| Author/Year |
Sample |
Country |
Methodology |
Instruments |
Dimensions evaluated |
Results |
Aim |
| Popp et al., [5] |
N= 289(147 adults with mild cognitive impairment (MCI),105 with ADdementia, 37 controls with normal cognition) |
Germany |
Cross-sectional
Longitudinal observational study |
Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological test battery,Trail-Making TestsA and B,Bayer Activities of DailyLiving Scale,Clinical Dementia Rating Scale,magneticresonance imaging |
Clinical, Neuropsychological, Laboratory |
- Increased baseline CSF cortisol levels in subjects with AD at the MCI stage are associated with faster cognitive decline and progression of dementia severity over time.
- HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline. |
To investigate whether HPA-axis dysregulationoccurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associatedwith clinical disease progression. |
| Gruber et al., [24] |
N= 59 (6 presymptomatic carriers ofmutation conditioning HD, 24 HD, 29 control) |
Poland |
Preliminary studies |
TANITA Body Fat Monitor/Scale TBF-604,Blood sampling,Canonical Discriminant Analysis |
Fat tissue,Muscle mass,Skin temperature, Biochemical profiles (metabolic state and proteinmetabolism) |
- Concerning amino acid profile and biochemical markers, Canonical Discriminant Analysis detected a panel of variables (Ser, Asn, Gln, Orn, Pro, Arg, Met, Cit, Val, TSH, glucose, urea, creatinine clirens, total protein, cortisol, CRP). Asn and Ser were revealed in all statistical analyses and could be considered as potential plasma HD biomarkers |
To determine the profileof the amino acidsprofile in plasma samples fromHD patients and presymptomatic carriers, compared to healthy subjects. |
| Toledo et al., [20] |
N=818 adult subjects (396 MCI,193 probable AD, 229 cognitively normal) |
USA andCanada |
Data were obtained fromthe Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. |
SPARE-AD (Spatial Pattern of Abnormality forRecognition of Early Alzheimer’s disease),Cognitive Test,Biomarker Collection and Analysis,Magnetic resonance imaging (MRI) Processing and Analysis, Positron emissiontomography (PET),Biological markers, Clinical and neuropsychological assessment |
Morphological brain,Blood-based biochemical biomarkers |
- Association between AD-like patterns of brain atrophy, quantified by the SPARE-AD index, and plasma cortisol, CgA, IGFBP-2 and MIP-1a levels.
- Stress and insulin responses and cytokines associated with recruitment of inflammatory cells in MCI-AD are associated with its characteristic AD-like brain atrophy pattern and correlate with clinical changes or CSF biomarkers. |
Relationship between a panel of plasma biomarkers and presence of AD-like brain atrophy patterns defined by a previouslypublished index (SPARE-AD) at baseline in subjects of the ADNI cohort.Test whether serialmagnetic resonance imaging, positron emissiontomography, other biological markers, and clinicaland neuropsychological assessment can be combined tomeasure the progression of MCI and early AD. |
| Shirbin et al., [4] |
N=59(19 early-HD, 20 pre-HD, and 20HD CAG normal controls) |
Australia |
Preliminary study |
Wechsler Adult Reading (WTAR),Inventory of Depressive Symptomatology—Self Report,Perceived
Stress Scale,
Pittsburgh Sleep Quality Index (PSQI),
California Verbal Learning Test,
Saliva collection |
Assessment of learning and memory,Diagnostic status on salivary cortisol concentration. |
- Suggest that dysregulation of cortisol concentrations may be involved in the decline of verbal learning and memory recall ability in HD (but no causal relationship).
- Not find relations between recognition memory performance and cortisol levels.- Cortisol neurotoxicity hypothesis (more relevant). Suggestive correlations showing that heightened stress was present in HD expansion carriers, and was related to evening salivary cortisol levels, as well as learning and memory performance.
