doi:10.1080/02699050802196037
PMCID: PMC3399688  PMID: 18568715
Closed head injury; 24-S-hydroxycholesterol; oxysterols
6.  Language in Alzheimer's Disease 
The Journal of clinical psychiatry  2008;69(8):1223-1227.
Objective
To ascertain the clinical utility of language examination by psychiatrists in evaluating Alzheimer's disease (AD) patients.
Method
Data collected between 1986 and 2003 from a standardized psychiatric examination and neuropsychological testing of probable AD patients (diagnosed according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) were gathered from the database of the University of Texas Southwestern Alzheimer's Disease Center, Dallas. The variables studied were articulation, word-finding ability, hypofluency, hyperfluency, repetition, confrontational naming, and semantic (category) fluency Articulation, word-finding ability, hypofluency, hyperfluency, repetition, and confrontational naming were rated as normal or abnormal. Semantic fluency was scored numerically as the number of animals named in a minute. Cognitive impairment was assessed with the Mini-Mental State Examination (MMSE) and global impairment by the Clinical Dementia Rating (CDR) scale.
Results
There was a significant association (p < .0001) between MMSE and CDR scores for all language measures except hyperfluency. The MMSE scores were higher in the group with responses rated as normal compared to those with abnormal responses. Patients with greater cognitive and global impairment named fewer animals in a minute.
Conclusions
Abnormal articulation and repetition of words were unusual and therefore would not be useful for early detection, but when present, were associated with more advanced disease. Impairment in fluency, animal naming, and confrontational naming were common and increased in frequency with greater cognitive and global impairment. Because animal naming is a numerical measure, changes in the number of animals named in a minute can be used to monitor disease progression.
PMCID: PMC3177322  PMID: 18505305
7.  Atherosclerosis Risk Factors in American Indians With Alzheimer Disease 
Factors predisposing to and associated with atherosclerosis may impact the onset and progression of Alzheimer disease (AD). The high prevalence of atherosclerosis and associated risk factors in American Indians makes them ideal subjects to test this association. We compared frequency of history of hypertension, myocardial infarction, stroke, diabetes, and high cholesterol in 34 American Indians with AD with 34 age-matched American Indian controls, and 34 age-matched whites with probable AD. We also measured waist size, height, and weight, and acquired blood for determination of plasma homocysteine and apolipoprotein E genotype. The 3 groups did not differ significantly in age or sex. History of hypertension and diabetes was significantly more common among American Indian AD patients than Indian controls or whites with AD. The 3 groups did not differ in history of stroke or myocardial infarction. Body mass index was significantly greater in both Indian groups than the white AD group. Plasma homocysteine levels were greater, but not significantly so, in the Indian AD than the Indian control group. Thus, there is preliminary evidence of a modest association between history of hypertension and diabetes and AD in a small sample of American Indians. This suggests that changes in lifestyle factors could influence the expression of AD in American Indians.
doi:10.1097/WAD.0b013e318169d701
PMCID: PMC3176329  PMID: 18580594
atherosclerosis; hypertension; diabetes; homocysteine; Alzheimer disease
8.  Perspective on Race and Ethnicity in Alzheimer’s Disease Research 
There are adequate scientific, public health and ethical justifications for studying Alzheimer disease (AD) in persons of varying race and ethnicity, but to be meaningful variables, race and ethnicity must be examined in context. The complex interactions between race, ethnicity, life style, and environmental factors such as climate and diet, require that future studies of AD in specific racial or ethnic groups attend to measures of racial/ethnic homogeneity and assessment of the environment and the elements that comprise the ethnicity of groups under study. Instead of arbitrarily selecting specific racial or ethnic groups in the hope of finding important differences, it may be in the long run less costly and more efficient to recruit families with highly positive (or negative) family histories, to search within these groups for possible racial or ethnic differences and to then investigate the possible racial or ethnic reasons for those differences.
doi:10.1016/j.jalz.2007.10.016
PMCID: PMC2570194  PMID: 18631972
9.  Impact of an activities-based adult dementia care program 
The investigators studied over one year the impact of a newly established once-a-week activity-based day care program for dementia patients combined with 17 educational sessions for caregivers held at the same facility. Outcome measures were patient and caregiver quality of life (QOL), patient behavioral disturbance, and use of community-based resources. Of the 37 enrollees, 3 chose not to start the program and 13 dropped out before the end of one year, largely due to health-related issues. Of the initial group, 21 attended for the entire year. The average patient Mini-Mental State Exam (MMSE) score at entry was 16, indicating a moderate level of dementia. Average score on the CERAD Behavior Rating Scale for Dementia (BRSD) was 30.1, indicating a mild level of behavioral disturbance. Attendance at day care was 91%; at the caregiver educational sessions, 74%. Patient and caregiver enthusiasm for the program was high and all wanted to continue attendance beyond the study period despite the fact that patients reported no change in QOL. Caregivers rated patients as having significantly less QOL, and rated their own QOL as unchanged. Symptomatic patient behaviors, as measured by the BRSD, increased significantly over the period of study. Caregivers reported greater use of community resources.
