Physical activity level in people with age related white matter changes correlates to better motor performance, lower comorbidity and higher cognitive level.

BACKGROUND: Physical activity plays a pivotal role in the development of disability and may modify the negative effect of vascular risk factors on progression of both cardio and cerebrovascular disorders. The aim of this study was to evaluate the activity level in people with age-related white matter changes as identified on magnetic resonance imaging (MRI) in relation to motor performance, cognition and perceived health. METHODS: Data came from the first year follow up of one participating centers of the LADIS study. Fifty one subjects were first enrolled in the study. Complete first year follow up data was available for 41 subjects. Information on comorbidity, physical activity level, physical function, cognition, level of white matter changes and perceived health was collected. Physical activity level was classified with a yes or no question and with the Frenchay Activities Index (FAI). RESULTS: Only 36% of the subjects in this study were physically active according to the yes/no question. 27.5% of the subjects were active according to the FAI score which evaluates the everyday activities. Being active discriminated subjects with better physical function. Subjects active according to the FAI score had a higher cognitive level (p ≤ 0.01), lower comorbidity (p = 0.02) and performed better on all motor function tasks as assessed by walking speed (p ≤ 0.01) and the Short Physical Performance battery (SPPB) (p ≤ 0.01). CONCLUSIONS: Being physically active seems to be a long term protective factor. In our study, the majority of subjects with Age Related White Mattter Changes (ARWMC) with no or mild Instrumental Activity of Daily Living (IADL) disability did not attain recommended level of activity at first year follow up. Whether or not increasing physical activity may slow down cognitive decline and lessen development of disability in physically inactive subjects with manifest ARWC remains to be studied. TRIAL REGISTRATION: not applicable.

Mixed brain lesions mediate the association between cardiovascular risk burden and cognitive decline in old age: A population-based study.

INTRODUCTION: The underlying pathological mechanisms linking cardiovascular burden to cognitive decline remain unclear. METHODS: We investigated the associations of the Framingham general cardiovascular risk score (FGCRS), apolipoprotein E (APOE) ε4, and brain structure with the Mini-Mental State Examination (MMSE) decline using the 9-year follow-up data from Swedish National Study on Aging and Care in Kungsholmen (n = 2189, age ≥60) and the embedded magnetic resonance imaging (MRI) (n = 448) studies. Volumes of white matter hyperintensities (WMHs), total gray matter, ventricles, and hippocampus were assessed in the MRI sample. RESULTS: A higher FGCRS was associated with faster MMSE decline in young-old people (60-72 years) but not in old-old (≥78 years). Larger volumes of cerebral WMHs and ventricles and smaller volumes of total gray matter and hippocampus were all associated with accelerated MMSE decline (P < .01); these associations were stronger among APOE ε4 carriers than noncarriers. Simultaneously entering multiple brain lesion markers as mediators in the model substantially attenuated the association between FGCRS and MMSE decline. DISCUSSION: The effect of cardiovascular risk burden on cognitive deterioration in old age is largely mediated by mixed brain lesions.

Overtime reliability of medial temporal lobe atrophy rating in a clinical setting.

BACKGROUND: Medial temporal lobe atrophy (MTA) is one of the first magnetic resonance imaging (MRI) signs in patients with Alzheimer's disease (AD) and used as a measure of disease progression. Visual assessment of MTA is easy to perform but the reliability of MTA rating over time has not been studied. PURPOSE: To investigate what happens to the MTA rating scores if two radiologists rate the same MRI scans six times over a period of 1 year. MATERIAL AND METHODS: One hundred outpatients were included in this study. All patients underwent MRI with a protocol and sequences used for geriatric patients, according to local clinical standards. One neuroradiologist and one general radiologist independently of each other performed retrospective visual assessments of MTA six times, using the same scans, over a period of 1 year. RESULTS: Intra-rater kappa varied between κ 0.65 and 0.84 for the neuroradiologist and κ 0.38 and 0.74 for the general radiologist. Intra-rater weighted kappa (wκ) values showed almost perfect agreement for both investigators (wκ 0.83-0.94). Inter-rater reliability showed fair to moderate agreement, with the kappa value varying from κ 0.29 to 0.48 and weighted kappa values ranging from wκ 0.72 to 0.84. There was a statistically significant difference in rating between the two investigators. CONCLUSION: Visual assessment of MTA repeated over time has a high grade of reproducibility when performed by an experienced investigator. The reproducibility drops when assessment is rarely performed. Inter-rater reliability is low when two investigators not working together are compared.

