White matter volumes and periventricular white matter hyperintensities in aging and dementia

OBJECTIVE: To determine the relationship between MRI periventricular white matter hyperintensities, cerebral white matter volumes, neuropathologic findings, and cognitive status in aged individuals. BACKGROUND: The significance of periventricular white matter hyperintensities seen on MR images in aged individuals remains controversial. The Nun Study is a longitudinal cohort aging study in which all 678 initially enrolled participants agreed to autopsy neuropathologic examination. METHODS: We used MRI to measure white matter volumes of the cerebral hemispheres in 52 formaldehyde-fixed brains for correlation with white matter and neocortical pathology, postmortem MRI observations, and cognitive measures. RESULTS: Reduced white matter volume is associated with dementia, but periventricular white matter hyperintensities were not related to white matter volume, stroke, or dementia. CONCLUSIONS: Our results do not support the hypothesis that periventricular hyperintensities seen on MR images have deleterious consequences in these aged individuals.     

White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer's disease, vascular dementia, and normal aging

OBJECTIVES: Alzheimer's disease and vascular dementia are associated with an increase in changes in white matter on MRI. The aims were to investigate whether white matter changes also occur in dementia with Lewy bodies and to examine the relation between white matter lesions and the cognitive and non-cognitive features of dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. METHODS: Proton density and T2 weighted images were obtained on a 1.0 Tesla MRI scanner in patients with dementia with Lewy bodies (consensus criteria; n=27, mean age=75.9 years), Alzheimer's disease (NINCDS/ADRDA; n=28, mean age=77.4 years), vascular dementia (NINDS/AIREN; n=25, mean age=76.8 years), and normal controls (n=26, mean age=76.2 years). Cognitive function, depressive symptoms, and psychotic features were assessed using a standardised protocol. Periventricular hyperintensities (PVHs), white matter hyperintensities (WMHs) and basal ganglia hyperintensities (BGHs) were visually rated blind to diagnosis using a semiquantitative scale. RESULTS: Periventricular hyperintensities were positively correlated with age and were more severe in all dementia groups than controls. Total deep hyperintensities scores (WMHs plus BGHs) were significantly higher in all dementia groups than controls and higher in patients with vascular dementia than those with dementia with Lewy bodies or Alzheimer's disease. In all patients with dementia, frontal WMHs were associated with higher depression scores and occipital WMHs were associated with an absence of visual hallucinations and delusions. CONCLUSION: In common with Alzheimer's disease and vascular dementia, PVHs and WMHs were significantly more extensive in dementia with Lewy bodies than in controls. This overlap between different dementias may reflect shared pathological mechanisms. The link between frontal WMHs and depression and the absence of occipital WMHs and psychotic symptoms has important implications for understanding the neurobiological basis of these symptoms.     

Subcortical hyperintensities on magnetic resonance imaging: a comparison of normal and depressed elderly subjects

Previous studies reported that depressed subjects had more signal hyperintensities on magnetic resonance imaging scans than control subjects, but the subjects had cerebrovascular disease risk factors. This study used subjects with a history of major depression and matched comparison subjects, screened to exclude cerebrovascular risk factors, to determine whether depressed subjects had more white matter hyperintensities and other lesions. We evaluated the prevalence and severity of MRI signal hyperintensities in 30 elderly depressed patients and 20 controls matched for age. Deep matter hyperintensities, periventricular hyperintensities and subcortical gray hyperintensities were rated on a standard 0-3 scale by two radiologists blind to clinical diagnosis. No significant differences were found between groups for the presence of subcortical gray matter, deep white matter and periventricular hyperintensities. These findings suggest that cerebrovascular disease risk factors most likely mediated the relationship between depression and hyperintensities in previous studies.     

Clinical correlates of white-matter changes on magnetic resonance imaging scans of the brain

We report our observations on the clinical and radiologic correlates of changes in cerebral white matter based on 94 subjects undergoing magnetic resonance imaging in a prospective study of dementia. Periventricular hyperintensity occurred twice as often in patients with Alzheimer's disease as in healthy control subjects. Within the control group, the presence of periventricular hyperintensity correlated significantly with one measure of cerebral atrophy and with the presence of changes in the adjoining deep white matter. The significance of white-matter changes distinct from the ventricles (leuko-araiosis) remains unsettled. Leuko-araiosis on the magnetic resonance imaging scan, unlike its correlate on the computed tomographic scan, was not shown to relate to cognitive decline or to the presence of focal abnormalities on neurologic examination. This is likely to reflect the heterogeneity of the changes detected with magnetic resonance imaging and their limited extent in our subjects.     

White matter magnetic resonance hyperintensities in dementia of the Alzheimer type: morphological and regional cerebral blood flow correlates.

In a prospective MRI study the presence, appearance, volume, and regional cerebral blood flow (rCBF) correlates of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) were examined in 18 patients with probable Alzheimer's disease and in 10 age matched healthy control subjects, all without major cerbrovascular risk factors. The 133Xe inhalation method and the [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) technique with single photon emission computed tomography (SPECT) were used to measure rCBF. Rating scores for PVHs were significantly higher in the Alzheimer's disease group (p < 0.01) and correlated significantly with the volume of ventricles (p < 0.05) and with systolic arterial blood pressure (p < 0.01), but not with rCBF. By contrast, there was no significant difference in the rating scores or volumes of DWMHs between the two groups, although three patients had extensive DWMH lesions in the central white matter. In the group of patients with Alzheimer's disease as a whole, the volume of DWMHs correlated well with rCBF in the hippocampal region ( r = -0.72; p < 0.001), but not with frontal, temporal, parietal, or occipital rCBF. Postmortem histopathology of extensive DWMH lesions in one patient with definite Alzheimer's disease showed a partial loss of myelin and astrocytic gliosis, but no ischaemic changes. It is concluded that DWMH lesions may be associated with reduced rCBF in the hippocampal region. The heterogenous topography of neocortical rCBF deficits in Alzheimer's disease could not be explained by deafferentation from underlying white matter hyperintensities and therefore may reflect variations in the topography of cortical abnormalities.     

The role of MRI in dementia

Neuroimaging techniques aimed at studying structural changes of the brain may provide useful information for the diagnosis and the clinical management of patients with dementia. Magnetic resonance imaging (MRI) may show abnormalities amenable to surgical treatment in a significant percentage of patients with cognitive impairment. MRI may also assist the differential diagnosis in dementia associated with metabolic or inflammatory diseases.MRI has the potential to detect focal signal abnormalities which may assist the clinical differentiation between Alzheimer's disease (AD) and vascular dementia (VaD). Severe temporal atrophy, hyperintensities involving the hippocampal or insular cortex, and gyral hypointense bands are more frequently noted in AD. Basal ganglionic/thalamic hyperintense foci, thromboembolic infarctions, confluent white matter and irregular periventricular hyperintensities are more common in VaD.The high sensitivity of MRI in detecting T2 hyperintense lesions and the low specificity off white matter lesions have resulted in a poor correlation between MRI findings and both neuropathological and clinical manifestations. In particular, MRI has disclosed a series of white matter focal changes in the elderly population, which are not necessarily associated with cognitive dysfunction.The recent advent of a new MRI method sensitive to the microstructural changes of white matter, the so-called diffusion tensor imaging, may be helpful in correlating clinical manifestations with white matter abnormalities.     

Carotid sinus syndrome is common in dementia with Lewy bodies and correlates with deep white matter lesions

BACKGROUND: Carotid sinus syndrome (CSS) is a common cause of syncope in older persons. There appears to be a high prevalence of carotid sinus hypersensitivity (CSH) in patients with dementia with Lewy bodies (DLB) but not in Alzheimer's disease. OBJECTIVE: To compare the prevalence of CSH in DLB and Alzheimer's disease, and to determine whether there is an association between CSH induced hypotension and brain white matter hyperintensities on magnetic resonance imaging (MRI). METHODS: Prevalence of CSH was compared in 38 patients with DLB (mean (SD) age, 76 (7) years), 52 with Alzheimer's disease (80 (6) years), and 31 case controls (73 (5) years) during right sided supine carotid sinus massage (CSM). CSH was defined as cardioinhibitory (CICSH; >3 s asystole) or vasodepressor (VDCSH; >30 mm Hg fall in systolic blood pressure (SBP)). T2 weighted brain MRI was done in 45 patients (23 DLB, 22 Alzheimer). Hyperintensities were rated by the Scheltens scale. RESULTS: Overall heart rate response to CSM was slower (RR interval = 3370 ms (640 to 9400)) and the proportion of patients with CICSH greater (32%) in DLB than in Alzheimer's disease (1570 (720 to 7800); 11.1%) or controls (1600 (720 to 3300); 3.2%) (p<0.01)). The strongest predictor of heart rate slowing and CSH was a diagnosis of DLB (Wald 8.0, p<0.005). The fall in SBP during carotid sinus massage was greater with DLB (40 (22) mm Hg) than with Alzheimer's disease (30 (19) mm Hg) or controls (24 (19) mm Hg) (both p<0.02). Deep white matter hyperintensities were present in 29 patients (64%). In DLB, there was a correlation between magnitude of fall in SBP during CSM and severity of deep white matter changes (R = 0.58, p = 0.005). CONCLUSIONS: Heart rate responses to CSM are prolonged in patients with DLB, causing hypotension. Deep white matter changes from microvascular disease correlated with the fall in SBP. Microvascular pathology is a key substrate of cognitive impairment and could be reversible in DLB where there are exaggerated heart rate responses to carotid sinus stimulation.     

Neuropathologic correlates of leuko-araiosis

We describe the pathologic findings in 17 persons with dementia, 12 of whom exhibited leuko-araiosis on computed tomographic scan. The presence of white matter pallor was confirmed on autopsy in 11 of these 12 cases, 9 with Alzheimer's disease and 2 with multi-infarct dementia. Two further patients, 1 with Alzheimer's disease and 1 with multi-infarct dementia, proved to have white matter changes on pathologic examination. White matter pallor coexisted with cerebral amyloid angiopathy in the brains of the patients with Alzheimer's disease. The presence of severe white matter pallor in patients with Alzheimer's disease correlated with early death, while the presence of cortical scars was associated with prolonged survival. Because early death in patients with Alzheimer's disease has been linked with severe pathologic and chemical changes, the presence of white matter pallor may be further evidence of a particularly severe process in patients with early onset of Alzheimer's disease.     

Clasmatodendrosis correlating with periventricular hyperintensity in mixed dementia

We report a 79-year-old woman with possible Alzheimer's disease and confluent periventricular white matter hyperintensities on magnetic resonance imaging in whom postmortem analysis unexpectedly demonstrated no periventricular demyelination or cerebral arteriosclerosis. However, astrocytes in the periventricular white matter exhibited clasmatodendrosis, defined as cytoplasmic swelling and vacuolation of astroglia, with beading of their dendrites. This finding represents a previously unrecognized correlate of periventricular white matter hyperintensities. Ann Neurol 2002;52:378-381     

Magnetic resonance findings in patients with early-onset Alzheimer's disease

The magnetic resonance scans of 22 patients with early-onset Alzheimer's disease (AD) were compared to 16 age-matched neurologically normal controls for the presence of white matter subcortical hyperintensities (SCH) and periventricular hyperintensities (PVH). Patients with AD were significantly more likely to have evidence of PVH (p less than 0.01) than age-matched controls. There was no significant difference between the two groups in either the frequency of SCH or the size of the largest lesion. Within the AD group, there was no difference demonstrated in the location of the SCH, either in the anterior-posterior plane or between the two hemispheres. Patients with AD more frequently demonstrated ventriculomegaly (p less than 0.001) and sulcal widening (p less than 0.05) compared with controls. This study suggests that the SCH seen in early-onset AD patients on MRI are related more to the aging process than to the AD process and that the increased frequency of PVH may have a relationship to the disease process.     

Comparison of magnetic resonance imaging in Alzheimer's disease, vascular dementia and normal aging.

MRI scans of 27 patients with probable Alzheimer's disease (mean age 68.2 years), 31 patients with vascular dementia (mean age 69.9 years) and 18 normal controls (mean age 66.3 years) were compared to evaluate possible distinguishing parenchymal abnormalities among these groups. Atrophy was quantitated by subjective rating, linear and volumetric measurements. A number of findings were significantly more common in vascular dementia than in the other subsets. These included (1) basal ganglionic/thalamic hyperintense foci, (2) thromboembolic infarctions, (3) confluent white matter and (4) irregular periventricular hyperintensities. Signal abnormalities on intermediate T2-weighted scans in the uncal-hippocampal or insular cortex were frequently and almost exclusively noted in Alzheimer's disease. Moderate and severe cortical and ventricular atrophy and a third ventricular to intracranial width ratio larger than 7% were good discriminators between demented groups and normally aging controls. Selective atrophy measurements, however, failed to separate dementia syndromes. These results suggest that MRI has the potential to increase the accuracy of the clinical diagnosis of Alzheimer's disease and vascular dementia.     

Comparison of MRI white matter changes with neuropsychologic impairment in Cockayne syndrome.

The neuropsychologic function and white matter changes observed on magnetic resonance imaging (MRI) in Cockayne syndrome were studied. MRI with T2-weighted sequences revealed periventricular hyperintensity and white matter hyperintensity in all 3 Cockayne syndrome patients examined; in contrast, 8 age-matched controls had no periventricular or white matter hyperintensity. MRI scans were graded according to the severity of periventricular or white matter hyperintensity using a scale applied to an elderly patient population. There was no difference in the severity of MRI white matter changes in these 3 Cockayne syndrome patients, 2 of whom had severe neuropsychologic functions and one a relatively milder one. There was no correlation between neuropsychologic impairment and MRI white matter changes.     

Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression

OBJECTIVE: This study examined whether evidence of cerebrovascular disease in the form of magnetic resonance imaging (MRI) signal hyperintensities in white matter was associated with depressive symptoms in a high-functioning group of normal elderly volunteers. METHOD: Ninety-two community-dwelling elderly individuals participating in a study of white matter hyperintensities (WMHs) in normal aging whose apolipoprotein E (APOE) genotype had been determined completed the Geriatric Depression Scale and received an MRI scan. Univariate analyses of variance were used to examine the relationship between depressive symptoms and the location of WMHs (in deep white matter versus in periventricular white matter) and to determine whether WMHs were more likely to be associated with symptoms of impaired motivation and concentration or with mood symptoms. The effect on depressive symptoms of the interaction between severity of cerebrovascular disease as evidenced by WMHs and APOE genotype was also examined. RESULTS: Hyperintensities in the deep white matter, but not in the periventricular white matter, were associated with depressive symptoms, especially symptoms of impaired motivation, concentration, and decision making. The relationship between deep WMHs and depressive symptoms was especially strong in individuals carrying the APOE-4 allele. CONCLUSIONS: The pattern of depressive symptoms associated with WMHs in this study was similar to the pattern described in the literature as characterizing "vascular" depression in older persons with major depression. The results suggest that cerebrovascular disease may also underlie the depressive symptoms often found in older individuals who are not clinically depressed.     

Comparative neuroimaging with pathologic correlates in Alexander's disease

We describe a case of pathologically confirmed Alexander's disease in which serial cranial ultrasound studies demonstrated unique findings of enlarging subependymal cysts with evolving periventricular hyperechogenicity. Computed tomographic scan of the head showed low attenuation of the periventricular white matter and centrum semiovale. Magnetic resonance imaging (MRI) demonstrated diffuse, confluent high signal predominantly in frontal white matter. These imaging modalities, particularly cranial ultrasound and MRI, may be useful tools in the diagnostic evaluation of children with degenerative neurologic disease, megalencephaly, and suspected Alexander's disease.     

