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Neuropsychological Function in Relation to Structural and Functional Brain Changes in Alzheimer’s Disease
Umeå University, Faculty of Medicine, Community Medicine and Rehabilitation, Geriatric Medicine.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this doctoral thesis was to study neuropsychological function in relation to structural and functional brain changes in Alzheimer´s disease (AD).

In the first study relations between hippocampal volume, neuropsychological function and limbic-hypothalamic-pituitary-adrenal (LHPA) axis disturbances in AD were investigated with magnetic resonance imaging (MRI). Reduced hippocampal CA1 volume and suppressed cortisol levels in combination, best predicted the variation in neuropsychological performance. The conclusion was that reduced hippocampal volume and LHPA axis disturbances are associated to level of cognitive function in AD.

The second study focused on whether patients with early AD showed an altered regional cerebral blood flow (rCBF) pattern compared to control persons, correlation between performance on memory tests and rCBF in sub-lobar volumes of the brain were investigated. The rCBF was measured with single photon emission computed tomography (SPECT). AD-patients showed a significantly lower rCBF in temporoparietal regions including left hippocampus compared to controls. The diagnostic sensitivity and specificity for AD was high in temporoparietal regions. AD-patients had significantly lower performance on semantic and, in particular, episodic memory-tests compared to the controls, and their performance on several episodic tests correlated with rCBF in parietal and temporal regions including left hippocampus, which suggest that abnormalities in the rCBF pattern underlie impaired episodic memory functioning in AD. The conclusion was that an observer-independent analyzing method for SPECT with sub-lobar volumes VOI´s is promising in the diagnosis of AD.

In a third study possible differences in memory-related functional brain activation between persons with high versus low risk for AD were examined with functional magnetic resonance imaging (fMRI). The high-risk individuals performed worse than low-risk individuals on tests of episodic memory. Patterns of brain activity during episodic encoding and retrieval showed significant group differences. During both encoding and retrieval, the low-risk persons showed increased activity relative to a baseline condition in prefrontal and hippocampal brain regions that previously have been implicated in episodic memory. By contrast, the high-risk persons did not significantly activate any prefrontal regions, but instead showed increased activity in visual occipito-temporal regions. The conclusion was that patterns of prefrontal brain activity related to episodic memory differed between persons with high versus low risk for AD, and lowered prefrontal activity may predict subsequent disease.

In a final study SPECT was used to map patterns of rCBF in an activated state (an episodic encoding task) and in a rest condition in persons with mild AD and in healthy elderly control persons. A reduction of rCBF in temporoparietal regions that was more pronounced in mild AD in the activated encoding task was observed. The conclusion was that there are rCBF differences between mild AD patients and healthy controls in temporoparietal regions, and the temporoparietal reduction is more pronounced during activation than during rest which might be important in the early diagnosis of AD.

Taken together, these findings show that level of neuropsychological function, notably episodic memory, can be systematically related to functional disturbances in the LHPA axis and to the function of temporoparietal and prefrontal brain regions in AD patients. These changes are detectable in patients with risk for AD and in an early phase of AD which suggests that the obtained results might be important for early diagnosis of AD.