PMCID: PMC2413197  PMID: 18568062
dementia; day care; quality of life; CERAD Behavior Rating Scale
10.  The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia 
Annals of internal medicine  2013;158(3):162-168.
Background
Primary prevention of Alzheimer disease and other types of dementia (all-cause dementia) is an important public health goal. Evidence to date is insufficient to recommend any lifestyle change to prevent or delay the onset of dementia.
Objective
To assess the association between objectively measured midlife cardiorespiratory fitness (“fitness”) levels and development of all-cause dementia in advanced age.
Design
Prospective, observational cohort study.
Setting
Preventive medicine clinic.
Patients
19 458 community-dwelling, nonelderly adults who had a baseline fitness examination.
Measurements
Fitness levels, assessed using the modified Balke treadmill protocol between 1971 and 2009, and incident all-cause dementia using Medicare Parts A and B claims data from 1999 to 2009.
Results
1659 cases of incident all-cause dementia occurred during 125 700 person-years of Medicare follow-up (median follow-up, 25 years [interquartile range, 19 to 30 years]). After multivariable adjustment, participants in the highest quintile of fitness level had lower hazard of all-cause dementia than those in the lowest quintile (hazard ratio, 0.64 [95% CI, 0.54 to 0.77]). Higher fitness levels were associated with lower hazard of all-cause dementia with previous stroke (hazard ratio, 0.74 [CI, 0.53 to 1.04]) or without previous stroke (hazard ratio, 0.74 [CI, 0.61 to 0.90]).
Limitations
Dementia diagnoses were based on Medicare claims, and participants generally were non-Hispanic white, healthy, and well-educated and had access to preventive health care. This study evaluated fitness levels, so a specific exercise prescription cannot be generated from results and the findings may not be causal.
Conclusion
Higher midlife fitness levels seem to be associated with lower hazards of developing all-cause dementia later in life. The magnitude and direction of the association were similar with or without previous stroke, suggesting that higher fitness levels earlier in life may lower risk for dementia later in life, independent of cerebrovascular disease.
doi:10.7326/0003-4819-158-3-201302050-00005
PMCID: PMC3926646  PMID: 23381040
11.  Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer’s disease: Preliminary report 
Journal of Alzheimer's disease : JAD  2012;31(0 3):S221-S226.
We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer’s disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas we examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls.
doi:10.3233/JAD-2012-120709
PMCID: PMC3749074  PMID: 22886013
Alzheimer’s disease; donepezil; functional connectivity; dorsolateral prefrontal cortex; hippocampus
12.  In reply 
Mayo Clinic Proceedings  2012;87(4):413.
doi:10.1016/j.mayocp.2012.01.011
PMCID: PMC3498166
13.  Luria’s three-step test: what is it and what does it tell us? 
International Psychogeriatrics / Ipa  2011;23(10):1602-1606.
Background
The purpose of this study is to determine if the three-step Luria test is useful for differentiating between cognitive disorders.
Methods
A retrospective record review of performance on the three-step Luria test was conducted on 383 participants from a university-based dementia clinic. The participants ranged in their diagnosis from frontotemporal dementia (FTD; n = 43), Alzheimer disease (AD; n = 153), mild cognitive impairment (MCI; n = 56), and normal controls (NC; n = 131). Performance of the Luria test was graded as normal or abnormal.
Results
An abnormal test occurred in 2.3% of NC, 21.4% of MCI, 69.8% of FTD, and 54.9% of AD subjects. The frequency of abnormal tests in all diagnostic groups increased with functional impairment as assessed by the Clinical Dementia Rating scale (CDR). When CDR = 3 (severe), 100% of the FTD and 72.2% of the AD subjects had abnormal Luria tests.
Conclusions
The three-step Luria test distinguished NC and persons with MCI from FTD and AD, but did not distinguish FTD from AD subjects.
doi:10.1017/S1041610211000767
PMCID: PMC3399685  PMID: 21554794
Luria test; mild cognitive impairment; frontotemporal dementia; Alzheimer’s disease
14.  Association Between Low Serum 25-Hydroxyvitamin D and Depression in a Large Sample of Healthy Adults: The Cooper Center Longitudinal Study 
Mayo Clinic Proceedings  2011;86(11):1050-1055.