Magnetic resonance imaging and other techniques in the diagnosis of multiple sclerosis

We evaluated 35 patients with multiple sclerosis (MS) by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, evoked potential testing, and computed tomographic (CT) scanning. As classified by the McAlpine et al and McDonald and Halliday criteria, 27 patients had definite MS, three had probable MS, and five had possible MS. All of the patients had multiple white matter lesions detectable by MRI that were evident predominantly in the periventricular areas but also in the cerebral or cerebellar white matter. The severity of the MRI abnormality, as judged by the number and size of the lesions, correlated with the likelihood of a positive CT scan but not with the duration of disease, the degree of disability, or positive CSF oligoclonal banding. Magnetic resonance imaging successfully demonstrated brain-stem lesions in 15 patients (none were seen on CT scans). Magnetic resonance imaging seems to be a sensitive indicator of MS lesions, but clinical assessment will continue to be crucial to the diagnosis of MS.     

Different associations of periventricular and deep white matter lesions with cognition, neuropsychiatric symptoms, and daily activities in dementia

We investigated the associations of periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) with cognition, activities of daily living (ADLs), and neuropsychiatric symptoms in dementia. This was a hospital-based MRI300 study. We recruited patients newly diagnosed with mild-to-moderate dementia caused either by Alzheimer's disease or subcortical ischemic vascular dementia from 13 dementia clinics at university or general hospitals in South Korea. We enrolled 289 patients aged over 50 from August 2007 to March 2008. We compared cognition, ADLs, and neuropsychiatric symptoms among 3 groups according to the severities of PWMHs and DWMHs, respectively, by adjusting for age, vascular risk factors, and level of other WMHs. A higher severity of PWMHs was related to lower cognitive function and severer neuropsychiatric symptoms, whereas basic ADLs were associated with DWMH. Both PWMHs and DWMHs exhibited different associations with cognition, neuropsychiatric symptoms, and daily activities.     

Progression of cerebral white matter lesions is not associated with development of depressive symptoms in elderly subjects at risk of cardiovascular disease: The PROSPER Study

BACKGROUND: Cerebral white matter hyperintensities on magnetic resonance imaging (MRI) scans have been associated with vascular disease and late-life depression, both in the general population and in psychiatric patients. Therefore, a cerebrovascular etiology for late-onset depression has been hypothesized. However, longitudinal studies on the causal role of white matter hyperintensities in the development of depressive symptoms in elderly adults are lacking. OBJECTIVE: To investigate the relation between white matter hyperintensities and depressive symptoms in elderly subjects at risk of cardiovascular disease. METHODS: In the Dutch sample of the PROSPER (PROspective Study of Pravastatine in the Elderly at Risk of cardiovascular disease) cohort, 527 non-demented elderly, all aged 70 years or older, received a cranial MRI scan and the 15-item Geriatric Depression Scale, at baseline and 33 months (SD 1.6) later. RESULTS: Presence of white matter hyperintensities at baseline was not related to baseline depressive symptoms nor to the development of depressive symptoms during follow-up. Moreover, no association was found between progression of white matter lesion volume and progression of depressive symptoms. CONCLUSION: This longitudinal study does not confirm the involvement of cerebrovascular disease expressed as MRI white matter hyperintensities in the development of depressive symptoms in elderly subjects.     

Does APO ε4 correlate with MRI changes in Alzheimer's disease?

