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Aspects on clinical diagnosis of dementia, with focus on biological markers
Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Linköping University, Faculty of Health Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The clinical dementia diagnosis has become more complex with increasing knowledge of the heterogeneity of the disorder and its different aetiological aspects. A clinical dementia population and a control group were investigated with the following aims: I. To study the CSF levels of tau phosphorylated at threonine 181 (P-tau), total tau (T-tau) and ß-amyloid1-42 (Aß42) in the different diagnoses. II. To study associations between dementia disorder, cobalamin and/or folate deficiency, and gastritis. III. To study the presence and severity of CT brain changes in different dementia diagnoses. IV. To investigate to what extent different biomarkers and disease history contribute to the diagnostics of clinical dementia.

I. CSF Levels of P-tau, T-tau and Aß42 were analysed with ELISA methods. Elevated CSF levels of P-tau were found in probable Alzheimer's disease (AD) patients compared with cognitively non-disturbed controls. Increased CSF T-tau, and decreased levels of Aß42 were found in both AD, mixed type of dementia, and vascular dementia (VaD) patients compared with the controls. Increased P-tau levels were more specific for AD pathology, but there was still an overlap with the controls, mixed dementia and VaD patients.

II. Serological markers for cobalamin and folate deficiencies, and for gastritis were assessed in patients with different dementia diagnoses. Hyperhomocysteinaemia were commonly found in dementia without predominance in any of the investigated categories. Low levels of serum cobalamin or blood folate rarely reflected the elevated Hey levels. A lack of association between serological markers for cobalamin and folate deficiencies and for gastritis was demonstrated.

III. A protocol for evaluation of the CT scans was used. Atrophy on the CT scans, although common in dementia, is an unspecific fmding in dementia of different backgrounds. White-matter changes and lacunes, indicating small-vessel disease, were common in dementia of different aetiologies. Dementia of mixed-type pathology was underestimated. More distinct criteria for this diagnostic category are warranted.

IV. Partial Least Squares Discriminant Analysis (PLS-DA) was used on a large number of variables covering cognitive and biological markers and disease history. There were good discriminations of subgroups of dementia from the controls. However, the included variables were not able to distinguish between the investigated groups, indicating that several clinical parameters used in diagnosing dementia are in fact observed across different subtypes of dementia.

It is concluded that there are no known biomarkers available that can provide a precise differential diagnosis of dementia. The clinical dementia diagnosis must still be based on a combination of a careful disease history, evaluation of risk factors, symptomatology, clinical findings, neurocognitive tests, blood analysis and other available methods such as CT and CSF markers.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2004. , 60 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 839
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24644Local ID: 6830ISBN: 91-7373-808-5 (print)OAI: oai:DiVA.org:liu-24644DiVA: diva2:244966
Public defence
2004-03-12, Elsa Brändströms sal, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-29Bibliographically approved
List of papers
1. Cerebrospinal fluid phospho-tau, total tau and β-amyloid1-42 in the differentiation between Alzheimer's disease and vascular dementia
Open this publication in new window or tab >>Cerebrospinal fluid phospho-tau, total tau and β-amyloid1-42 in the differentiation between Alzheimer's disease and vascular dementia
2002 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 14, no 3-4, 183-190 p.Article in journal (Refereed) Published
Abstract [en]

The two most frequently examined biomarkers in the diagnosis of dementia are cerebrospinal fluid (CSF) tau and β-amyloid1-42 (Aβ1-42). An assay for tau phosphorylated at threonine 181 (phospho-tau) has recently been developed. We studied these three markers in patients with possible Alzheimer's disease (AD; n = 23), probable AD (n = 50), AD with relevant cerebrovascular disease (AD with CVD; n = 14), possible vascular dementia (VaD; n = 39), probable VaD (n = 36), cognitively impaired (n = 13) and 27 neurologically healthy controls. Compared with the controls, tau levels were significantly increased in possible AD, probable AD, AD with CVD and probable VaD. Aβ1-42 was decreased in all dementia groups compared with the controls. In contrast, phospho-tau levels were increased only in probable AD compared with the controls. From the results of the present study, it is concluded that neither measurement of phospho-tau, tau nor Aβ1-42 in CSF can discriminate entirely between dementia and cognitively non-disturbed controls or between dementia of different aetiologies in the clinical diagnostic procedure.

Keyword
ß-Amyloid, Alzheimer's disease, Biochemical markers, Cerebrospinal fluid, Phosphorylated tau, Tau, Vascular dementia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46841 (URN)10.1159/000066023 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
2. Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia
Open this publication in new window or tab >>Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia
Show others...
2003 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 16, no 4, 269-275 p.Article in journal (Refereed) Published
Abstract [en]

The prevalence of dementia disorders, cobalamin and/or folate deficiency as well as gastritis increases with age. To investigate whether there is an association between these conditions, plasma homocysteine (Hcy), serum methylmalonic acid, serum cobalamin and blood folate concentrations were measured. Gastritis was indirectly diagnosed by measuring serum antibodies against H,K-ATPase, Helicobacter pylori and intrinsic factor, using enzyme-linked immunosorbent assays. The studied groups consisted of 47 patients with Alzheimer’s disease (AD), 9 with AD pathology in combination with additive vascular lesions, 59 with vascular dementia, 8 who were cognitively impaired, and 101 control cases. Plasma Hcy concentrations were significantly elevated in the dementia groups, with the highest levels in patients with vascular pathology. We conclude that hyperhomocysteinemia is a common finding in patients with dementia disorders of different etiologies. The markers for gastritis did not contribute to an elucidation of a possible connection between this condition, dementia disorders, or cobalamin/folate deficiency.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24967 (URN)10.1159/000072812 (DOI)9378 (Local ID)9378 (Archive number)9378 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
3. CT brain findings in clinical dementia investigation: underestimation of mixed dementia
Open this publication in new window or tab >>CT brain findings in clinical dementia investigation: underestimation of mixed dementia
2004 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 18, no 1, 59-66 p.Article in journal (Refereed) Published
Abstract [en]

Dementia has been found to display a more heterogeneous clinical picture than previously recognized. We investigated brain changes on computed tomography (CT) in a clinical dementia population consisting of 67 cases with Alzheimer's disease (AD), 13 with mixed dementia (AD and vascular dementia, VaD), 71 with VaD, and 12 cases that were not demented. Temporal cortical atrophy and atrophy around the temporal horns were more common in patients with mixed dementia compared to patients with VaD and the non-demented, respectively. Frontal white matter changes were present in 64% of AD, in 85% of mixed dementia and in 79% of VaD cases, but there were no differences between the dementia groups. Lacunes were present in almost 40% of AD cases and in 80 and 85% of VaD and mixed dementia cases, respectively. Only 14% of the VaD cases had large infarcts on the CT. We conclude that large infarcts were rare, even in VaD cases. The increased incidence of white matter changes and lacunes in AD patients strongly indicates an underestimation of the mixed dementia diagnosis. More distinct criteria for this diagnostic category are warranted.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24010 (URN)10.1159/000077737 (DOI)3565 (Local ID)3565 (Archive number)3565 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
4. Evaluation of factors of importance for clinical dementia diagnosis
Open this publication in new window or tab >>Evaluation of factors of importance for clinical dementia diagnosis
Show others...
2005 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 19, no 5-6, 289-298 p.Article in journal (Refereed) Published
Abstract [en]

Diagnosing clinical dementia is based on an assessment of different variables, such as the patient’s medical history, known risk factors, and biochemical features. Partial least squares discriminant analysis was used to evaluate variables of importance for diagnosing dementia in a clinical dementia population. Polymorphism for genotypes of glutathione S-transferase (GST) and sulfotransferase 1A1, hypothetically of importance in dementia disorders, was also included in the analysis. The study population consisted of 73 patients with Alzheimer’s disease (AD), 14 with mixed dementia, 75 patients with vascular dementia, and 28 control cases. We found that several of the variables, such as the presence of ApoE4 allele, high cerebrospinal fluid levels of total tau protein, low levels of β-amyloid(1–42), and a low score on the Mini-Mental State Examination, facilitated a discrimination between the diagnoses compared with the controls. The different diagnoses overlapped. There were indications that genotypes of GSTs contributed to a subgrouping within AD.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-29991 (URN)10.1159/000084554 (DOI)15431 (Local ID)15431 (Archive number)15431 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13

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