OBJECTIVE: To investigate the association between serum vitamin D levels and depression in a large database of patients from the Cooper Clinic.
PATIENTS AND METHODS: We conducted a cross-sectional study of 12,594 participants seen at the Cooper Clinic from November 27, 2006, to October 4, 2010. Serum 25-hydroxyvitamin D [25(OH)D] was analyzed, and depression was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score of 10 or more. Those with and those without a history of depression represented 2 distinct populations with respect to CES-D scores; accordingly, they were analyzed separately.
RESULTS: In the total sample, higher vitamin D levels were associated with a significantly decreased risk [odds ratio, 0.92 (95% confidence interval, 0.87-0.97)] of current depression based on CES-D scores. The finding was stronger in those with a prior history of depression [odds ratio, 0.90 (95% confidence interval, 0.82-0.98)] and not significant in those without a history of depression [odds ratio, 0.95 (95% confidence interval, 0.89-1.02)].
CONCLUSION: We found that low vitamin D levels are associated with depressive symptoms, especially in persons with a history of depression. These findings suggest that primary care patients with a history of depression may be an important target for assessment of vitamin D levels.
doi:10.4065/mcp.2011.0208
PMCID: PMC3202994  PMID: 22033249
15.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
16.  Effect of a Serotonin Reuptake Inhibitor on Irritability, Apathy and Psychotic Symptoms in Patients with Alzheimer’s Disease 
Objective
To ascertain the impact of treatment with citalopram on irritability, apathy, delusions and hallucinations in non-depressed behaviorally disturbed Alzheimer’s disease (AD) patients.
Method
This was a retrospective review of data from the 36-week CATIE trial in which AD patients were treated in a naturalistic manner with placebo, citalopram, risperidone, olanzapine or quetiapine, comparing scores on the Irritability, Apathy, Delusions and hallucinations subscales of the Neuropsychiatric Inventory.
Results
Of the 421 patients enrolled, 34 had been started on placebo and had been later randomized to citalopram treatment. There were data available for 34 subjects who had been on placebo for at least 14 days. In this group there was a 60% reduction in irritability and apathy scores, no effect on score for delusions, and a clinically insignificant drop in score for hallucinations.
Conclusion
The use of citalopram was associated with greatly reduced irritability without sedation in a group of behaviorally disturbed AD patients.
doi:10.4088/JCP.08m04828
PMCID: PMC3236068  PMID: 19422762
Alzheimer disease; serotonin reuptake inhibitor; apathy; irritability; psychosis
17.  Independent contributions of neural and “higher-order” deficits to symptoms in Alzheimer’s disease: A latent variable modeling approach 
Background
Analytic models of Alzheimer’s disease (AD) tend to focus on one type of symptom and assume implicitly that no measurement error is present. These tendencies render changes in symptom domains difficult to model mathematically, although latent variable methods can accommodate both multiple symptom domains and error. This study formulated and compared underlying (latent) factor structures representing previously reported dependence and independence of symptoms of cognitive decline, functional impairment, and behavioral disturbance in AD.
Methods
In confirmatory factor analyses of data from 2 cohorts of AD patients, 2 levels of latent variables were conceptualized. One general neurologic factor represented disease, and symptom factors represented cognition, function, and behavior. Two “null” models had either a single factor or 3 symptom factors. Two 2-level models treated the general factor as underlying both the observed variables and the symptom factors or treated the symptom factors as explaining variability in the observed variables after taking the general factor into account (“residualized”).
Results/Conclusions
The residualized model fit the data in both cohorts significantly better than the other models, and relations in this model between some observed and latent variables were different across cohorts. Neither cohort supported a single factor model; both cohorts independently supported a residualized model that may permit differentiation of symptom- from disease-modifying effects of treatment.
doi:10.1016/j.jalz.2006.08.001
PMCID: PMC3118012  PMID: 19595904
Factor analysis; Statistical; Statistics; Data interpretation; Statistical; Activities of daily living; Cognition disorders; Behavior disorders; Geriatric assessment
18.  FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration 
Acta neuropathologica  2010;120(1):33-41.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
doi:10.1007/s00401-010-0698-6
PMCID: PMC2887939  PMID: 20490813
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
19.  FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration 
Acta Neuropathologica  2010;120(1):33-41.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
doi:10.1007/s00401-010-0698-6
PMCID: PMC2887939  PMID: 20490813
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
20.  High Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer’s Disease: A Randomized Controlled Trial 
Context
Blood levels of homocysteine may be elevated in Alzheimer’s disease (AD), and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B6 and B12. Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess impact on cognitive decline.