Suggest hypercortisolism and the underlying pathological changes may begin many years before a clinical diagnosis is made, but the memory decline associated with HPA axis disturbance may only become detectable once motor signs become pronounced. |
To identify whether there is an association between cortisol levels and verbal learning and memory in the early stages of HD. |
| Czech et al., [12] |
N= 130 (59 AD, 51 healthyControls) |
Germany, France, Switzerland, Sweden |
Cross-sectional |
NINCDS-ADRDAand DSM IV criteria.MRI examination or PET,mass spectrometryanalysis |
Metabolite profiling |
- Significant changes in the metabolite profile of AD patients compared to healthy controls have been identified.
- Increased cortisol levels related to the progression of AD and detected AD.
- Several combinations of three to five metabolites, including cortisol and various amino acids, in addition to cysteine and uridine. |
To identify the metabolic changes resulting from the disease phenotype by a thorough and systematic metabolite profiling approach. |
| Doecke et al., [13] |
N=961(754 health adult,207 AD). |
Australia |
LongitudinalData where obtained fromAustralian Imaging Biomarker and Lifestyle study (AIBL) |
151-analyte multiplex panel (Human DiscoveryMAP, version 1.0; RBM) |
Blood pathology testing |
- Biomarker panel was identified in AD:
a) markers significantly increased (cortisol, pancreatic polypeptide, insulinlike growth factor binding protein 2, β2 microglobulin, vascular cell adhesion molecule 1, carcinoembryonic antigen, matrix metalloprotein 2, CD40, macrophage inflammatory protein 1α, superoxide dismutase, and homocysteine)
b) markers significantly decreased (apolipoprotein E, epidermal growth factor receptor, hemoglobin, calcium, zinc, interleukin 17, and albumin). |
To identify plasma biomarkers for the diagnosis of AD. |
| Roozendall et al., [3] |
N=29 ALS patients |
Republic of Korea |
Cross-sectional nature. |
ALS functional rating scale (ALSFRS),Manual muscle test(MMT),Beck Depression Inventory (BDI),Hamilton Depression Rating Scale (HDRS) |
Salivary cortisol collection and assay,Clinical and depressive status |
- CAR was significantly smaller in ALS patients than in caregiver controls.
- A smaller CAR in ALS patients was significantly correlated to poorer clinical status ( as assessed with both the ALSFRS and MMT rating instruments) and a more severe depressive mood status.
- No correlations were observed between total cortisol outputs during the first 45 min post awakening and clinical or depressive status. |
Investigated whether the cortisol awakening response (CAR) of patients with ALS differed from that of a carefully selected group of age-matched caregiver control subjects. Examined whether the magnitude of the CAR in ALS patients correlated with their clinical and/or depressive mood status. |
| Soares et al., [14] |
N=566 (396 mild cognitive impairment, 112 AD, 58 healthy control) |
USA andCanada |
Longitudinal |
Alzheimer’s Disease NeuroimagingInitiative (ADNI) cohort |
Plasma sample collection,Laboratory tests |
- All participants with Apo ε3/ε4 or ε4/ε4 alleles showed a distinct biochemical profile characterized by low C-reactive protein and ApoElevels and by high Cortisol, interleukin 13, apolipoprotein B, and gamma interferon levels.
- Plasma biomarkers improved specificity in differentiating patients with AD from controls, and ApoE plasma levels were lowest in patients whose mild cognitive impairment had progressed to dementia.
- Incorporation of plasma biomarkers yielded high sensitivity with improved specificity. |
To apply a multiplex immunoassay panel to identify plasma biomarkers of AD using plasma samples from the Alzheimer’s Disease Neuroimaging Initiative cohort. |
| Toledo et al., 2012 |
N= 819 adult subjects (229 cognitively normal(CN), 398 mild cognitive impairment (MCI), 192 AD) |
USA |
Cross-sectional |
Pittsburgh Compound B-positronemission tomography (PiB-PET) studies,Mini-Mental State Examination. |
Physical and neurologic examinations,Standardized neuropsychological assessments, Biological samples(blood, urine, cerebrospinal fluid) |
- Association between Aβ brain burden measured in vivo and diastolic blood pressure and cortisol, indicating a possible link between these cardiovascular risk factors and Aβ burden measured by PiB-PET. |
Relationship between body mass index, systolic blood pressure, diastolic blood pressure, altered fasting glucose, plasma levels of cortisol, acute-phase proteins, and amyloid-β (Aβ) burden, as measured by Pittsburgh Compound B-positron emission tomography (PiB-PET) studies. |
| Laske et al., [18] |
N= 310(170 AD,140 healthy controls) |
Gemany |
Longitudinal |
Mini-Mental State Examination(MMSE) |
Blood sampling |
- Identified a panel of three blood markers, which allowed support vector machine (SVM)-based distinguishing of AD patients from healthy controls.
