Case report
Complications of severe cerebral amyloid angiopathy in the course of dementia with Lewy bodies. A case report

Introduction

Cerebral amyloid angiopathy (CAA) is a progressive degenerative process of leptomeningeal and brain parenchymal vessels caused by accumulation of amyloid deposits in their walls [3,30,39,45].

Amyloid deposition is a prominent feature of nu­merous brain disorders, in which amyloid fibrils are found in blood vessel walls, the neuropil and neurons. These include Alzheimer’s disease (AD), neurologically asymptomatic amyloidosis, Parkinson dementia of Guam, dementia with Lewy bodies (DLB), hereditary ce­rebral haemorrhage with amyloidosis of Dutch origin (HCHWA-D), hereditary cerebral haemorrhage with amyloidosis of Icelandic origin (HCHWA-I), AD changes associated with Down’s syndrome (DS) and sporadic cerebral amyloid angiopathy [1,7,11,12,18,19,41,48].

CAA has a fundamental aspect of many pathologies leading to dementia. Brain lobar haemorrhage and/or necrosis are common in this condition, but focal subarachnoid haemorrhage is rare [26].

Deposits of β-amyloid, the fibrillogenic product of the cell surface protein AβPP (amyloid-β protein precursor), occur in the cerebral cortex of patients with DLB [5,25,49]. Amyloid deposits occur in the common form, which is defined by changes consistent with diffuse Lewy body (DLBc) disease accompanied by AD, and also in a pure form (DLBp), in which neurofibrillary tangles are absent [4].

The number of publications on this subject is very limited [24,49].

The aim of this study was to analyse morphological changes in a patient with DLB co-existing with CAA and multiple changes, such as hemorrhagic infarct, subarachnoid haemorrhage and ischaemic cerebral lesions.

Case report

A 68-year-old male who suffered from dementia progressing for four months, without Parkinson’s symptoms, was admitted to the Department of Neurology. He was treated with risperidone and done­pezil. On admission he showed vertigo, slight left hand paresis, central left facial nerve paresis and liability of his Romberg test. During previous months he had two episodes of transient ischaemic attacks, manifested by left hemiparesis with left facial nerve central paresis and decreased consciousness. During hospitalization the patient’s status suddenly deteriorated, he lost consciousness and quadriparesis was observed. CT scan revealed hemorrhagic infarct in the right frontal lobe, superficial haematoma on the surface of the frontal lobe, subarachnoid haemorrhage and multiple ischaemic lesions. Angio-CT and angiography showed no abnormality. EEG showed no pathological discharges. The intracerebral haemorrhage, subarachnoid haemorrhage and ischaemic lesions observed on CT scans suggested the clinical diagnosis of CAA. He died after 53 days due to pneumonia.

Methods

The brain autopsy material was fixed in 4% paraformaldehyde in 0.1 M phosphate-buffer saline and embedded in paraffin. The specimens were stained with H&E, PAS, Congo red, Klüver-Barrera me­thods and immunohistochemically with the following antibodies: neurofilaments (NFTs, Novocastra, 1 : 50), tau (DAKO, 1 : 200), β-amyloid 40 (Aβ 40) (Sero­tec, 1 : 250), β-amyloid (Aβ 42) (Serotec 1 : 250) and α-synuclein (Novocastra, 1 : 30). The grade of CAA was asses­sed according to Vonsattel [46]. The type and grade of DLB were classified according to Consortium [34].

Results

On macroscopic examination, the brain showed general cortical atrophy and ventricular dilatation. Frontal lobar haemorrhage and focal subarachnoid haemorrhage were seen on the brain autopsy (Fig. 1). We observed slight paleness of the substantia nigra in the mesencephalon.

Microscopic observation demonstrated neuronal loss and microspongiosis in the hippocampus, and severe neuronal loss and depigmentation in the substantia nigra pars compacta and locus coeruleus. Lewy bodies were visible in the substantia nigra (Fig. 2).

Neuronal loss and α-synuclein-positive Lewy bodies (LBs) and Lewy neurites were observed in the brainstem and in the temporal lobe, particularly in the entorhinal cortex (Fig. 3). The presence of amyloid plaques consistent with AD pathology was revealed.

Numerous amyloid plaques were visible in the temporal lobe (Fig. 4A). Neurofibrillary tangles in the temporal lobe, particularly in the entorhinal cortex, were observed (Fig. 4B). Amyloid angiopathy, predominantly severe CAA according to the Vonsattel scale, were found in the meningeal and cortical vessels (Fig. 5A). A characteristic picture of severe cerebral amyloid angiopathy, named “double barrel”, could be observed using Congo red staining (Fig. 5B). Many other different ischaemic and hemorrhagic changes with different time of onset were revealed in the patient’s brain. Disperse microinfarcts in the neocortex and in the white matter as a complication of severe CAA were observed (Fig. 6). In addition, lobar infarct in the temporal lobe (Fig. 7) and frontal lobar hemorrhagic infarct in the cortico-subcortical region were revealed (Fig. 8). Amyloid overloaded meningeal vessels at the border of the hemorrhagic lobar infarct (Fig. 9) and amyloid overloaded cortical vessels at the border of the brain pale infarct area were observed (Fig. 10).

