Biomedical subjects

O Almkvist

Publications and source records attributed to O Almkvist.

At least 19 recordsLinked to original sources

PubMed2006

Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine.

The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

Acetylcholinesterase↗

PubMed2006

Differential CSF butyrylcholinesterase levels in Alzheimer's disease patients with the ApoE epsilon4 allele, in relation to cognitive function and cerebral glucose metabolism.

Butyrylcholinesterase (BuChE) is increased in the cerebral cortex of Alzheimer's disease (AD) patients, particularly those carrying epsilon4 allele of the apolipoprotein E gene (ApoE) and certain BuChE variants that predict increased AD risk and poor response to anticholinesterase therapy. We measured BuChE activity and protein level in CSF of eighty mild AD patients in relation to age, gender, ApoE epsilon4 genotype, cognition and cerebral glucose metabolism (CMRglc). BuChE activity was 23% higher in men than women (p<0.03) and 40-60% higher in ApoE epsilon4 negative patients than in those carrying one or two epsilon4 alleles (p<0.0004). CSF BuChE level correlated with cortical CMRglc. Patients with high to moderate CSF BuChE showed better cognitive function scores than others. We hypothesize that CSF BuChE varies inversely with BuChE in cortical amyloid plaques. Thus, low BuChE in a patient's CSF may predict extensive incorporation in neuritic plaques, increased neurotoxicity and greater central neurodegeneration.

Acetylcholine↗

PubMed2005

Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer's disease.

In this study 11 patients with mild Alzheimer's disease (AD) were treated with the cholinesterase inhibitor rivastigmine (mean dose 8.6 +/- 1.3'mg) for 12 months and underwent positron emission tomography (PET) studies of cerebral glucose metabolism (CMRglc) and neuropsychological testing at baseline and after 12 months. An untreated group of 10 AD patients served as control group. While the untreated AD patients showed a significant decline of CMRglc in the temporo-parietal and frontal cortical regions after 12 months follow-up the rivastigmine-treated patients showed no decline in CMRglc in corresponding cortical brain regions. Furthermore, a significant dose-related increase in CMRglc was recorded in the right frontal association region after 12 months rivastigmine treatment. A positive correlation was observed between changes in CMRglc and several cognitive tests in patients receiving higher doses (10.5-12'mg) of rivastigmine. These results suggest a stabilization effect of rivastigmine on CMRglc in mild AD patients receiving long-term rivastigmine treatment.

Adult↗

PubMed2004

Preserved cognitive function after 12 months of treatment with rivastigmine in mild Alzheimer's disease in comparison with untreated AD and MCI patients.

Cholinesterase inhibitors (ChEIs) have shown positive symptomatic effects on cognition, activities of daily living, and behavior in patients with Alzheimer's disease (AD). Rivastigmine is a slowly reversible ChEI that inhibits acetylcholinesterase and butyrylcholinesterase. We evaluated the effects of long-term rivastigmine treatment on cognitive function and plasma levels of ChE activity, and the relationship between ChE activity and cognition. Patients with mild AD (n = 11) treated with rivastigmine for 12 months were compared with matched groups of untreated patients with AD (n = 21) or mild cognitive impairment (MCI; n = 22) representing the natural course of the pre-clinical and very early stage of disease. For untreated AD patients, neuropsychological assessment was made at baseline and 12 months. Determination of ChE activity in plasma and assessment of global cognition, episodic memory, visuospatial ability, and attention were performed at 0 (baseline), 3, 6, and 12 months for treated AD patients and untreated MCI patients. At 12 months, cognitive function was slightly improved or maintained in mild AD patients treated with rivastigmine. In contrast, cognition was markedly worsened in untreated AD patients and unchanged or slightly worsened in untreated MCI patients. In the group of treated AD patients, there was a significant correlation between plasma ChE inhibition and cognition, particularly in relation to attention. This effect was most apparent at 3 months of treatment. In conclusion, a clear beneficial effect of rivastigmine was shown on cognitive function for patients with mild AD and plasma values of ChE inhibition were associated with attention.

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PubMed2004

Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.

The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.

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PubMed2004

Mild cognitive impairment: a cross-national comparison.

OBJECTIVE: The main aim of this collaborative study was to assess the comparability of the most commonly used criteria for mild cognitive impairment (MCI) by comparing the cognitive performance of patients with MCI from the Mayo Clinic (USA) and the Karolinska Institutet (Sweden). METHODS: Standardised neuropsychological test scores were used to compare the two samples from the two institutions with regard to the number of cognitive domains in which performance was below 1.5 SD. Possible predictors for the conversion from MCI to Alzheimer's disease (AD) were assessed. RESULTS: When the two institutions were considered together in the Cox proportional hazard model, the number of affected cognitive domains below 1.5 SD was a significant predictor of time to AD diagnosis with age, education, and APOE epsilon4 genotype entered into the same model as covariates. The number of affected cognitive areas remained as a significant predictor when the institutions were considered separately. The logistic regression model of conversion to AD showed that only tests assessing learning and retention were predictors of developing AD. CONCLUSIONS: Differences in population as well as in methodology of case ascertainment as well as other aspects may account for the observed variability between samples of patients with MCI. The number of impaired cognitive factors at baseline can predict the progression from MCI to AD. Furthermore, tests assessing learning and retention are the best predictors for progression to AD.