Place, publisher, year, edition, pages
2004. , 78 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 903
Keyword [en]
Alzheimer´s disease, neuropsychological function, episodic memory, hippocampus, prefrontal cortex, brain imaging, MRI, fMRI, SPECT, LHPA-axis, cortisol
Research subject
Geriatrics
Identifiers
URN: urn:nbn:se:umu:diva-323ISBN: 91-7305-691-X (print)OAI: oai:DiVA.org:umu-323DiVA: diva2:143106
Public defence
2004-10-22, Betula, 6M, 09:00 (English)
Opponent
Available from: 2004-09-29 Created: 2004-09-29 Last updated: 2010-03-19Bibliographically approved
List of papers
1. Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer's disease.
Open this publication in new window or tab >>Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimer's disease.
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2006 (English)In: Biological Psychiatry, ISSN 0006-3223, Vol. 59, no 2, 155-161 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The hippocampal formation is damaged early in Alzheimer's disease (AD). An association between temporal lobe volume and cognitive function has been shown in several studies. Increased limbic-hypothalamic-pituitary-adrenal (LHPA) axis function has been suggested to be related to hippocampal atrophy and cognitive impairment. Our hypothesis was that there is a clear link between hippocampal volume -- notably of the CA1 region -- memory (episodic and visuospatial) and decreased feedback sensitivity in the LHPA axis in AD. METHODS: Sixteen medication-free outpatients with mild to moderate AD were included. Hippocampal volume was measured with magnetic resonance imaging. Dexamethasone suppression tests were performed using .5 mg and .25 mg dexamethasone. Three different components in the neuropsychological battery -- Rey 15 item memory test, Alzheimer's Disease Assessment Scale (ADAS) word recall and spatial span from Wechsler Adult Intelligence Scale - Revised neuropsychological instrument (WAIS-R NI) -- were found to represent episodic and visuospatial memory. RESULTS: Low hippocampal CA1 volume and high post-dexamethasone cortisol levels in combination were significantly associated with Rey 15 item memory and spatial span test outcomes. No association was found between LHPA feedback and hippocampal volume. CONCLUSIONS: Low hippocampal volume and a disturbed negative feedback in the LHPA axis link to specific cognitive impairments in Alzheimer's disease.

Keyword
Aged, Aged; 80 and over, Alzheimer Disease/blood/*complications/pathology, Atrophy, Cross-Sectional Studies, Cushing Syndrome/blood/*complications/diagnosis, Dexamethasone/diagnostic use, Feedback; Biochemical, Female, Hippocampus/*pathology, Humans, Hydrocortisone/*blood, Hypothalamo-Hypophyseal System/physiopathology, Limbic System/physiopathology, Magnetic Resonance Imaging, Male, Memory Disorders/blood/*complications/diagnosis, Middle Aged, Neuropsychological Tests, Organ Size, Pituitary-Adrenal System/physiopathology, Principal Component Analysis, Severity of Illness Index
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-15322 (URN)10.1016/j.biopsych.2005.06.017 (DOI)16125145 (PubMedID)
Available from: 2008-01-16 Created: 2008-01-16 Last updated: 2010-03-19Bibliographically approved
2. Memory functions and rCBF (99m)Tc-HMPAO SPET: developing diagnostics in Alzheimer's disease
Open this publication in new window or tab >>Memory functions and rCBF (99m)Tc-HMPAO SPET: developing diagnostics in Alzheimer's disease
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2002 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, ISSN 1619-7070, Vol. 29, no 9, 1140-1148 p.Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a primary degenerative disease of the brain. The prevalence increases with age, with devastating consequences for the individual and society. The aim of this study was to evaluate whether patients with early AD show an altered regional cerebral blood flow (rCBF) compared with control persons. Furthermore, we aimed to investigate the correlation between rCBF in sublobar volumes of the brain and performance on memory tests. Memory tests were chosen to evaluate episodic and semantic memory. Fourteen patients (aged 75.2+/-8.8 years) with early AD and 15 control persons (aged 71.4+/-3.2 years) were included. rCBF measurements with single-photon emission tomography (SPET) using technetium-99m hexamethylpropylene amine oxime (HMPAO) were performed. The rCBF (99m)Tc-HMPAO SPET images were spatially transformed to fit a brain atlas and normalised for differences in rCBF (Computerised Brain Atlas software). Cortical and subcortical volumes of interest (VOIs) were analysed and compared. Compared with the controls, AD patients showed a significantly lower rCBF ratio in temporoparietal regions, including the left hippocampus. The diagnostic sensitivity and specificity for AD were high in temporoparietal regions. AD patients had significantly reduced performance on semantic and, in particular, episodic memory tests compared with age-matched normative data, and their performance on several episodic tests correlated with rCBF ratios in parietal and temporal regions, including the left hippocampus. The correlation between rCBF ratio and level of episodic memory performance suggests that abnormalities in rCBF pattern underlie impaired episodic memory functioning in AD.

