White Matter Lesions of the Elderly

98.1 Clinical Features

and Laboratory Findings

Age-related changes of the brain have been docu- mented in numerous MRI and histopathological studies. Changes that are found at histopathological examination in elderly individuals without neurolog- ical or neuropsychological deficits – in other words, in normal aging – include enlargement of the ventri- cles and the cerebral sulci reflecting gray and white matter loss, decrease in neurons and synapses, and in- crease in lipofuscin and mineral deposits in brain structures. On MRI white matter hyperintensities may appear on T

-weighted and FLAIR images, in- creasing with age, varying from multifocal spots in the deep white matter or a pencil-stripe-like rim around the ventricles to a confluent, bilateral, more or less symmetrical, periventricular leukoencephalopa- thy. The more or less extensive signal changes of the periventricular and deep white matter have been giv- en the descriptive name “leukoaraiosis” (white matter rarefaction) by Hachinski et al. (1987), and have been the subject of many studies since then. Attempts have been made to document these changes more precise- ly with a variety of MR techniques, to search for neu- ropathological correlates, and to find out which white matter signal alterations represent apparently inno- cent changes by clinical standards, and which signal alterations indicate future clinical progress towards cognitive impairment and eventually vascular de- mentia. Similar attempts have been made from the neuropsychological point of view, where the search is still going on to define “age-related memory disor- der,” “age-associated mental impairment,” “benign senescent forgetfulness,” and “mild cognitive impair- ment” (with decliners and nondecliners) in such a way that homogeneous subgroups can be identified for further studies. Again an important aim is predic- tion of outcome. The combined efforts of all disci- plines involved so far have not come up with a final answer.

Much was expected of quantitative MR techniques.

These techniques can more precisely indicate that with age more white matter than gray matter is lost;

that increases in relaxation times are more pro- nounced in white matter than gray matter; that there is an increase of apparent diffusion coefficients in both white and gray matter, but more so in white than in gray matter, indicating more free water movement

and change of water content, with consequently loss of fractional anisotropy; and that there are decreasing magnetization transfer ratios, indicating loss of structural integrity of the brain tissue. MRS reveals a decrease of N-acetylaspartate, reflecting loss of neu- rons and axons. Reduced cerebral perfusion is report- ed as measured with MR techniques and PET, with unchanged oxygen extraction on PET. Impressive as these findings may seem, they have not enabled defi- nition of clear cut-off points between successful ag- ing, mild cognitive impairment, and progression to- wards multi-infarct dementia in the individual case.

98.2 Pathology

Reports on the pathological substrate of leukoaraio- sis on MRI, either in normal aging or in patients with different degrees of cognitive decline, show a wide variety of findings. This is not surprising, given the bias in the examined populations, which most often involve only a small number of patients. In nearly all cases gross anatomy shows that the cerebral cortex appears normal or shows only minor changes. The white matter is either macroscopically normal or shows a grayish discoloration, with a rubbery consis- tency. White matter volume may be reduced. White matter abnormalities may be focal, isolated, or more confluent. The basal ganglia do not, as a rule, show changes. At microscopy, there are variable degrees of ependymal denudation and frontal and peritrigonal white matter changes, consisting of loosely struc- tured tissue with widened Virchow–Robin spaces.

The periventricular changes vary from white matter pallor (meaning less intensive myelin staining, the earliest change in the periventricular white matter, without overt demyelination, axonal loss, presence of foamy macrophages, or gliosis) to periventricular de- myelination (describing overt myelin loss with astro- cytic proliferation and in some cases some inflamma- tory reaction). The lesions may be patchy or more confluent. In more severe cases the periventricular and deep white matter changes are continuous. The cause of these changes is to be found in vessel wall abnormalities. These abnormalities range from non- specific intima thickening without narrowing of the lumen, to changes in the smooth muscle walls of the small vessels leading to gradual narrowing or occlu- sion of the small vessels.

White Matter Lesions of the Elderly

There is no sharp transition between these rela- tively mild changes and the pattern seen in vascular dementia patients. In patients with vascular demen- tia, there are also lacunar infarctions, involvement of the corpus callosum, involvement of the basal ganglia (the latter often showing an état criblé or état lacu- naire or both), abnormalities of the transverse fibers of the pons, and coagulation necrosis and cavitation of the deep white matter.

98.3 Pathogenetic Considerations

There are large differences in the estimation of the presumed clinical significance of white matter abnor- malities in the elderly, and there is a great variability in reported histopathological correlates. The most prevalent morphological substrate is perivascular tissue change. Reasons for the perivascular tissue changes are supposed to be the thickening of vessel walls (by a number of different causes), damage to the surrounding tissue by a waterhammer effect of pulsating arterioles with diminished elasticity, and perivascular edema resulting from leakage of the blood–brain barrier. In a high percentage of cases hypertension plays a prominent role, and it is cer- tainly a major factor in changing the vessel walls by lipohyalinosis and consequently narrowing of the lumina of small brain vessels. Several other disorders lead to the same result, despite the different material deposited in the vessel walls, with amyloid angio- pathy, arteriosclerosis, and CADASIL as examples.

Some factors must be responsible for the selective involvement of the periventricular and deep white matter as a common finding. Several factors have been suggested.

Chronic hypoperfusion may have a selective influ- ence on oligodendrocytes and myelinated axons, as was supported by animal experimentation. Experi- mental studies of brain ischemia on rat and gerbil brains show that both oligodendrocytes and myeli- nated axons are highly vulnerable to ischemia and that chronic cerebral hypoperfusion leads to progres- sive rarefaction and glial activation in the white mat- ter. Three hours after carotid occlusion in rats, oligo- dendrocytes display characteristics of irreversible injury, such as pyknosis and plasma membrane rup- ture. Three factors, in these experiments, led to vac- uolation of the white matter: intramyelinic fluid accu- mulation, enlarged extracellular spaces, and swelling of astrocytic processes. These changes precede irre- versible neuronal injury, indicating a time-indepen- dency of these processes and partly explaining the selective vulnerability of white matter in chronic hypoperfusion. Animal models, however, cannot easi- ly be designed to mimic the age-related changes in the human brain and explain the various kinds of pathol-

ogy and the influence of lesions on neuropsychologi- cal functioning.

The distribution of the lesions may also be ex- plained by the unique blood supply to the periven- tricular and deep white mater. Arteries originating in the arachnoid spaces perforate the brain tissue, run- ning from the cortical surface towards the periven- tricular white matter. Although De Reuck’s hypothe- sis (1971) of subependymal border zones has been challenged, it remains true that there is a scarcity of anastomoses of the large perforating arteries in these areas, so that in fact one vessel irrigates only one metabolic unit. Recurrent transient drops in cerebral blood flow can lead to ischemia in these units, often referred to as incomplete infarction. These changes may progress in some patients, explaining the whole range of abnormalities found in histopathology, from white matter sponginess, pallor, patchy demyelina- tion, astrocytic proliferation, to more serious changes such as coagulative necrosis and cavitation. In this view leukoaraiosis is the expression of a diffuse cere- bral hypoperfusion of variable severity, in its mildest form showing changes in the white matter on MRI without pertinent pathological findings other than possibly death of oligodendrocytes, and without neu- rological and/or neuropsychological deficits, and in its most severe form bearing the characteristics of subcortical arteriosclerotic encephalopathy.

Focusing on white matter abnormalities in the elderly, population-based studies have tried to identi- fy risk factors for both the occurrence of white matter hyperintensities on T

-weighted images, and factors predicting the long-term outcome of members of these populations. Not surprisingly, these factors include higher age, higher ischemic score on the Hachinski scale (0–18), history of stroke, lacunar in- farction on MRI, hypertension (systolic >140 mmHg;

diastolic >95 mmHg), male gender, atrial fibrillation, coronary artery infarcts, diabetes mellitus, smoking, alcohol abuse, drug abuse, hyperhomocysteinemia, antiphospholipid antibodies, several coagulation dis- orders, the presence of the apolipoprotein E e4 allele, and probably other genetic factors. A study involving psychiatric patients showed periventricular and deep white matter abnormalities in a high percentage of patients with major depression. Important as these

Chapter 98 White Matter Lesions of the Elderly 760

Fig. 98.1. a FLAIR (upper two rows) and T

-weighted (lower two rows) images of a 64-year-old woman with “benign senes- cent memory impairment.” The images show hyperintense changes in the deep and periventricular white matter and basal ganglia. The FLAIR images show the abnormalities with greater conspicuity. Clinical and MRI follow-up over the course of 4 years did not show any progression (nondecliner)

䊳

Fig. 98.1. a

studies are to establish rules for population-based prevention, in individual cases they offer only guide- lines.

The overall impression one may develop is that leukoaraiosis is too general a concept, so that exam- ined populations and selected cases do not form a ho- mogeneous entity. Certainly some general rules for prevention have been drawn from the research results obtained so far, but future research should aim at the definition of more homogeneous subgroups to obtain better insight in the pathophysiological mechanisms underlying the final common visual product leuko- araiosis.

98.4 Therapy

The development of leukoaraiosis is strongly related to age, and secondarily to risk factors. As they get older, nearly 100% of people will have white matter lesions. At the moment of detection of white matter lesions, whether related to neurological or neuropsy- chological complaints or as an incidental finding, risk factors should be searched for, where possible treated, and habits such as smoking, excessive drinking, and lack of exercise should be changed. The most impor- tant way to take action is by promoting preventive measures that would improve the lifestyle and health of the general population.

98.5 Magnetic Resonance Imaging

With the introduction of CT it became clear that there were age-related changes of the brain, amongst them more or less extensive periventricular areas of hypo- density. MRI showed these changes to better advan- tage as hyperintense changes on T

-weighted images, and later even better on FLAIR images. Many scales were developed to grade these signal abnormalities and to relate them to neurofunctional deficits, when

present. The lesions seen on MRI in older individuals can be graded as follows:

∑ Frontal and occipital caps: white matter hyperin- tensity around the frontal horns and the triangu- lar area of the ventricles

∑ A periventricular 1- to 3-mm-thick rim of high signal intensity, best seen on proton density or FLAIR images

(These two findings are considered to be without clinical significance and represent areas of looser tissue and widened Virchow–Robin spaces)

∑ Patchy deep white matter lesions, partly isolated, partly confluent

∑ Confluent deep white matter hyperintensity, con- tinuous with periventricular white matter changes

∑ One or a few lacunar infarctions within the affect- ed deep white matter

MR has been used extensively to study the process of aging of brain structures in vivo. Pathological studies of the brain depict the terminal phases of disease on- ly and are limited by the relatively small number of samples that can be examined per patient, as a rule in the order of 350–450 at most. In contrast, MR data about normal aging are abundant and can be used as reference data for MR studies in older patients, for example to provide normal values per age group of ventricular and sulcal width, hippocampal and temporal lobe volume, magnetization transfer ratios and histograms, fractional anisotropy, apparent dif- fusion coefficients, T

and T

relaxation times, region- al cerebral blood volume, and metabolite concentra- tions.

General experience is that over the age of 50 years one may expect to see white matter abnormalities in patients and controls, increasing exponentially with age (Figs. 98.1 and 98.2). Population-based studies have linked these white matter abnormalities to vari- ous risk factors, and also tried to find predictive fac- tors that would indicate risks for future strokes and cognitive decline. The problem with these studies,

Chapter 98 White Matter Lesions of the Elderly 762

Fig. 98.1. b The gradient echo images

of the same 64-year-old woman show

hemosiderin deposits, residues of

microhemorrhages, in the basal

ganglia, more prominent on the left

side, and around the anterior commis-

sure. CT scan showed no calcifications

especially those that include large populations, is that only basic MR techniques have been used – T

- and T

-weighted images – without employment of techniques that allow a better definition of tissue characteristics. The inclusion, for example, of gradi- ent echo refocusing pulse sequences would have shown the members of these populations with micro-

hemorrhages (Fig. 98.1) and thus have identified a group with possibly a different pathogenesis, other risk factors, and different prognosis. Other MR se- quences would possibly have led to further differenti- ation, for example, on the basis of the estimation of tissue integrity with magnetization transfer ratios, or on the basis of the change of brain metabolites in

Fig. 98.2. FLAIR images of a 71-year-old man presenting with mild apraxia of the left arm and no cognitive impairment. In the periventricular white matter hyperintensities a few lacunar

infarctions are noted.The Trace diffusion-weighted image and

ADC map (third row, middle and right) show a small recent

infarction with low ADC values in the right periventricular area

Chapter 98 White Matter Lesions of the Elderly 764

Fig. 98.3.