Objective
To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.
Design
We conducted a multicenter, randomized, double-blind controlled clinical trial of high-dose folate/B6/B12 supplementation in individuals with AD.
Setting
The study was conducted between March, 2003 and February, 2007 at clinical research sites of the Alzheimer’s Disease Cooperative Study located throughout the US.
Patients
A total of 409 participants (out of 601 screened) with mild to moderate AD (Mini-Mental Status Scores between 14 and 26, inclusive) and normal folic acid, B12 and homocysteine levels were enrolled in this trial; 340 completed the trial on study medication.
Intervention
Participants were randomly assigned to two groups of unequal size: 60% were treated with daily high-dose supplements (folate 5mg, vitamin B6 25mg, vitamin B12 1 mg), and 40% were treated with identical placebo; the duration of treatment was 18 months.
Main Outcome Measure
The primary outcome measure was the change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAScog).
Results
Although the vitamin supplement regimen was effective in reducing homocysteine levels (active −2.42±3.35; placebo -0.86±2.59; p<0.001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-Cog over 18 months (placebo: 0.372 point/month vs active: 0.401 point/month, p-value=0.522, CI of rate difference: (−0.06, 0.12), based on the Generalized Estimating Equations (GEE) model), or on any secondary measures. A higher rate of adverse events involving depression was observed in the group treated with vitamin supplements.
Conclusion
This regimen of high dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.
doi:10.1001/jama.300.15.1774
PMCID: PMC2684821  PMID: 18854539
21.  Brain MRI, Apoliprotein E Genotype, and Plasma Homocysteine in American Indian Alzheimer Disease Patients and Indian Controls 
Current Alzheimer research  2009;6(1):52-58.
We obtained brain MRIs, plasma homocysteine levels and apolipoprotein E genotyping for 11 American Indian Alzheimer disease (AD) subjects and 10 Indian controls. We calculated white matter hyperintensity volume (WMHV), whole brain volume (WBV), and ratio of white matter hyperintensity volume to whole brain volume (WMHV/WBV). There were no significant differences between AD subjects and controls in gender, history of hypertension, diabetes, or history of high cholesterol, but hypertension and diabetes were more common among AD subjects. There was no difference between AD and control groups in age (range for all subjects was 61–89 years), % Indian heritage, waist size or body mass index. Median Indian heritage was 50% or greater in both groups. Range of education was 5–13 years in the AD group and 12–16 years in controls. Median plasma homocysteine concentration was higher in AD subjects (11 μmol/L vs. 9.8 μmol/L), but did not achieve statistical significance. Significantly more AD subjects had apolipoprotein Eε4 alleles than did controls (63% vs.10%). Neuroimaging findings were not significantly different between the 2 groups, but AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far greater range of WMHV. In combined AD subjects and controls, WBV correlated with BMI and age. WMHV and WMHV/WBV correlated inversely with MMSE scores (p = 0.001, 0.002, respectively). In addition, WMHV correlated positively with % Indian heritage (p = 0.047).
PMCID: PMC2752625  PMID: 19199875
Alzheimer disease; American Indian; white matter hyperintensities; homocysteine; apolipoprotein E
22.  Can a Direct IADL Measure Detect Deficits in Persons with MCI? 
Current Alzheimer research  2009;6(1):48-51.
Objective
To determine if a direct measure of instrumental activities of daily living (IADL) scale designed for use with dementia patients can detect differences between persons with mild cognitive impairment (MCI) and normal elderly control subjects (NC).
Methods
This study used cross-sectional and longitudinal IADL scale data from MCI and NC subjects followed at an Alzheimer’s Disease Center.
Results
On a 52-point scale, MCI subjects (n = 30) scored significantly lower than NC subjects (n = 30) on the IADL scale (total score 47.17 vs. 48.77 points; t (58) = 2.34, p = .011) and its Memory subscale (5.27 vs. 6.6 points; t (58) = 3.29, p = .002).Examination of annualized IADL scale change scores revealed that 50% of MCI subjects had declined by one point, compared with 29% of NC.
Conclusion
A direct IADL measure for dementia patients is able to detect small differences between MCI and NC and cross-sectionally and longitudinally, but does not distinguish between groups.
PMCID: PMC2655701  PMID: 19199874
Mild cognitive impairment; IADL; texas functional living scale

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