FNOA: Antioxidants (2011-2012)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To investigate whether the metal pattern in plasma and cerebrospinal fluid (CSF) in patients with Alzheimer's Disease (AD) and AD with vascular components (AD + vasc) differed from healthy controls.

Inclusion Criteria:
  • Patients in the Malmo Alzheimer's Study
  • Clinical diagnosis of Alzheimer's Disease (AD) or AD + vascular components (vascular dementia or mixed dementia)
  • No medical history of kidney disease.
Exclusion Criteria:
  • Participants in the Malmo University Hospital Study who had other forms of dementia or psychiatric diseases that explained cognitive decline
  • Those who had severe AD.
Description of Study Protocol:

Recruitment

  • All subjects were outpatients at the Neuropsychiatric Clinic, Malmo University Hospital, Malmo Sweden
  • Only AD patients showing mild or moderate disease and with a complete investigation, including sampling of CSF, were selected to participate in the study
  • Controls were recruited by advertisements at senior clubs and among relatives of health care personnel
  • Controls were selected by telephone interview and then went through physical and cognitive testing
  • Controls showing mild cognitive impairment, dementia or other mental or physical illness were not included.

Design

Case-control study.

Statistical Analysis
  • Non-parametric statistical processing was applied because most of the variables showed a skewed distribution (Kruskal-Wallis one-way ANOVA, Mann-Whitney U-test, Spearman's correlation coefficients)
  • P-values under 0.05 were regarded as statistically significant (two-tailed tests)
  • To adjust for multiple comparisons, only P-values of up to 0.01 were considered when evaluating the correlation coefficients.
Data Collection Summary:

Timing of Measurements

  • Subjects had gone through a clinical investigation of dementia in 1999 to 2003. No further information on timing was provided.
  • The investigation included anamnestic data, physical and neuropsychiatric exams, tests of cognitive function, blood and cerebrospinal fluid (CSF) sampling, computerized tomography, regional cerebral blood flow, electrocardiogram, blood pressure measurements and routine laboratory tests including the determination of the apolipoprotein E genotype and albumin CSF-to-serum ratio.

Dependent Variables

  • Presence of probable AD, as diagnosed by NINCDS-ADRDA
  • Presence of vascular dementia, as diagnosed by the Diagnostic and Statistical Manual of Mental Disorders form 1994 (DSM-IV) by the American Psychiatric Association.

Independent Variables

Plasma and CSP were analyzed for magnesium, calcium, vanadium, manganese, iron, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, tin, antimony, cesium, mercury and lead.

Description of Actual Data Sample:
  • Initial N: 260 patients with a diagnosis of AD (N=173; 51 males and 122 females) or AD + vascular (N=87; 33 males, 54 females). The Control Group consisted of 54 subjects, 18 males and 36 females.
  • Attrition (final N): All subjects were accounted for. No attrition was reported.
  • Age: The ages of the cases ranged from 52 to 87 (mean, 75 for AD and 76 for AD + vasc) at the onset of the study, while the controls ranged from 60 to 94 (mean, 73 years old)
  • Ethnicity: No information on ethnicity of cases or controls was reported
  • Other relevant demographics: MMSE scores for the AD Group were 22 (two to 30), for the AD + Vasc Group, 22 (six to 30), while the Control Group was 30 (28 to 30). Alzheimer's Disease Assessment scale for cognition scores were 27 (nine to 73) for the AD Group, 30 (10 to 65), for the AD + Vasc Group, and eight (one to 12) for the Control Group.
  • Anthropometrics: No information on anthropometrics of cases or controls was reported
  • Location: Malmo, Sweden.
Summary of Results:

Key Findings

  • The plasma concentrations of manganese and total mercury with significantly higher among subjects with AD (P<0.001) and AD + vasc (P≤0.013), as compared with healthy controls
  • The subjects with AD (P≤0.01) and AD + vasc (P≤0.007) showed significantly lower plasma levels of cobalt, selenium and cesium, when compared with the controls
  • No increases in metal concentrations were observed in the CSF among the patients
  • The levels of vanadium, manganese, rubidium, antimony, cesium and lead were all significantly lower among the subjects with AD (P≤0.010) and AD + vasc (P≤0.047), than in the controls.

Metal Concentrations (Median Values and Ranges) in CSF in Patients with AD, AD + vasc and Controls

Variables

AD
AD + Vasc
Controls
Number
173
87
54
Magnesium (mg/lL)

28 (23-36)