MRS, including the presence of lactate in the lesions.

Probably the most important MR technique to relate the white matter abnormalities to clinical findings is perfusion imaging. This allows not only the estima- tion of the degree of hypoperfusion in the involved areas, but also the reserve capacity of the tissue, giv- ing a quantitative measure of the severity of the white matter damage.

In daily routine one will be confronted mainly with patients referred for memory disorders and cognitive decline. Apart from ruling out rare causes such as brain tumors, chronic subdural hematomas, and so on, a protocol should be used that will enable assess- ment of most of the factors responsible for cognitive decline according to present knowledge. This means an inventory of cerebral and cerebellar cortical and deep gray matter structures, including the hippocam- pus and temporal lobe structures, of white matter ab- normalities, and of the presence of microhemor- rhages (Fig. 98.1). In patients with rapidly progressive cognitive decline diffusion-weighted imaging with ADC maps should be added to the program (Figs. 98.2 and 98.3). In centers dedicated to the research of mild cognitive impairment, or where vascular factors seem to be important, MR angiography should be included.

MRS and chemical shift imaging may give additional

information about neuronal and axonal loss, and about the presence of lactate, indicating anaerobic glycolysis.

In many patients follow-up studies will be re- quired. Postprocessing of data is then also very im- portant, to obtain adequate comparable information.

This will give a clue with respect to the rate of pro- gression, and information about the efficacy of thera- peutic measures and changes in lifestyle (Fig. 98.4).

Differential diagnosis is important, because many other disorders may present with deep white matter abnormalities. Disorders with multifocal and partial- ly confluent white matter abnormalities, often accom- panied by cognitive impairment, are amyloid an- giopathy, CADASIL, multiple sclerosis, cerebral vas- culitis, systemic lupus erythematosus, chronic expo- sure to organic solvents (housepainter’s dementia), and several infections including HIV encephalopathy and progressive multifocal leukoencephalopathy. In Alzheimer disease, in particular in the late-onset forms, white matter abnormalities are common.

Disproportional hippocampal atrophy suggests Alz- heimer disease. It is important to realize that more and more “mixed” dementias are being recognized, caused by a combination of vascular and neurode- generative factors.

Fig. 98.3. (continued). A 62-year-old man without cognitive complaints, presenting with left-sided hemianopia. The FLAIR images (upper two rows) show hyperintensities consistent with normal aging, except for the left parietal lesion, involving cor- tex and subcortical white matter. The gradient echo images (third row) show a few low-intensity spots in the left parietal

area, and a single spot in the right parietal area.The fourth row

shows Trace diffusion-weighted images with b = 1000; the fifth

row shows ADC maps. The left parietal lesion is bright on the

Trace images and has ADC values as low as 0.52 ¥ 10

mm

/s,

confirming the presence of a fresh infarction

Chapter 98 White Matter Lesions of the Elderly 766

Fig. 98.4. FLAIR images of a 67-year-old woman with mild cognitive impairment (first row).There are white matter hyper- intensities in the deep and periventricular white matter and corpus callosum, and scattered small lesions in the basal ganglia. Images of the same patient 4 years later (second row) show progression of the abnormalities, with lacunar in- farctions in both hemispheres and the brain stem (not shown).

Also clinically there was clear progression of the cognitive

disorder. ADC values in this patient in the centrum semiovale

had gone up from 0.85–0.95 ¥ 10

mm

/s to 1.20–1.25 ¥

10

mm

/s; fractional anisotropy values changed from 0.450

to 0.224, indicating loss of structural integrity. MRS showed

lactate in the lesions in the last examination. All evidence is

that this patient is a decliner