Discussion

Dementia with Lewy bodies represents the second largest neuropathological subgroup of neurodegenerative dementia after Alzheimer’s disease in the elderly [6,34]. A 30.5% prevalence of DLB is registered among dementia patients, whereas its annual incidence in the general population is 0.1% [36,50].

Although most patients have sporadic DLB, a small number of DLB families have been described, suggesting that genetic factors may contribute to DLB pathogenesis [8].

DLB patients present progressive dementia, recurrent visual hallucinations and parkinsonism. Features suggestive for DLB are REM sleep disorder, severe neuroleptic sensitivity and low dopamine reuptake in basal ganglia upon functional imaging. Repeated falls, transient loss of consciousness, severe autonomic dysfunction and depression can confirm a clinical diagnosis of DLB [13,21,34]. Clinically, only progressive dementia and decreased consciousness were observed in our patient. Neuropathologically, DLB is classified into three types, brainstem-predominant, limbic (transitional) and neocortical (also known as diffuse Lewy body disease), depending on the distribution and density of Lewy bodies (LB) [27,34].

In the literature the most frequently used terms are “diffuse Lewy body disease” (DLBD), “Lewy body variant of Alzheimer’s disease” (LBV) and “senile dementia of Lewy body type” (SDLT). These terms are interchangeable [22,28,29].

DLB with no AD changes is known as the pure form of DLB (DLBp), whereas DLB associated with AD is recognized as the common form of DLB (DLBc). However, none of the 201 autopsies in the CERAD study showed Lewy bodies without concomitant AD changes [22].

Little is known about the aetiology of DLB. DLB is generally a sporadic disorder, and is considered to be a complex disorder, resulting from the interaction between genetic and environmental risk factors. Most studies have reported DLB as autosomal dominant, rarely as a recessive trait [10,15,37,44,47].

Molecular genetic studies have identified several mutations associated with DLB, suggesting a large genetic heterogeneity in the development of DLB.

The є4 allele of the apolipoprotein E gene (APOE) is the major genetic risk factor for AD and also can be a risk factor for DLB [2,5,8,14,38,40].

Parkinson disease (PD) and DLB are characterized by the presence of intracytoplasmic neuronal inclusions called Lewy bodies (LBs) and α-synuclein-containing aberrant neurites in the substantia nigra pars compacta, locus coeruleus and other selected nuclei of the brain stem, and also in several nuclei of the basal forebrain and hippocampus [6,20,23, 24,31,38,40]. DLB is also characterized by a widespre­ad distribution of LBs and α-synuclein-containing neurites in the cerebral cortex [20,22,35]. Amyloid plaques and neurofibrillary tangles are frequent in DLB [16,22,32-34,42,43].

Alzheimer’s disease is an amyloidopathy in view of the central role of β-amyloid accumulation, but it also shares features of tauopathy because of its neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. Diseases including PD, DLB and multiple system atrophy (MSA), which exhibit α-synuclein lesions, are termed “synucleinopathies” [9,17,42,43].

The relationships between DLB, PD and AD are complex and incompletely understood. Genetic studies indicate that DLB cases tend to share many risk factors for AD [22,25].

Many elderly demented patients with Lewy body pathology have autopsy findings which are compatible with a diagnosis of DLB or can be interpreted as “AD with incidental Lewy bodies” or “Parkinson’s dementia”.

The final diagnosis of DLB in our patient was made postmortem on the basis of typical histological changes in association with progressive intellectual decline and decreased consciousness as a clinical manifestation of the disease. Focal subarachnoid haemorrhage and superficial and hemorrhagic lobar as well as ischaemic cerebral lesions were seen on the brain autopsy.

In the presented case, the microscopic findings were typical of DLB with concomitant severe CAA. Severe CAA is a cause of many pathologies, such as intracerebral haemorrhage and focal subarachnoid haemorrhage or brain ischaemic changes, leading to fatal outcome. Our patient met the criteria of the common form of dementia with Lewy bodies, due to the presence of numerous Lewy bodies in the brain steam and cortex.

In cases of progressive dementia, neurological deterioration, presence of lobar hemorrhagic infarcts and ischaemic lesions suggest the coexistence of CAA with DLB and/or AD.

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