Comparison between visual assessment of MTA and hippocampal volumes in an elderly, non-demented population.

BACKGROUND: It is important to have a replicable easy method for monitoring atrophy progression in Alzheimer's disease. Volumetric methods for calculating hippocampal volume are time-consuming and commonly used in research. Visual assessments of medial temporal lobe atrophy (vaMTA) is a rapid method for clinical use. This method has not been tested in a large non-demented population in comparison with volumetry measurements. Since hippocampal volume decreases with time even in normal aging there is also a need to study the normal age differences of medial temporal lobe atrophy. PURPOSE: To compare visual assessment of medial temporal lobe atrophy (vaMTA) with hippocampal volume in a healthy, non-demented elderly population. To describe normal ageing using vaMTA. MATERIAL AND METHODS: Non-demented individuals aged 60, 66, 72, 78, 81, 84, and ≥87 years old were recruited from the Swedish National study on Ageing and Care in Kungsholmen (SNAC-K), Sweden. Standard magnetic resonance imaging (MRI) scans, vaMTA, and calculations of hippocampal volumes were performed in 544 subjects. RESULTS: Significant correlation (r(s) = -0.32, P < 0.001, sin; and r(s) = -0.26, P < 0.001, dx) was found between hippocampal volume measurements and vaMTA. In normal ageing, almost 95% of ≤66-year-olds had a medial temporal lobe atrophy (MTA) score ≤1, with possible scores ranging from 0 to 4. Subjects aged 72, 78, and 81 years scored ≤2, while the two oldest age groups had scores ≤3. CONCLUSION: There was a highly significant correlation between volumetric measurements of the hippocampus and MTA scoring. In normal ageing, there is increasing MTA score. For non-demented elderly individuals ≤70 years, an MTA score of 0-1 may be considered normal, compared with MTA ≤2 for 70-80-years and MTA 3 for >80-year-old individuals.

Association between subcortical lesions and behavioral and psychological symptoms in patients with Alzheimer's disease.

BACKGROUND/AIMS: The most devastating features of Alz-heimer's disease (AD) are often the behavioral and psychological symptoms in dementia (BPSD). There is controversy as to whether subcortical lesions contribute to BPSD. The aim of this study was to examine the relationship between BPSD and subcortical lesions (white-matter lesions and lacunes) in AD. METHODS: CT or MRI from 259 patients with mild-to-moderate AD were assessed with the Age-Related White Matter Changes scale. Linear measures of global and temporal atrophy and Mini-Mental State Examination scores were used to adjust for AD pathology and disease severity in logistic regression models with the BPSD items delusions, hallucinations, agitation, depression, anxiety, apathy and irritability. RESULTS: Lacunes in the left basal ganglia were associated with delusions (OR 2.57, 95% CI 1.21-5.48) and hallucinations (OR 3.33, 95% CI 1.38-8.01) and lacunes in the right basal ganglia were associated with depression (OR 2.13, 95% CI 1.01-4.51). CONCLUSION: Lacunes in the basal ganglia resulted in a 2- to 3-fold increased risk of delusions, hallucinations and depression, when adjusting for cognition and atrophy. This suggests that basal ganglia lesions can contribute to BPSD in patients with AD, independently of the AD process.

Acceleration of hippocampal atrophy in a non-demented elderly population: the SNAC-K study.

BACKGROUND: Brain atrophy in Alzheimer's disease (AD) includes not only AD-specific brain atrophy but also the atrophy induced by normal aging. Atrophy of the hippocampus has been one diagnostic marker of AD, but it was also found to emerge in healthy adults, along with increasing age. It was reported that the important age when age-related shrinkage of the hippocampus starts was around the mid-40s. The aim is to study the aging atrophy speed and acceleration of brain atrophy in a cross-sectional database, to identify the age at which acceleration of hippocampal atrophy starts in non-demented elderly persons. METHODS: 544 subjects (aged 60-97 years; 318 female and 226 male) were recruited into the MRI study by using a subsample of an epidemiological sample of 3363 healthy non-demented elderly people (over 60 years of age). Hippocampus and ventricle sizes were measured. RESULTS: The normalized volumes (by intracranial volume, ICV) of the hippocampus in males were smaller than those in females. The right hippocampus was larger than the left. The expansion of the lateral ventricles (2.80% per year in males, 2.95% in females) and third ventricle (1.58% and 2.28%, respectively) was more marked than the hippocampal shrinkage (0.68% and 0.79%, respectively). The suggested age at which acceleration of hippocampal atrophy starts is 72 years. CONCLUSIONS: Males present smaller hippocampus volumes (normalized by ICV) than females; however, females are more vulnerable to hippocampal atrophy in a non-demented elderly population. An acceleration of hippocampal atrophy may emerge and start around 72 years of age in a non-demented elderly population.

Associations of Vascular Risk Factors and APOE Genotype With Perivascular Spaces Among Community-Dwelling Older Adults.

Background Evidence suggests that enlarged perivascular spaces (PVSs) may represent a marker for cerebral small-vessel disease. We investigated whether vascular risk factors are correlated with visible PVS in older adults. Methods and Results This population-based study included 530 participants (age ≥60 years) who were free from dementia and functional dependence, derived from the Swedish National study on Aging and Care in Kungsholmen (2001-2003). We collected data on demographics, vascular risk factors, and health conditions through interviews, clinical examinations, laboratory tests, and patient registers. Cerebral PVSs and white matter hyperintensities on magnetic resonance images were visually assessed with semiquantitative visual rating scales. Data were analyzed using the general linear regression models. After controlling for demographics and cardiovascular disease, very high blood pressure (≥160/100 mm Hg) was significantly associated with global PVS score (ß-coefficient, 1.30; 95% CI, 0.06-2.53) and orthostatic hypotension was associated with PVS score in the basal ganglia (ß-coefficient 0.37; 0.03-0.70), but the associations became non-significant when adjusting for white matter hyperintensity load. Orthostatic hypotension was significantly associated with global and lobar PVS scores in carriers but not in noncarriers of the APOE ε4 allele. Global or regional PVS score was not significantly associated with other traditional vascular risk factors such as smoking, diabetes mellitus, physical inactivity, and overweight or obesity. Conclusions This study provides limited evidence supporting a correlation of magnetic resonance imaging-visible PVS with traditional vascular risk factors in older adults. The association of orthostatic hypotension with lobar PVS among APOE ε4 carriers suggests that lobar PVS may be a marker for amyloid-associated small-vessel disease.

Different clinical phenotypes in monozygotic CADASIL twins with a novel NOTCH3 mutation.

BACKGROUND AND PURPOSE: CADASIL is a hereditary arteriopathy causing recurrent strokes and cognitive decline. Because monozygotic twins have identical genetic background, differences in their environment and lifestyle could reveal factors that may influence CADASIL patients' clinical course, which is highly variable even within the same family. METHODS: We describe differences in clinical and imaging findings in a pair of monozygotic CADASIL twins. RESULTS: Twin B experienced his first-ever stroke 14 years earlier than twin A, and his symptoms, signs, and imaging findings were more severe. Distinguishing factors were twin B's smoking as well as twin A's physical activity and earlier statin treatment. Causative NOTCH3 mutation was a novel c.752G>A -substitution (p.Cys251Tyr). CONCLUSIONS: The phenotypic differences in these monozygotic twins suggest influence of environmental and lifestyle factors on the clinical course of CADASIL.

First administration of the Fc-attenuated anti-ß amyloid antibody GSK933776 to patients with mild Alzheimer's disease: a randomized, placebo-controlled study.

OBJECTIVE: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-ß amyloid (Aß) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer's disease (AD) or mild cognitive impairment (MCI). METHODS: This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001-6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1-6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436). RESULTS: There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or -hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t1/2) was 10-15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aß42 and Aß increased whereas plasma levels of free Aß decreased dose dependently; no changes were observed for placebo. For total Aß42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aß the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aß showed increases from baseline to week 12 for Aß X-38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aß X-42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses. CONCLUSION: In this FTIH study the Fc-inactivated anti-Aß mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00459550.

White matter lesions and soluble interleukin-1 receptor type II in CSF from demented and non-demented subjects.

White matter lesions (WMLs) in the brain is a common, unspecific finding on magnetic resonance imaging appearing both in the healthy elderly as well as in a number of different diseases including dementia disorders. However, the pathophysiological and clinical significance of WMLs in dementia disorders is still unknown. In this study, we investigated the possibility of their origin being inflammatory by studying the correlation between WMLs and cerebrospinal fluid (CSF) levels of the proinflammatory cytokine soluble interleukin-1 receptor type II (sIL-1RII). The sIL-1RII is a member of the IL-1 family, and has been found to be elevated in CSF from Alzheimer's disease (AD) patients. In the present study, two groups of patients complaining of memory disturbances with little or extensive WMLs respectively, were examined, as well as healthy subjects. In accordance with other reports, WML scores (total, periventricular as well as deep lesions) were positively correlated with age but not mini mental state examination (MMSE) scores, and were significantly higher in patients with a dementia diagnosis as compared to non-demented subjects. There were no differences in sIL-1RII levels in CSF regardless of amount of total, periventricular or deep WMLs, nor were there any differences between demented and non-demented subjects. In conclusion, sIL-1RII levels in CSF are not correlated to magnetic resonance imaging WMLs in patients with dementia disorders or in healthy subjects.

Decreased levels of CD95 and caspase-8 mRNA in multiple sclerosis patients with gadolinium-enhancing lesions on MRI.

Magnetic resonance imaging (MRI) allows examining inflammation and central nervous system (CNS) tissue damage in patients suffering from multiple sclerosis (MS), a demyelinating disease of the CNS. Using real-time PCR, we quantified mRNA levels of apoptosis regulators CD95, CD95 ligand, caspase-8, -10 and cellular FLICE-inhibitory protein (cFLIP), and cytokines IL-10 and TNF-alpha in blood mononuclear cells of MS patients at the time of MRI examination. Patients with detectable gadolinium-enhancing lesions had lower expression of CD95 and caspase-8 (P<0.05). Lesion load and brain atrophy did not correlate with expression levels of any of the target molecules studied. Disease duration correlated positively with both FLIP/caspase-8 and CD95/CD3 ratios (P<0.05). These results support the notion that the CD95-dependent pathway plays a complex role in the regulation of survival of activated immune cells in MS.

Prognostic significance of white matter changes in a memory clinic population.