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PubMed2003

Cerebral glucose metabolism, cerebrospinal fluid-beta-amyloid1-42 (CSF-Abeta42), tau and apolipoprotein E genotype in long-term rivastigmine and tacrine treated Alzheimer disease (AD) patients.

We evaluated cerebral glucose metabolism (CMRglc) and cerebrospinal fluid (CSF) levels of tau and beta-amyloid(1-42) (Abeta42), in relation to apolipoprotein E (ApoE) genotype, in patients with mild Alzheimer disease (AD) treated with rivastigmine (n=11) and tacrine (n=16) for 1 year; and two untreated AD groups. The rivastigmine-treated AD patients showed a significant increase in CMRglc as compared to both tacrine-treated and untreated AD subjects. The rivastigmine-treated AD group showed no change in CSF-tau levels after 1 year, while in contrast a significant increase as seen in tacrine-treated and untreated AD patients. The CSF-tau changes were mainly seen in ApoE epsilon4 carriers. There was no significant change in Abeta42 after 1-year treatment with either rivastigmine or tacrine. This study shows that the two long-term cholinesterase inhibitor treatments exert different effects on biological markers for AD.

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PubMed2003

Quantitative EEG abnormalities and cognitive dysfunctions in frontotemporal dementia and Alzheimer's disease.

OBJECTIVE: To investigate the relationship between quantitative EEG (qEEG) measurements in frontotemporal dementia (FTD), Alzheimer's disease (AD) and healthy controls and to study to what extent qEEG in FTD and AD or neuropsychological test results of FTD and AD patients or a combination of both contribute to classification accuracy. METHOD: The FTD sample consisted of 19 patients, the AD sample of 16 patients, and the control group of 19 subjects. Groups were matched on the group level with respect to demographic variables. For qEEG the global field power was calculated for six frequency bands: delta (1.0-3.5 Hz), theta (4.0-7.5 Hz), alpha (8.0-11.0 Hz), beta1 (12.0-15.5 Hz), beta2 (16.0-19.5 Hz), beta3 (20.0-23.5 Hz), and spectral ratio as the ratio of the sum of fast frequency bands alpha + beta1 + beta2 + beta3 and slow frequency bands delta + theta. RESULTS: In comparison to controls FTD patients were marked by an absence of an increase in slow qEEG activities and a decrease in fast activities, whereas AD patients were marked by an increase in slow activities and a smaller decrease in fast activities. According to the Mann-Whitney U test the cognitive functions of attention, visuospatial thinking and episodic memory were significantly better in FTD than in AD. Using logistic regression analysis the best predictors of FTD and AD were in a model using the delta and theta activities, and high levels of visuospatial ability and episodic memory. Classification accuracy of the model was 93.3%. CONCLUSION: FTD patients reveal a different pattern of qEEG changes than AD patients. This result demonstrates the importance of qEEG for FTD diagnosis. Cognition is selectively better in FTD than in AD. A combination of qEEG and neuropsychology is recommended for differential diagnoses of FTD and AD.

Alzheimer Disease↗

PubMed2003

Visual rating of age-related white matter changes on magnetic resonance imaging: scale comparison, interrater agreement, and correlations with quantitative measurements.

BACKGROUND AND PURPOSE: To provide further insight into the MRI assessment of age-related white matter changes (ARWMCs) with visual rating scales, 3 raters with different levels of experience tested the interrater agreement and comparability of 3 widely used rating scales in a cross-sectional and follow-up setting. Furthermore, the correlation between visual ratings and quantitative volumetric measurement was assessed. METHODS: Three raters from different sites using 3 established rating scales (Manolio, Fazekas and Schmidt, Scheltens) evaluated 74 baseline and follow-up scans from 5 European centers. One investigator also rated baseline scans in a set of 255 participants of the Austrian Stroke Prevention Study (ASPS) and measured the volume of ARWMCs. RESULTS: The interrater agreement for the baseline investigation was fair to good for all scales (kappa values, 0.59 to 0.78). On the follow-up scans, all 3 raters depicted significant ARWMC progression; however, the direct interrater agreement for this task was poor (kappa, 0.19 to 0.39). Comparison of the interrater reliability between the 3 scales revealed a statistical significant difference between the scale of Manolio and that of Fazekas and Schmidt for the baseline investigation (z value, -2.9676; P=0.003), demonstrating better interrater agreement for the Fazekas and Schmidt scale. The rating results obtained with all 3 scales were highly correlated with each other (Spearman rank correlation, 0.712 to 0.806; P< or =0.01), and there was significant agreement between all 3 visual rating scales and the quantitative volumetric measurement of ARWMC (Kendall W, 0.37, 0.48, and 0.57; P<0.001). CONCLUSIONS: Our data demonstrate that the 3 rating scales studied reflect the actual volume of ARWMCs well. The 2 scales that provide more detailed information on ARWMCs seemed preferential compared with the 1 that yields more global information. The visual assessment of ARWMC progression remains problematic and may require modifications or extensions of existing rating scales.

