S. G. van Duinen

Epidemiology of inclusion body myositis in the Netherlands: A nationwide study

Article abstract Epidemiologic data on inclusion body myositis (IBM) are scarce, and possibly biased, because they are derived from larger neuromuscular centers. The present nationwide collaborative cross-sectional study, which culminated on July 1, 1999, resulted in identification of 76 patients with IBM and the establishment of a prevalence of 4.9 patients with IBM per million inhabitants in the Netherlands. Several discrepancies suggest that this may be an underestimation. The most frequently identified pitfall in diagnosing IBM was an erroneous diagnosis of polymyositis or motor neuron disease.

Dystrophin levels and clinical severity in Becker muscular dystrophy patients

Objective Becker muscular dystrophy (BMD) is characterised by broad clinical variability. Ongoing studies exploring dystrophin restoration in Duchenne muscular dystrophy ask for better understanding of the relation between dystrophin levels and disease severity. We studied this relation in BMD patients with varying mutations, including a large subset with an exon 45–47 deletion. Methods Dystrophin was quantified by western blot analyses in a fresh muscle biopsy of the anterior tibial muscle. Disease severity was assessed using quantitative muscle strength measurements and functional disability scoring. MRI of the leg was performed in a subgroup to detect fatty infiltration. Results 33 BMD patients participated. No linear relation was found between dystrophin levels (range 3%–78%) and muscle strength or age at different disease milestones, in both the whole group and the subgroup of exon 45–47 deleted patients. However, patients with less than 10% dystrophin all showed a severe disease course. No relation was found between disease severity and age when analysing the whole group. By contrast, in the exon 45–47 deleted subgroup, muscle strength and levels of fatty infiltration were significantly correlated with patients’ age. Conclusions Our study shows that dystrophin levels appear not to be a major determinant of disease severity in BMD, as long as it is above approximately 10%. A significant relation between age and disease course was only found in the exon 45–47 deletion subgroup. This suggests that at higher dystrophin levels, the disease course depends more on the mutation site than on the amount of the dystrophin protein produced.

Age-related plaque morphology and C-terminal heterogeneity of amyloid β in Dutch-type hereditary cerebral hemorrhage with amyloidosis

Abstract The evolvement of amyloid β (Aβ) deposition in the frontal cerebral cortex of 24 patients of increasing age with Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) was studied using end-specific monoclonal antibodies to Aβx-42 (Aβ42) or Aβx-40 (Aβ40) and markers for degenerating neurites. Aβ42 immunostaining revealed parenchymal Aβ deposits with a heterogeneous morphology and distribution, i.e., clouds, fine/dense diffuse, coarse, and homogeneous plaques. Clouds and diffuse plaques were associated with glial Aβ granules. Aβ40 labeling was absent in clouds/fine diffuse plaques, inconsistent and variably intense in dense diffuse/¶coarse plaques and consistent in homogeneous plaques. In a subset of Aβ40-positive plaques, degenerating neurites – without tauopathy – and/or amyloid cores were observed. Electron microscopy revealed no apparent amyloid fibrils in fine diffuse plaques, small bundles of fibrils in dense diffuse/homogeneous plaques, and amyloid masses in coarse plaques. The parenchymal Aβ pathology was age-related: the ratio of fine to dense diffuse plaques decreased with age, clouds were limited to younger patients; coarse plaques to the oldest old. Homogeneous/cored plaques were present most consistently in older patients. Plaque density did not increase with age. Vascular Aβ deposits stained for both Aβ species, but exclusively Aβ42-positive, presumably recent deposits were also observed. This study suggests that HCHWA-D is a model of plaque evolution in which clouds leave fine diffuse plaques, which may become dense diffuse and ultimately coarse or homogeneous plaques.