27 (24-34.0)
28 (25-37)
Calcium (mg/lL)
50 (42-67)
50 (43-64)
50 (44-68)
Vanadium (mcg/L)
2.9 (<2.2-5.2)
2.9 (<2.2-5.2)
3.2 (2.3-5.1)
Manganese (mcg/L)
0.61 (0.25-3.4)
0.63 (0.21-2.0)
0.73 (0.41-2.0)
Iron (mg/lL)
0.19 (0.10-0.43)
0.17 (0.11-0.44)
0.23 (0.12-0.40)
Cobalt (mcg/L)
0.08 (<0.03-0.19)
0.07 (0.04-0.16)
0.08 (0.04-0.13)
Nickel (mcg/L)
0.36 (<0.28-3.8)
0.43 (<0.28-2.6)
<0.28 (<0.28-5.4)
Copper (mcg/L)
18 (9.0-109)
18 (8.4-84)
18 (13-35)
Zinc (mcg/L)
17 (9.0-137)
17 (8.4-67)
17 (9.0-167)
Selenium (mcg/L)
1.8 (<0.89-7.7)
1.8 (<0.89-4.8)
1.9 (0.89-3.6)
Rubidium (mg/lL)
67 (138-122)
68 (46-118)
73 (51-116)
Strontium (mcg/L)
14 (5.7-65)
14 (6.4-84)
14 (5.1-33)
Molybdenum (mcg/L)
0.23 (<0.10-1.7)
0.26 (<1.0-1.2)
0.24 (<1.0-0.73)
Cadmium (mcg/L)
<0.04 (<0.04-0.15)
<0.04 (<0.04-0.12)
<0.04 (<0.04-0.08)
Selenium (mcg/L)
0.21 (<0.09-1.9)
0.16 (<0.09-6.3)
0.25 (<0.09-3.4)
Antimony (mcg/L)
<0.02 (<0.02-0.08)
<0.02 (<0.02-0.08)
<0.02 (<0.02-0.17)
Cesium (mcg/L)

0.20 (0.07-0.62)

0.22 (0.11-0.43)

0.28 (0.14-0.62)

Mercury (mcg/L)
<0.21 (<0.21-0.28)
<0.21 (<0.21-1.3)
<0.21 (<0.21-0.30)
Lead (mcg/L)

0.23 (<0.07-5.4)

0.24 (<0.07-5.7)

0.32 (<0.07-4.7)

< denotes undetectable levels.

Background Variables (Median Values and Ranges) and Metal Concentrations (Median Values and Ranges) in Plasma in Patients with AD, AD + vasc and Controls

Variables

AD AD + vasc Controls
Number
173
87
54
Age at onset
72 (47-84)
74 (55-86)
---
Age at time of study
75 (52-86)
76 (57-87)
73 (60-94)
MMSE
22 (2-30)
22 (6-30)
30 (28-30)
ADAS-cog
27 (9-73)
30 (10-65)
8 (1-12)
Mercury (mg/L)
21 (15-19)
21 (13-25)
21 (18-28)
Calcium (mg/L)
97 (83-126)
98 (71-114)
98 (83-142)
Vanadium (mcg/L)
<2.2 (<2.2-3.1)
<2.2 (<2.2-2.7)
<2.2 (<2.2-2.9)
Manganese (mcg/L)
1.5 (0.48-6.0)
1.4 (0.51-4.5)
0.94 (0.63-2.2)
Iron (mg/L)
1.6(0.72-3.2)
1.5 (0.75-2.9)
1.8 (1.0-3.5)
Cobalt (mcg/L)
0.87 (0.14-5.6)
0.80 (0.15-3.8)
1.1 (0.71-1.4)
Nickel (mcg/L)
2.9 (1.4-10.8)
2.7 (1.4-6.6)
2.8 (1.9-4.3)
Copper (mcg/L)
1.2 (0.79-2.2)
1.2 (0.78-2.0)
1.2 (0.81-3.4)
Zinc (mcg/L)
0.87 (0.57-2.5)
0.85 (0.55-1.2)
0.85 (0.53-1.4)
Selenium (mcg/L)
86 (30-158)
87 (43-148)
99 (70-167)
Rubidium (mg/L)
0.29 (0.17-0.48)
0.30 (0.18-0.44)
0.29 (0.22-0.43)
Strontium (mcg/L)
31 (12-166)
30 (15-176)
31 (13-63)
Molybdenum (mcg/L)
1.0 (0.24-15)
1.1 (0.36-2.9)
1.0 (0.38-5.3)
Cadmium (mcg/L)
0.05 (<0.04-0.34)
0.05 (<0.04-0.16)
0.05 (<0.04-0.27)
Selenium (mcg/L)
0.9 (0.17-5.2)
0.81 (0.27-4.9)
0.85 (<0.09-2.4)
Antimony (mcg/L)
6.9 (0.03-11)
6.9 (3.2-10.5)
6.4 (3.5-10)
Cesium (mcg/L)

0.78 (0.36-9.9)

0.77 (0.35-9.0)

0.95 (0.55-3.7)

Mercury (mcg/L)
0.28 (<0.21-2.1)
0.23 (<0.21-1.2)
<0.21 (<0.21-0.41)
Lead (mcg/L)

0.72 (0.11-6.9)

0.59 (0.15-3.4)

0.61 (0.16-5.2)

< denotes undetectable levels
MMSE: Mini Mental State Examination
ADAS-cog: Alzheimer's Disease Assessment Scale for cognition.

Author Conclusion:

The authors conclude that aside from raised plasma mercury concentrations, no consistent metal pattern in plasma or cerebrospinal fluid was observed in patients with Alzheimer's Disease.

Funding Source:
University/Hospital: Sahlgrenska Academy, University Hospital, Goteborg, University Hospital, Lund, Lund University
Reviewer Comments:
  • Groups were not similar
  • There are factors that might affect the plasma or CSF levels of metals, including environmental exposure, occupational exposure, use of medications containing metals, use of mineral supplements, etc. It does not appear that these potential confounding factors were taken into account in this study.
  • The ranges of some metals found in subject and controls was very broad, making this reviewer unclear on how meaningful the median range was. Standard deviation was not reported.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) N/A
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? No
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? No
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? No
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) ???
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? N/A
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes