J. Jolles

Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study

OBJECTIVE White matter lesions are often seen on MR scans of elderly non-demented and demented people. They are attributed to degenerative changes of small vessels and are implicated in the pathogenesis of cognitive decline and dementia. There is evidence that especially periventricular white matter lesions are related to cognitive decline, whereas subcortical white matter lesions may be related to late onset depression. The frequency distribution of subcortical and periventricular white matter lesions according to age and sex reported. METHODS A total of 1077 subjects aged between 60–90 years were randomly sampled from the general population. All subjects underwent 1.5T MR scanning; white matter lesions were rated separately for the subcortical region and the periventricular region. RESULTS Of all subjects 8% were completely free of subcortical white matter lesions, 20% had no periventricular white matter lesions, and 5% had no white matter lesions in either of these locations. The proportion with white matter lesions increased with age, similarly for men and women. Women tended to have more subcortical white matter lesions than men (total volume 1.45 ml v 1.29 ml; p=0.33), mainly caused by marked differences in the frontal white matter lesion volume (0.89 ml v 0.70 ml; p=0.08). Periventricular white matter lesions were also more frequent among women than men (mean grade 2.5 v 2.3; p=0.07). Also severe degrees of subcortical white matter lesions were more common in women than in men (OR 1.1; 95% confidence interval (95% CI) 0.8–1.5) and periventricular white matter lesions (OR 1.2; 95% CI 0.9–1.7), albeit that none of these findings were statistically significant. CONCLUSIONS The prevalence and the degree of cerebral white matter lesions increased with age. Women tended to have a higher degree of white matter lesions than men. This may underlie the finding of a higher incidence of dementia in women than in men, particularly at later age.

Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas : a comparative study

BACKGROUND Because survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy. METHODS 195 patients with low-grade glioma (of whom 104 had received radiotherapy 1-22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability. FINDINGS Low-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function. INTERPRETATION Our findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.

The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women : A meta-analysis

We reviewed epidemiological and experimental studies of female gonadal hormone replacement therapy (HRT) on cognitive function in post-menopausal women and carried out meta-analyses. In healthy ageing women, HRT has small and inconsistent effects that include enhancement of verbal memory, abstract reasoning and information processing. Epidemiological studies show larger effects than experimental studies, which is not related to sample size. Important confounds may be that women who start using HRT are healthier than women who do not. Also, controlling for socio-economic status diminishes the effect of HRT. The effects of HRT may depend on the age and type of menopause and the therapeutic intervention used, with the most widely used drug, Premarin, having least effect. However, the effects are independent of mood and climacteric symptom alleviation. There is a paucity of experimental studies that include healthy elderly women. The evidence for an estrogen deficiency in women with dementia and cognitive dysfunction is inconsistent. Nevertheless, epidemiological studies suggest that HRT protects against the development of clinically diagnosed Alzheimers disease. However, poor recall of HRT use by patients and altered physician behaviour may have confounded the effects. Surprisingly, both healthy and demented women with low education seem to benefit most from HRT. Three recent controlled experimental studies using Premarin showed no effects of HRT in preventing further cognitive decline in women who already have Alzheimers disease. Duration of treatment seems to play an important role, with beneficial effects declining-and even reversing-with longer treatment in women with Alzheimers disease.Future research should further investigate the cognitive effect of different HRT preparations, serum estrogen levels, and the interactions of HRT with age, menopausal status and existing protective (e.g. education) and risk factors (e.g. smoking and apolipoprotein E genotype) for cognitive decline and Alzheimers disease.

Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment

Abstract To determine whether the medial temporal lobe is atrophic in subjects with mild cognitive impairment, and whether atrophy of this structure is a better predictor of dementia than memory dysfunction. Forty-five noninstitutionalized subjects aged 65–85 years were randomly selected from a population based study to obtain a sample with Alzheimer’s disease (AD; n = 7), and a clinically nondemented sample (n = 38). Twenty of the latter subjects displayed some cognitive impairment and fulfilled CAMDEX criteria for “minimal dementia.” Coronal T1-weighted magnetic resonance imaging was used to visualize the medial temporal lobe. The volume of the parahippocampal gyrus and hippocampus was measured, and medial temporal lobe atrophy was assessed qualitatively. The memory subscore from the CAMCOG was used as a measure of memory functioning. The follow-up period was 3 years. Nine subjects who were diagnosed as being minimally demented at baseline met the criteria for AD during follow-up. At baseline the volume of the parahippocampal gyrus of these subjects was smaller than that of the other subjects with minimal dementia. The memory score was the best predictor of clinical outcome. All medial temporal lobe measures increased the accuracy of prediction compared with only the memory score, by reducing the number of false-negative classifications of dementia. Severe medial temporal lobe atrophy is present even in some subjects with mild cognitive impairment and is an indicator of subsequent AD. The absence of medial temporal lobe atrophy, however, does not exclude the development of dementia. In the majority of subjects memory impairment was a better predictor of dementia than atrophy of the medial temporal lobe. The combination of the two increased predictive accuracy. Nondemented subjects with severe atrophy of the medial temporal lobe could be enrolled in drug trials aimed at slowing the progression of AD.

Stroop interference: aging effects assessed with the stroop color-word test

A large, cross-sectional aging investigation of performance on the Stroop Color-Word Test (SCWT) was carried out. Subjects were 247 volunteers, ages 20-80 in seven age levels. Although all subjects thought themselves to be normal and healthy, a post hoc division could be made on the basis of biological life events (BLE). BLE are mild biological or environmental factors, such as repeated experiences of general anesthesia, that can hamper optimal brain functioning. Apart from the anticipated age effects, performance was poorer in subjects who had experienced one or more BLE: The slowing due to BLE was comparable to the effect of age, especially on the task involving language interference in color-naming. Education had a significant effect on performance: More highly educated subjects performed better than less educated subjects. No sex differences were observed. These findings replicate observations made with other tests in parallel studies. They are also in line with several other studies reporting interactions between the effects of aging and physical fitness. This study questions some of the validity of cognitive aging research, as our data suggest that screening for BLE as age-extrinsic factors in nondiseased subjects can reduce many of the performance deficits usually ascribed to aging per se.

Medial temporal lobe atrophy predicts Alzheimer's disease in patients with minor cognitive impairment

Objectives: To investigate whether medial temporal lobe atrophy predicted outcome in patients with minor cognitive impairment and whether assessment of the medial temporal lobe could increase the predictive accuracy of age and delayed recall for outcome. Quantitative and qualitative methods of assessing the medial temporal lobe were also compared. Methods: Patients with minor cognitive impairment older than 50 years (n=31) were selected from a memory clinic and were followed up for on average 1.9 years. The medial temporal lobe was assessed in three different ways: volumetry of the hippocampus, volumetry of the parahippocampal gyrus, and qualitative rating of medial temporal lobe atrophy (MTA). Outcome measures were Alzheimer type dementia or cognitive decline at follow up. Delayed recall was tested with a verbal learning test. Results: Ten patients had experienced cognitive decline at follow up, of whom seven had probable Alzheimer type dementia. All medial temporal lobe measurements were associated with cognitive decline at follow up (p trend analysis between 0.001 (hippocampus) and 0.05 (parahippocampal gyrus)). Only the hippocampal volume and MTA score were associated with Alzheimer type dementia at follow up (p trend analysis respectively 0.003 and 0.01). All medial temporal lobe measurements increased the predictive accuracy of age and the delayed recall score for cognitive decline (p increase in predictive accuracy varied between <0.001 (hippocampus) and 0.02 (parahippocampal gyrus and MTA score)) and the hippocampal volume and the MTA score increased the predictive accuracy of age and the delayed recall score for Alzheimer type dementia (p= 0.02). Conclusions: The ability to detect patients at high risk for Alzheimer type dementia among those with minor cognitive impairment increases when data on age and memory function are combined with measures of medial temporal lobe atrophy. Volumetry of the hippocampus is preferred, but qualitative rating of medial temporal lobe atrophy is a good alternative.

Cerebral white matter lesions and subjective cognitive dysfunction: The Rotterdam Scan Study

Objective: To determine the relationship between cerebral white matter lesions (WML) and subjective cognitive dysfunction. Background: Subjective cognitive dysfunction is present when a person perceives failures of cognitive function. When annoying enough, these failures will be expressed as complaints. Subjective cognitive dysfunction may be a prelude to or coincide with objective cognitive impairment. WML have been related to objective cognitive impairment and dementia, but their relationship with subjective cognitive dysfunction is not clear. Previous population-based studies on the latter relationship have been limited in sample size, recording of subjective cognitive function, and assessment of WML severity. Methods: We randomly sampled 1,049 elderly nondemented participants from the general population. Data on subjective cognitive dysfunction and its progression were derived from a 15-item questionnaire. Objective cognitive performance was assessed using a series of neuropsychological tests. WML were scored on MRI for periventricular and subcortical regions separately. Results: WML were associated with more subjective cognitive failures. WML were more severe for participants reporting progression of these failures compared with participants without these failures, especially within participants with better than average cognitive performance (p = 0.008, for periventricular WML). Participants with severe WML reported progression of cognitive failures more than twice as often than did those with little or no WML. The relationship between the severity of WML and subjective cognitive failures was present for periventricular and subcortical WML. Conclusions: WML are associated with subjective cognitive failures and in particular with reporting progression of these failures, even in the absence of objective cognitive impairment.

Homocysteine and cognitive function in the elderly : the Rotterdam scan study

Background: Elevated plasma total homocysteine (tHcy) concentrations are associated with AD and vascular dementia, but the relation with cognitive performance in nondemented elderly people is not known. Objective: To examine the association of tHcy and cognitive function in the elderly, and assess whether this may be mediated by structural brain changes on MRI. Methods: The Rotterdam Scan Study is a population-based study of 1,077 nondemented elderly. Cognitive performance was assessed, and compound scores were constructed for psychomotor speed, memory function, and global cognitive function. Cerebral infarcts, white matter lesions, and generalized brain atrophy were measured on MRI. The cross-sectional relationship between tHcy levels and neuropsychological test scores was assessed by multiple regression. Results: Mean tHcy level was 11.5 μmol/L (SD 4.1). Increasing tHcy levels were associated with lower scores for psychomotor speed, memory function, and global cognitive function, and this was largely due to the association with tHcy levels in the upper quintile (>14 μmol/L). Adjusted differences between test scores of participants in the upper quintile as compared with the lower four quintiles of tHcy were −0.26 (95% CI: −0.37; −0.14) for psychomotor speed, −0.13 (95% CI: −0.27; 0.01) for memory function, and −0.20 (95% CI: −0.30; −0.11) for global cognitive function. These associations were not mediated by structural brain changes on MRI. Conclusion: Elevated tHcy levels are associated with decreased cognitive performance in nondemented elderly people, and the relation was most marked for psychomotor speed. This association was independent of structural brain changes on MRI.

Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population

Objective: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. Methods: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. Results: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. Conclusion: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.

Ten-year risk of dementia in subjects with mild cognitive impairment

Objective: To investigate the 10-year risk of dementia in subjects with mild cognitive impairment (MCI) ages 40 to 85 years. Methods: We selected subjects from a memory clinic if they met one of the following definitions of MCI: cognitive complaints (n = 181), aging-associated cognitive decline (AACD) (n = 163), mild functional impairment (n = 86), or amnestic MCI (n = 64). Subjects were reassessed after 2, 5, and 10 years. The risk of dementia was calculated with Kaplan-Meier statistics. Analyses were conducted in the entire sample and in subgroups of subjects aged 40 to 54 years, 55 to 69 years, and 70 to 85 years. Results: The 10-year risk of dementia was 0.27 (95% CI 0.20 to 0.34) in subjects with cognitive complaints, 0.28 (95% CI 0.21 to 0.35) in subjects with AACD, 0.44 (95% CI 0.32 to 0.56) in subjects with mild functional impairment, and 0.48 (95% CI 0.35 to 0.61) in subjects with amnestic MCI. Ninety-one percent of the demented subjects had probable AD. The risk of dementia increased with increasing age for all MCI definitions (p < 0.001). Depending on the MCI definition used, the risk for dementia ranged from 0 to 0.06 in subjects aged 40 to 54 years, from 0.37 to 0.52 in subjects aged 55 to 69 years, and from 0.77 to 1.0 in subjects aged 70 to 85 years. Conclusions: The majority of subjects with MCI do not progress to dementia at the long term. Age strongly influences the dementia risk. MCI often represents the predementia stage of a neurodegenerative disorder in elderly subjects but rarely in younger subjects.