Adult↗

PubMed2002

Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months.

OBJECTIVE: To study the long-term dual inhibitory effects of rivastigmine on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in patients with AD. METHODS: Eleven patients with mild AD received rivastigmine for 12 months. Cholinesterase (ChE) activities in the CSF and plasma were assessed colorimetrically. Immunoblot analysis was used to evaluate AChE isoforms. Neuropsychiatric tests were performed throughout the study. RESULTS: At 12 months, the mean dose of rivastigmine was 8.6 mg/d and specific activities of ChE in the CSF were lower than baseline values (by 36% for AChE and 45% for BuChE), correlating with parallel reductions in the plasma (27% for AChE and 33% for BuChE). The reduction of specific activities in the CSF, but not in the plasma, appeared to be dependent on the dose and duration of treatment. Scores of some of the neuropsychological tests associated with memory and attention were correlated with both plasma and CSF AChE and BuChE inhibition for up to 6 months. Immunoblot analysis revealed up-regulation of the "read-through" AChE isoform (AChE-R), whereas levels of the synaptic isoform were unchanged. CONCLUSIONS: Rivastigmine causes persistent inhibition of AChE and BuChE in CSF as well as plasma. The persistent CSF inhibition contrasts with earlier findings after long-term treatment by the reversible ChE inhibitor tacrine, which demonstrated increased AChE activity in the CSF but not in the blood. Rivastigmine's effects on the preferential up-regulation of the AChE-R isoform may have a favorable effect on disease stabilization.

Acetylcholinesterase↗

PubMed2002

Conversion from preclinical to dinical stage of Alzheimer's disease as shown by decline of cognitive function in carriers of the Swedish APP-mutation.

The characterisation of the borderline syndrome between normal cognitive function and Alzheimer's disease (AD), often mentioned as Mild Cognitive Impairment (MCI) has been a goal for recent research. However, a variety of definitions of MCI-like syndromes and the uncertainty about the final diagnosis have hampered progress. To overcome these problems, the present study will describe cognitive function in two healthy mutation carriers and two matched non-carriers of the Swedish double mutation family, during the time period when carriers convert to a symptomatic stage, i.e., true preclinical AD, and finally into the stage when a clinical diagnosis of AD is first possible. The findings question the generality of common MCI concepts and the commonly held beliefs about cognitive features in late preclinical stage of AD.

Alzheimer Disease↗

PubMed2001

Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4.

The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE epsilon4 is a genetic risk factor for FTD.

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PubMed2001

Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment.

The objective of this study was to assess whether reduced glucose metabolism (rCMRGlu) and cognitive functioning could predict development of Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Twenty MCI patients underwent baseline and follow-up investigations of rCMRGlu, as measured by PET, and cognitive function measured by neuropsychological test assessments. Subjects were clinically followed up with an average interval of 36.5 months. Two groups were obtained after the second clinical assessment. Nine patients were diagnosed as AD and classified as progressive MCI (P-MCI), whereas 11 patients remained clinically stable and were classified as stable MCI (S-MCI). There were no differences in demographic variables or baseline MMSE between the two subgroups. Logistic regression indicated the two variables that most effectively predicted future development of AD were rCMRGlu from the left temporoparietal area and performance on the block design. These combined measures gave an optimal 90% correct classification rate, whereas only rCMRGlu or neuropsychology alone gave 75% and 65% correct classification, respectively. Measures of temporoparietal cerebral metabolism and visuospatial function may aid in predicting the evolution to AD for patients with MCI.

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PubMed2001

Confabulation and memory in patients with Alzheimer's disease.

Confabulation occurs in many brain diseases and concomitant with various cognitive disturbances. The purpose of the present study was to describe semantic features of confabulation and to investigate the relationship between these features and aspects of memory in Alzheimer's disease (AD). A group of 15 AD patients were asked questions aiming to evoke confabulations. The answers were analyzed with focus on semantic remoteness to the target answers into four different categories that made it possible to study the genesis of confabulation. Cognitive tests measuring episodic and semantic memory, priming as well as global cognitive functioning were performed, and the results were related to semantic features of confabulation. Results showed that semantic remoteness to the target answers was positively related to poor performance on Mini Mental State Examination but not to item recall, word fluency, or priming. It appears that difficulties with retrieval of recent autobiographical memories may have resulted in substitution of correct information with remote autobiographical memories, that is primary dysdeictic confabulations.