Hereditary cerebral hemorrhage with amyloidosis (Dutch): a model for congophilic plaque formation without neurofibrillary pathology

Plaque-like lesions and amyloid angiopathy were investigated in the frontal cerebral cortex of four patients with hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D), using immunohistochemical [antibodies to β amyloid protein (Aβ), β protein precursor (βPP), synaptophysin, ubiquitin (UBQ), cathepsin D, paired helical filaments (PHF) and glial fibrillary acidic protein (GFAP)], enzymehistochemical (acid phosphatase) and silver [methenamine silver (MS) and Palmgren] staining methods. Whereas Aβ-and MS-positive diffuse plaques were found in all patients, only the three older patients showed neuritic or congophilic plaques, which were acid phosphatase and cathepsin D positive and contained βPP-, synaptophysin-and UBQ-positive, but PHF-negative neurites. These plaques were surrounded by reactive astrocytes. Similar immuno-and enzymereactivity was found around congophilic blood vessels. Thus, apart from neuronal degeneration in a subset of plaque-like lesions and around blood vessels, this study shows an age-related morphology of the plaques in HCHWA-D, corresponding to that in Downs syndrome (DS), with the difference that neurofibrillary (NF) pathology is absent in HCHWA-D in contrast to DS. HCHWA-D may be considered as a model for congophilic plaque formation not associated with NF pathology.

Numerous and widespread α-synuclein-negative Lewy bodies in an asymptomatic patient

Abstract Lewy bodies (LB) and pale bodies (PB), their putative precursors, can be found in a spectrum of diseases characterized by parkinsonism and/or dementia. Furthermore, LB are occasionally observed in some other neurodegenerative diseases and in normal aging. Classical LB are typically found in the brain stem, especially in the substantia nigra, where these inclusions are associated with neuronal loss and clinical signs of idiopathic Parkinson’s disease (PD). The so-called cortical LB occur in the cerebral cortex, amygdala and claustrum with little or no neuronal loss and are clinically associated with dementia in dementia with LB (DLB). We describe a patient without apparent clinical signs of parkinsonism and/or dementia, whose brain contained numerous classical-like LB, pale inclusions with features of PB and transitions between these two. These inclusions had similar immunohistological (ubiquitin positive; neurofilament positive; tau negative) and ultrastructural features as the LB in PD and DLB except for the lack of immunoreactivity for α-synuclein. The pons and cerebral cortex showed the highest number of LB, up to 165/1.76 mm2. These numbers were contrasted by the lack of obvious neuronal loss or gliosis. The absence of α-synuclein reactivity in the LB in this symptomless patient corroborates the hypothesis that α-synuclein accumulation in LB is an important step in neurodegeneration in PD and DLB, but tones down the role of α-synuclein in LB formation in general. This patient seems to represent a new variant in the spectrum of diseases associated with LB.

TRANSMIGRATION OF BETA AMYLOID SPECIFIC HEAVY CHAIN ANTIBODY FRAGMENTS ACROSS THE IN VITRO BLOOD-BRAIN BARRIER

Previously selected amyloid beta recognizing heavy chain antibody fragments (VHH) affinity binders derived from the Camelid heavy chain antibody repertoire were tested for their propensity to cross the blood-brain barrier (BBB) using an established in vitro BBB co-culture system. Of all tested VHH, ni3A showed highest transmigration efficiency which is, in part, facilitated by a three amino acid substitutions in its N-terminal domain. Additional studies indicated that the mechanism of transcellular passage of ni3A is by active transport. As VHH ni3A combines the ability to recognize amyloid beta and to cross the BBB, it has potential as a tool for non-invasive in vivo imaging and as efficient local drug targeting moiety in patients suffering from cerebral amyloidosis such as Alzheimers disease (AD) and cerebral amyloid angiopathy (CAA).