Identifiers
urn:nbn:se:umu:diva-5084 (URN)10.1007/s00259-002-0829-y (DOI)12192558 (PubMedID)
Available from: 2006-04-19 Created: 2006-04-19 Last updated: 2010-01-28Bibliographically approved
3. Altered prefrontal brain activity in persons at risk for Alzheimer's disease: an f-MRI study
Open this publication in new window or tab >>Altered prefrontal brain activity in persons at risk for Alzheimer's disease: an f-MRI study
2003 (English)In: International psychogeriatrics, ISSN 1041-6102, E-ISSN 1741-203X, Vol. 15, no 2, 121-133 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is critical for adequate treatment and care. Recently it has been shown that functional magnetic resonance imaging (fMRI) can be important in preclinical detection of AD. The purpose of this study was to examine possible differences in memory-related brain activation between persons with high versus low risk for AD. This was achieved by combining a validated neurocognitive screening battery (the 7-minutes test) with memory assessment and fMRI. METHODS: One hundred two healthy community-living persons with subjective memory complaints were recruited through advertisement and tested with the 7-minutes test. Based on their test performance they were classified as having either high (n = 8) or low risk (n = 94) for AD. Six high-risk individuals and six age-, sex-, and education-matched low-risk individuals were investigated with fMRI while engaged in episodic memory tasks. RESULTS: The high-risk individuals performed worse than low-risk individuals on tests of episodic memory. Patterns of brain activity during episodic encoding and retrieval showed significant group differences (p < .05 corrected). During both encoding and retrieval, the low-risk persons showed increased activity relative to a baseline condition in prefrontal brain regions that previously have been implicated in episodic memory. By contrast, the high-risk persons did not significantly activate any prefrontal regions, but instead showed increased activity in visual occipito-temporal regions. CONCLUSION: Patterns of prefrontal brain activity related to episodic memory differ between persons with high versus low risk for AD, and lowered prefrontal activity may predict subsequent disease.

Keyword
fMRI, 7-minutes test, Alzheimer's disease, episodic memory
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-4129 (URN)10.1017/S1041610203008810 (DOI)14620071 (PubMedID)
Available from: 2004-09-29 Created: 2004-09-29 Last updated: 2014-07-18Bibliographically approved
4. Memory-provoked rCBF-SPECT as a diagnostic tool in Alzheimer's disease?
Open this publication in new window or tab >>Memory-provoked rCBF-SPECT as a diagnostic tool in Alzheimer's disease?
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2006 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, Vol. 33, no 1, 73-80 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Alzheimer's disease (AD) is a primary degenerative disease that progressively affects all brain functions, with devastating consequences for the patient, the patient's family and society. Rest regional cerebral blood flow (rCBF) could have a strategic role in differentiating between AD patients and normal controls, but its use for this purpose has a low discriminatory capacity. The purpose of this study was to evaluate whether the diagnostic sensitivity of rCBF single-photon emission computed tomography (SPECT) could be increased by using an episodic memory task provocation, i.e. memory-provoked rCBF-SPECT (MP-SPECT). METHODS: Eighteen persons (73.2+/-4.8 years) with mild AD and 18 healthy elderly (69.4+/-3.9 years) were included in the study. The subjects were injected with (99m)Tc-hexamethylpropylene amine oxime (HMPAO) during memory provocation with faces and names, followed by an rCBF-SPECT study. The rCBF (99m)Tc-HMPAO SPECT images were analysed using statistical parametric mapping (SPM2). Peaks with a false discovery rate corrected value of 0.05 were considered significant. RESULTS: On MP-SPECT, the AD group showed a significant rCBF reduction in the left parietal cortex in comparison with healthy elderly. At rest, no significant group differences were seen. CONCLUSION: Memory provocation increased the sensitivity of rCBF-SPECT for the detection of AD-related blood flow changes in the brain at the group level. Further studies are needed to evaluate MP-SPECT as a diagnostic tool at the individual level. If a higher sensitivity for AD at the individual level is verified in future studies, a single MP-SPECT study might be sufficient in the clinical setting.

Identifiers
urn:nbn:se:umu:diva-13544 (URN)10.1007/s00259-005-1874-0 (DOI)16151770 (PubMedID)
Available from: 2007-02-27 Created: 2007-02-27 Last updated: 2010-03-19Bibliographically approved

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