OBJECTIVE: To assess the relation between APO E genotype and MRI white matter changes in Alzheimer's disease. The APO epsilon4 allele is correlated with amyloid angiopathy and other neuropathologies in Alzheimer's disease and could be associated with white matter changes. If so, there should be a dose effect. METHODS: 104 patients with probable Alzheimer's disease (NINCDS-ADRDA criteria) in this Alzheimer's Disease Research Centre were studied. Patients received MRI and APO E genotyping by standardised protocols. Axial MRI was scored (modified Schelten's scale) for the presence and degree of white matter changes and atrophy in several regions by a neuroradiologist blinded to genotype. Total white matter and total atrophy scores were also generated. Data analysis included Pearson's correlation for regional and total imaging scores and analysis of variance (ANOVA) (or Kruskal-Wallis) and chi(2) for demographic and disease related variables. RESULTS: 30 patients had no epsilon4, 53 patients were heterozygous, and 21 patients were homozygous. The three groups did not differ in sex distribution, age of onset, age at MRI, MMSE, clinical dementia rating, or modified Hachinski ischaemia scores. There were no significant correlations between total or regional white matter scores and APO E genotype (Pearson correlation). CONCLUSIONS: No correlation between total or regional white matter scores and APO E genotype was found. The pathogenesis of white matter changes in Alzheimer's disease may be independent of APO E genotype.     

Correlates of leukoaraiosis and ventricular enlargement on magnetic resonance imaging: a study in normal elderly and cerebrovascular patients

Several studies have repeatedly demonstrated that leukoaraiosis as well as ventricular enlargement are common findings in normal elderly and in stroke patients, although there is no general consensus on prevalence rate as well as on their clinical correlations. It is also controversial whether white matter changes and ventricular enlargement are reciprocally related. In this study we investigated the prevalence and extent of white matter hyperintensities and the degree of ventricular enlargement on magnetic resonance imaging in 50 normal elderly individuals (mean age 62.1 ± 7.3 years) and in 50 consecutive chronic ischemic stroke patients (mean age 66.1 ± 7.7 years). All subjects underwent extensive clinical assessment. White matter hyperintensities were graded from 0 to 3 on a semi-quantitative scale, while bifrontal horn, bicaudate, and third ventricle ratio indices were used as measures of brain atrophy. Hypertension, diabetes, alcohol consumption, cardiac disease, carotid pathology occurred significantly more often in patients than in controls. Prevalence rates of white matter hyperintensities were 30% in controls and 82% in patients. Patients had significantly larger ventricular indices than controls. Significant univariate correlations for the extent of white matter hyperintensities were found with age, sex, hypertension, cardiac disease, carotid pathology, diabetes, history of stroke and ventricular enlargement. Age, sex, cardiac disease, alcohol habit, cerebrovascular disease and extent of white matter hyperintensities correlated with severity of ventricular enlargement. Multivariate regression analysis identified age, hypertension and history of stroke as independent predictors of white matter hyperintensities, while history of stroke, age and alcohol consumption were found as the only independent predictors of ventricular enlargement Separate analysis between periventricular, subcortical or deep white matter hyperintensities and each of the three ventricular indices failed to show a significant association after adjustment for clinical and demographic factors. We suggest that leukoaraiosis and ventricular enlargement are independent pathological processes associated with different risk factors in addition to age and stroke disease.     

Neuropsychiatric correlates of cerebral white-matter radiolucencies in probable Alzheimer's disease.

We evaluated the neuropsychological functions, rate of disease progression, and psychiatric characteristics of 22 patients with probable Alzheimer's disease in whom periventricular white-matter radiolucencies (PWMRs) were seen on the computed tomographic scan of the brain and compared them with 22 matched patients with Alzheimer's disease without PWMRs. Executive/attention, lexical/semantic, memory/learning, and visuospatial functions did not differ between the two groups at baseline or at the 1-year follow-up examination. The frequency of major depression, delusions, and hallucinations did not differ between the groups. However, patients with PWMRs had significantly higher Hachinski Rating scores at both visits and were more likely to develop cerebrovascular disease during follow-up than were controls with Alzheimer's disease. These preliminary results suggest that the presence of PWMRs is not associated with specific cognitive and psychiatric features or with an altered rate of progression of Alzheimer's disease but does predict the development of clinically significant cerebrovascular disease.