- Blood-based biomarkers might have utility in AD diagnostics. |
To determine whether multivariate data analysis (with use of SVM) of a blood-based biomarker panel allows discriminationbetween AD patients and healthy controls at theindividual level. |
| Laske et al., [18] |
N=46(26 AD,20 healthy controls) |
Gemany |
Cross-section |
ICD-10,DSM-IV,National Institute of neurologic and communicative disorders andstroke and the Alzheimer’s disease and related disorders association association(NINCDS-ADRDA) |
Serumcollection,Physical,Neurological, and Psychiatric examination. |
- Higher cortisol serum but not CSF levels are associated with minor signs of AD pathology.
- Neuroprotective effect of moderately elevated cortisol serum levels in patients with mild AD dementia. |
Measure cortisol levels (bothin serum and CSF), in patients with mild AD dementia.Evaluate their correlation with biomarker levelsof AD in CSF to assess the association of cortisol withAD pathology. |
| Popp et al., [17] |
N=133 subjects (66 AD, 33 with mild cognitive impairment (MCI) and 34 cognitively normal participants). |
Germany |
Longitudinal |
Cognitive Testing,Biomarker Collection and Analysis,MRI Processing and Analysis |
Diagnostic lumbar punctures;Serum cortisol RIA |
- Higher CSF cortisol levels in AD compared to control subjects after controlling for the APOE genotype effect.
- Normal cortisol level in MCI subjects compared to cognitively healthy controls.
- Several AD related biological alterations, hippocampal atrophy and reduced glucose metabolism, and CSF biomarker changes occur early in the course of AD and can be demonstrate already in subjects with MCI.
- Not known, whether HPA axis dysfunction also occurs in pre-dementia AD.
- CSF cortisol concentrations in MCI and in cognitively healthy controls indicates that a marked cortisol increase does not arise early inAD. |
To investigate whether CSF cortisol levels are elevated in AD.To determine if the increase of CSF cortisol represents an early event in the course of AD and can be detected already in MCI. |
| Umegaki et al., [23] |
N=115 (66 AD, 28 with vascular dementia and 21 non-demented controls). |
Japan |
Cross-sectional findings of cortisol profiles |
Mini-Mental State Examination |
Basal plasma cortisol levels,Radioimmunoassay |
- AD and vascular dementia subjects had higher levels of plasma cortisol than ND subjects.
- Cortisol levels in AD subjects did not change significantly.
- In AD subjects in relatively early stages of the disease who had higher cortisol levels, an accelerated progression of the disease was observed. |
To investigate the plasma cortisol levels at a fasting state in elderly female Alzheimer’s disease (AD), vascular dementia (VD), and non-demented subjects. |
| Miller et al., [16] |
N=27 patients with diagnosis of probable AD |
California |
Longitudinal |
Alzheimer’s disease assessment scale |
Complete medical, psychiatric, neurologic, neuroimaging and neuropsychological assessment |
- Cortisol and dehydroepiandrosterone (DHEA) were determined using conventional radioimmunoassay procedures.
- Not document relationship between cortisol or DHEA levels and non-cognitive measures.
- Significant correlation between both the initial MMSE and ADAS cognitive measures and initial DHEA level, with lower DHEA levels unexpectedly being associated with better performance on these measures.
- potential usefulness of DHEA as a therapeutic agent. |
To investigate the relationship between basal cortisol and dehydroepiandrosterone levels and impairment in different cognitive and non-cognitive measures and the possible interaction of dehydroepiandrosterone with hypercortisolemia in dementia. |
