Article Type : Review Article
Authors : De Reuck J
Keywords : Magnetic resonance imaging; White matter hyperintensities; Vascular dementia; Alzheimer’s disease; Frontotemporal lobar degeneration; Lewy body disease; Progressive supranuclear palsy; Corticobasall degeneration
White matter hyperintensities (WMHs) are frequently observed
on magnetic resonance imaging (MRI) in brains of patients with dementia.
Initially they were considered as the reflection of ischemic changes in the
white matter. However, more recently this statement has been questioned. The
most relevant articles concerning the presence of WMHs on MRI in patients with
different types of dementia are presently reviewed. In vascular dementia and in
its more specific form, called Binswanger’s disease, the WMHs are to be
considered as representing ischemic changes. This is based on the frequent
association with small-vessel disease and lacunar infarcts. Also hereditary
cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (Cadasil) is a significant ischemic cause of WMHs on MRI.
The WMHs are linked to the most relevant cortical neurodegenerative changes in
“pure” Alzheimer’s disease, frontotemporal lobar degeneration, Lewy body
disease, and progressive supranuclear palsy and corticobasal degeneration. They
have to be considered as the expression of Wallerian degeneration with
secondary myelin loss, rather than ischemic of origin. In most mixed dementias
vascular ischemic lesions are combined with neurodegenerative changes in the cerebral
white matter.
White matter changes are frequently observed in
several diseases of infancy and adult life, including in demyelinising
diseases, such as multiple sclerosis [1-5]. The development of brain white
matter microstructure starts during the first 3 years of life with further
continued white matter maturation during later childhood and adolescence [6]. The
diffusion characteristics on magnetic resonance imaging (MRI) differ between
the regions of white matter changes and the surrounding normal looking white
matter, suggestive of a Wallerian-type degenerative pattern [7]. There exist
different visual MRI rating scales for the white matter hyper-intensities
(WMHs) [8-10]. Overall, WMHs are considered to mainly reflect white matter
ischemia [11-15]. However some studies suggest that they also can be due to
Wallerian degeneration and demyelisation as result of the severe overlying
cortical neurodegenerative changes [16-18].
Even in cognitive normal elderly brains an increase of
WMHs is observed compared to those of young and middle-aged persons [19]. The
mixed forms of dementia occur in 30% of all dementia cases. They are more
frequent in the oldest patients and have more severe WMHs than in those with a
single type of dementia [20-22]. So the question remains whether the WMHs in
all dementia diseases are due to cerebrovascular disturbances or secondary to
neurodegenerative changes of the overlying cerebral cortex.
Arterial
vascularisation of the cerebral white matter
The majority of the cerebral white matter is supplied
by medullary branches issued from the leptomeningeal cerebral arteries. In
contrast to the cortical branches, they have no significant side branches and
cross perpendicularly the cerebral cortex to reach the white matter. The short
medullary branches end in the subcortical arcuate fibres. The long ones end in
the periventricular white matter at some distance from the ventricular wall
[23]. The deep periventricular white matter is supplied in the frontal regions
by ventriculofugal end-branches of the lateral striatal arteries and in the
parieto-occipital regions by ventriculufugal branches issued from the choroid
arteries. They form together with the medullary branches the periventricular
arterial border-zones [24]. They are the remnants of the continuous loops,
which connect the surface vessels in the premature brains to the
periventricular located germinal layer, from which maturating neurons migrate
to the surface to form the cerebral cortex. The regression of these continuous
loops lead to the development of the periventricular arterial border-zones
[25].
Vascular
dementia
Periventricular infarction due to carotid artery
stenosis can be the cause of a single stroke. This rare type of stroke is
considered as a pure hemodynamic induced event [26]. Vascular dementia is
causing around 15% of all dementia cases [27]. It is the second most frequent
cause of dementia [28]. The most classical vascular dementia due to selective
white matter ischemia with lacunar infarcts and without cortical involvement is
the chronic Binswanger’s subcortical encephalopathy [29]. A severity scale has
been proposed for vascular dementia [30]. Another rare cause of dementia with
selective white matter ischemia is the hereditary cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) due to
the Notch homolog 3 [31]. However many cases of vascular dementia are due to a
mixture of WMHs with cortical macro- and micro-infarcts, macro- and
micro-bleeds, and lacunar infarcts. The WMNs are more severe and widespread
than in most neurodegenerative diseases [32,33]. Cerebral amyloid angiopathy
(CAA) can contribute to vascular dementia [34]. The number of cortical
micro-infarcts and cortical micro-bleeds is increased in CAA but the severity
of the WMCs is not amplified [35-37].
Alzheimer’s
disease
Alzheimer disease (AD) is by far the most frequent
form of dementia with an incidence of 15% in the overall population older than
65 years [38]. On MRI WMHs are found in approximately 62% of patients with AD.
CAA is present in 58% of the cases [39]. Overall patients with AD-CAA have more
WMHs than in those without CAA [40]. However, only those with severe CAA
display the most severe cerebrovascular lesions, including an increase in WMHs
[41]. The frontal, central and parieto-occipital white matters are
approximately involved to the same degree in the severe forms of AD [42]. The
patients with CAA are overall older than those without [43].
Frontotemporal
lobar degeneration
Frontotemporal lobar degeneration (FTLD) is a
heterogeneous disorder with various genetic and histological subtypes. This
entity is characterised by severe atrophy of the frontal cortex and the
superior temporal gyrus. The underlying white matter is severely affected in
the frontal and temporal lobes [44]. On MRI, in addition to the severe WMHs,
the incidence of cortical micro-bleeds is increased in the most affected
regions [45,46]. A low incidence of cerebrovascular risk factors has been
observed in FTLD [47]. Also CAA is very rare in this disease [48]. Amyotrophic
lateral sclerosis (ALS) has been linked to FTLD [49]. Positron emission
tomography of the brain shows functional imaging abnormalities predominantly in
the frontal and temporal regions in a mixed ALS-FTLD case [50]. The WMHs in ALS
are also predominant in the frontal and temporal regions. These findings are
mainly observed in patients with memory disturbances [51,52]. Similar to FTLD a
favourable vascular risk profile is observed in ALS [53].
Lewy
body dementia
Lewy body dementia (LBD) is related to Parkinson’s
disease dementia. They are considered as the extremes of a continuous spectrum
[54]. WMHs are a relative early feature in LBD [55]. They can be more severe
than in Parkinson’s disease with dementia. Also the cortical gray matter is
more severely affected [56]. AD-related pathology is frequently associated to
LBD and considered as the main cause of the WMHs [57, 58]. CAA is present in
30% of the cases and lipohyalinosis in 10% [57]. CAA does not increase the
degree of the WMHs [59]. Associated cerebrovascular lesions are frequently
associated and for frequent in Parkinson’s disease compared to their incidence
in other neurodegenerative diseases, including AD [60].
Progressive
supranuclear palsy
Progressive supranuclear palsy (PSP) is a sporadic
disease with tau pathology, mainly involving the thalamus, the pallidum and the
brainstem [61]. However, neocortical areas can also be involved [62]. The
global severity of the WMHs in the cerebral hemispheres of PSP is more or less
similar to that in normal age-matched controls [63]. The association of CAA
does not influence the degree of WMHs [64]. In PSP the midbrain, pons and the
regions close to the basal ganglia are the regions where the main WMHs occur
[65]. The pathways of degeneration mainly involve the connections between
frontal areas and deep gray matter structures [66]. The WMHs are less severe in
PSP than in Parkinson’s patients [61]. The degree of the WMHs correlates with
the clinical scores of disease severity and cognitive impairment [67]. The classic
Rirchardson’s syndrome of PSP has more spatial abnormalities in the frontal
white matter than in the parkinsonian type [68]. However, overall the WMHs
progress more significantly over time in PSP-parkinsonism [69].
Corticobasal
degeneration
Corticobasal degeneration (CBD) is a rare disease characterised by a
progressive asymmetrical severe cortical atrophy, mainly of the frontal and
temporal lobes [70]. There are sporadic case reports mentioning white matter
degeneration in the adjacent regions [71,72]. In our recent study of 8 CBD
cases the WMHs are significantly more severe in the affected hemisphere,
compared to their occurrence in age-matched non-demented controls [73]. The
WMHs are, however, less severe in CBD than in Parkinson’s patients with and
without dementia [60].
MRI is the best way to detect the severity of grey and
white matter changes, using visual rating scales [74]. In the white matter of
the brain myelin and iron are closely linked due to the presence of iron in
myelin generating oligodendrocytes [75]. Myelin loss is followed by increase of
intra- and extra-cellular water content. These changes are more pronounced
among elderly people [76].
In vascular dementia the WMHs are to be considered as
reflecting ischemic changes [77,78]. Small vessel disease causes the WMHs on
MRI [79]. In young adults without evidence of cerebrovascular disease control
of modifiable cardiovascular risk factors induces less occurrence of WMHs on
MRI [80]. In particular control of blood pressure in hypertensive patients
reduces significantly the occurrence of WMHs [81]. The impact of WMHs has been
demonstrated to be a major risk factor for progressive cognitive decline [82].
However, the progression of WMHs does not predict the conversion from mild cognitive
impairment to dementia [83]. The progression of the WMHs in AD is similar to
that in the correspondent cortical regions with the most severe
neurodegeneration and to be considered as due to Wallerian degeneration with
secondary myelin loss [84]. The degree of WMHs is related to the amyloid load
of the brain but not to the tau burden [85].
The co-occurrence of vascular brain damage is frequent
and underscored in AD brains. Most AD cases are frequently to be considered as
a mixed type of dementia [86]. In FTLD the severity of the WMHs is clearly
linked to the underlying most affected cortical regions and probably reflects
Wallerian degeneration with secondary myelin loss [87-88]. FTLD has a very low
vascular risk profile so that an additional ischemic contribution is highly
improbable [46-47]. Global cortical amyloid burden is high in LBD [89].
However, the WMHs reflect mainly AD-related pathology rather than
cerebrovascular changes [58]. Apolipoprotein (AOE) E 4 may influence the
association between WMHs and cognitive performance [90]. Severe WMHs appear to
be predominantly associated with frontal/executive dysfunction, irrespective of
APOE 4 allele presence [91]. So the Increase of WMHs in LBD has to be
considered as mainly reflecting neurodegenerative changes.
WMHs contribute to the motor, cognitive and
behavioural deficits in PSP [92]. Mainly axial and diffusivity changes are
prominent [93]. The cognitive impairment is mainly related to decreased gray
matter of deep nuclei and cerebellum [94]. The clinical phenotypes of CBD vary
considerably and can change according to the disease progression [71]. CBD has
a low vascular risk factor [47]. The MRI of the brain shows mainly focal
atrophy of the bilateral frontal cortex and aymmetrical regional WMHs of the
sub-adjacent white matter. The latter changes primarily reflect the progression
of neuronal degeneration, especially the demyelination secondary to axon loss
or change [95]. The long fronto-parietal connecting tracts, the intraparietal
associative fibres, and the corpus callosum are predominantly affected [96-98].
It can be concluded that WMHs only reflect ischemic changes in VaD. In all
single forms of neurodegenerative dementia diseases WMHs on MRI reflect
Wallerian degeneration with myelin lost, secondary to the main cortical
lesions. AD brains are frequently mixed forms of dementia with associated
cerebrovascular pathology.
The authors have nothing to declare in relation to
this article. No funding was received for the publication of this article.