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PubMed2000

Functional brain imaging as a looking-glass into the degraded brain: reviewing evidence from Alzheimer disease in relation to normal aging.

Research on the real-time relationship between brain activity and mental performance is intense. However, relatively few studies have been devoted to patients with different diseases or lesions. Such studies may cast light on certain aspects of brain activity, such as plasticity. This review summarizes studies on Alzheimer's disease (AD) patients where the techniques to map brain activity in relation to mental performance have been utilized. Research findings suggest, that there is a spectrum of changes in AD patients that is distinct from that seen in healthy aging. These changes include: (i) loss of activated regions, (ii) reduced activation possibly due to brain degeneration typical of AD, (iii) the emergence of newly activated regions in order to compensate for minor brain deterioration (e.g., an enlargement of activated regions sometimes manifested as an increased bilaterality or a hemispheric shift of activation, and dedifferentiation), (iv) decreased level of activation, and (v) no change at all, which may occur in easy tasks or tasks that do not involve regions exposed to brain atrophy. In conclusion, the pattern of activation in AD depends on interactions between the clinical stage of patients, and the pattern of brain degeneration, as well as the task difficulty and specific networks necessary for solving the task.

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PubMed2000

Outcome measures in Alzheimer's disease: do they go far enough?

As the interest in Alzheimer's disease (AD) and its treatment has grown, so has the sophistication of clinical trials of potential drug therapies. In particular, interest has focused on outcomes used to assess the severity of the illness and the effectiveness of treatment. This paper reviews the assessments that are used frequently in trials of AD therapy and describes further measures that may be of value in determining effective treatments for the disease. The review concludes that it is important that evaluation of drug effects on AD is not confined solely to the assessment of cognitive function. To gain a true overview of the impact of AD on patients, carers and society, areas such as activities of daily living, caregiver burden, quality of life, behavioural symptoms and resource utilization need to be comprehensively determined.

Alzheimer Disease↗

PubMed2000

Functional changes in brain activity during priming in Alzheimer's disease.

Patients with Alzheimer's disease (AD) are often impaired on certain forms of implicit memory, such as word-stem completion priming (WSCP). Lesion data suggest that deficient WSCP may be associated with abnormal functioning in the posterior neocortex. Using positron emission tomography (PET), we here provide direct support for this view. Compared with normal old adults, AD patients showed reduced priming on a word-stem completion task. The normal old showed decreased activity in right occipital cortex (area 19), whereas the AD patients showed increased activity in this region during priming. To the extent that decreased activity during priming reflects an experience-dependent reduction of the neuronal population involved, these results indicate that shaping of the relevant neurons is slower in AD, possibly as a result of inadequate initial stimulus-processing.

Adult↗

PubMed1999

Brain regions associated with episodic retrieval in normal aging and Alzheimer's disease.

OBJECTIVE: To examine patterns of brain activation during verbal episodic retrieval in normal elderly subjects and patients in an early phase of AD. BACKGROUND: It is established that 1) a profound episodic memory impairment is a cardinal symptom of AD; and 2) some of the earliest brain changes in this disease occur in regions critical to episodic memory, such as the hippocampus and neighboring regions. Yet, it remains largely unknown whether the episodic memory deficit seen in AD is paralleled by concomitant alterations in brain activity during actual task performance in these or other brain areas. METHODS: Using PET, blood flow was assessed in normal elderly subjects and patients with early AD during two retrieval conditions involving completion of word stems: baseline and cued recall. RESULTS: The patients with AD showed a marked performance deficit in cued recall, although the two groups were indistinguishable in the baseline task condition. Both groups showed bilateral activity in orbital and dorsolateral prefrontal cortex, left precuneus, and right cerebellum, as well as decreased activity in distinct left temporal regions during cued recall. The normal elderly alone activated the left parietal cortex and the left hippocampal formation during episodic retrieval. By contrast, AD-related increases in activity during cued recall were observed in the left orbital prefrontal cortex and left cerebellum. CONCLUSIONS: The similar patterns of activations in the two groups suggest that a large distributed network involved in episodic memory retrieval functions relatively normally in early AD. Those retrieval activations seen in the normal elderly, as opposed to the patients, may reflect AD-related failures in semantic processing and successful recollection of the target information, respectively. Finally, the AD-related increases in activity were interpreted in terms of compensatory reactions to the difficulties in performing the episodic memory task.

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