Non-specific white matter changes (WMC) can be seen on neuroimaging of the brain in healthy elderly but are more common in dementia. WMC are correlated to specific cognitive deficits and might also contribute to global cognitive decline. The value of WMC as a predictor of cognitive impairment has been incompletely elucidated. We studied the prognostic significance of extensive WMC in a group of patients with memory disturbances, to evaluate if the presence of such changes predicts a poorer outcome. We retrospectively selected a group of 24 patients with prominent WMC on magnetic resonance imaging (MRI) and with different grades of memory impairment. We matched each patient, with regard to age, education, length of follow-up, initial score on the Mini Mental State Examination (MMSE) and initial diagnosis, to a patient without white matter pathology. The matched pairs were evaluated and the decrease in MMSE score after follow-up (range 2-4 years) was used as the outcome measure. Results showed no difference in the decrease in MMSE score at follow-up between patients with or without WMC. In conclusion, the presence of WMC in cognitively impaired patients had no effect on the progression rate of dementia, as measured by MMSE decline.

Magnetic resonance imaging in dementia. A study of brain white matter changes.

Non-specific white matter changes (WMC) in the brain are common findings in the elderly population. Although they are frequently seen in non-demented persons, WMC seem to be more common in demented patients. The significance of these changes, as well as their pathophysiological background, is incompletely understood. The aim of this thesis was to study different aspects of WMC using MR imaging (MRI) and to investigate the clinical significance of such changes in subjects with mild cognitive impairment or dementia. In study I post-mortem MRI of the brain was compared to corresponding neuropathology slices. WMC were quantified and found to be more extensive on neuropathology. The areas that appeared normal on MRI but not on histopathology represented only minor changes with increased distance between the myelinated fibres but with preserved axonal network and glial cell density. Study II evaluated the blood-brain barrier (BBB) integrity to investigate if an increased permeability could be shown in WMC. A contrast-enhanced MRI technique was used to detect small degrees of enhancement. No general increase in BBB could be detected in the WMC areas. In study III the relation between WMC and apolipoprotein E (APOE) genotype was explored in patients with Alzheimer's disease (AD). Results showed that AD patients, who were homozygous for the APOE epsilon 4 allele had more WMC than patients with other genotypes. This was most significant for changes in the deep white matter. Results also indicated that in AD patients carrying the epsilon 4 allele, WMC are not age-related phenomena, but might be related to the aetiology of the disease. Study IV aimed to investigate if WMC in a specific brain region affect cognitive functions related to that area. Periventricular WMC in the left frontal lobe predicted a decrease in initial word fluency, a test though to reflect left frontal lobe functioning. This indicates that WMC might have specific effects in different brain regions. In study V we evaluated the prognostic significance of WMC in patients with memory impairment, regarding the rate of further global cognitive decline. There was no difference in outcome between patients having extensive WMC and a matched control group, during 2-4 years of follow up, and assessed by the "Mini-Mental State Examination". In conclusion, this work has shown and characterised pathological changes in the white matter not visible on conventional MRI. We have also shown that there is no major general increase in BBB permeability in areas of WMC. In addition, homozygosity with regard to the APOE epsilon 4 gene allele implies an increased extent of WMC in AD patients. In AD patients carrying this gene allele, WMC are not merely age-related phenomena, but might be related to the aetiology of the disease. We also claim that WMC in a specific location might impair cognitive functions that rely on those specific pathways. In contrast, WMC do not seem to have any prognostic value in predicting the rate of global cognitive decline in patients at a memory clinic.

Postmortem MRI and histopathology of white matter changes in Alzheimer brains. A quantitative, comparative study.

To evaluate whether magnetic resonance imaging (MRI) of white matter changes in Alzheimer's disease either under- or overestimates the findings on neuropathology. Postmortem MRI and neuropathological examination were performed on 6 brains from elderly individuals with a postmortem diagnosis of AD. Using a specially designed brain slicer, the brains were cut corresponding to the MRI images, and stained by Luxol Fast Blue. Quantitative analysis of white matter changes on MRI and neuropathology was performed using stereological principles. Measures from MRI and pathology were highly correlated (r(2) = 0.71). However, pathology showed significantly more extensive changes than did MRI in all cases, with a mean of 54% larger areas. The lesions not identified with MRI represented, however, only minor changes with lower intensity of myelin staining and with an accentuation of the distance between fibres but with preserved axonal network and glial cell density.