Morphology of cerebral plaque-like lesions in hereditary cerebral hemorrhage with amyloidosis (Dutch)

SummaryWe studied the presence and morphology of plaque-like lesions in the frontal cortex of six patients, aged 40 to 76 years, with hereditary cerebral hemorrhage with amyloidosis — Dutch type (HCHWA-D), using β/A4 immuno-, silver, Congo red and thioflavin S staining. Two types of β/A4 immunoreactive and Congo red-negative plaques were detected. The first type was composed of argyrophilic fibrous material in periodic acid-methenamine silver (PAM) and modified Bielschowsky staining and lacked silver-stained degenerating neurites. Therefore, this type of plaque has the same staining properties as the diffuse plaque described in Alzheimers disease, Downs syndrome and nondemented elderly. The second type of plaque, occurring only in the three oldest patients and numerically increasing with age, consisted of a spherical non-argyrophilic area of granular texture with a rim of PAM-positive material. The PAM-positive fibrous material of both types of plaques was mingled with coarser and compact, irregular-shaped argyrophilic structures in the oldest patient. The described plaques did not show bright fluorescence with thioflavin S staining. These results indicate, that the morphology of plaques, encountered in HCHWA-D, is diverse and changes with age.

Presence of immunoreactive β-endorphin in human skin

Abstract: The production and its induction by ultraviolet radiation (UVR) of proopiomelanocortin (POMC)‐derived peptides by keratinocytes has been reported, albeit not consistently. Recently we demonstrated that only under specific culturing conditions human keratinocytes are capable of producing a β‐endorphin (βE)‐like peptide with the characteristics of β‐lipotropin (βLPH). Here the presence and UV‐induction of βE‐immunoreactivity (βE‐IR) in keratinocytes in human skin in vivo was investigated. βE‐IR was detectable by immunohistochemistry in keratinocytes of the follicular matrix and to some extent in cells of sweat ducts, but was absent from epidermal keratinocytes. Absence of βE‐IR was confirmed by radioimmunoassay of HPLC‐fractionated extracts of normal epidermis. Repeated exposure to solar‐simulated UVR had no effect. This investigation is the first to demonstrate the presence of βE‐immunoreactive material in the follicular matrix of corporal hairs and in duct cells of sweat glands. The possible meaning of these results is discussed.

Hemichorea reversible after operation in a boy with cavernous angioma in the head of the caudate nucleus.

further arterial desaturation to a mean of 73% occurred with an increased end tidal Pco, of 7-8 kPa. These episodes were associated with hypoventilation (reduced abdominal and chest wall movements) without apnoea or airway obstruction. She was given a continuous positive airway pressure device, which provided minor symptomatic relief and improved the mean baseline arterial saturation to 97 5% but failed to abolish the high nocturnal waves of intracranial pressure. A ventriculoperitoneal shunt was therefore inserted and a further period of monitoring undertaken (fig 2). The changes in middle cerebral artery flow velocity and cerebrovascular resistance still occurred with the episodes of desaturation, but the associated increases in intracranial pressure

CNS involvement in primary Sjögren's syndrome: a case with a clue for the pathogenesis.

Sirs: A 72-year-old woman was admitted with aphasia, right hemianopsia, and right hyperreflexia with Babinski’s sign without apparent paresis. Previously, the diagnosis primary Sjögren’s syndrome (pSS) was made because of fatigue, xerostomia, keratitis filamentosa, an elevated erythrocyte sedimentation rate, the presence of rheumatoid factor, and a salivary gland biopsy specimen showing a polymorphic infiltrate with destruction of salivary epithelium, thus fulfilling the Californian criteria [4]. Magnetic resonance imaging demonstrated periventricular and subcortical white matter abnormalities (Fig.1). In the CSF a maximum of one mononuclear cell and one erythrocyte were seen per high-powered field. The CSF albumen quotient was 9.4 (normal: < 7.6) and IgG index 0.47 (normal: 0.20–0.85). No oligoclonal bands indicative of multiple sclerosis or pSS with CNS involvement were demonstrated [1, 9]. Subsequently she experienced an episode of unconsciousness and contractions of the right arm, interpreted as a seizure. Electroencephalography analysis showed diffuse hypofunctional abnormalities without epileptic charges. The diagnosis of pSS with CNS involvement was suspected, and the patient was treated with 500 mg t.i.d. sodium valproate and 1000 mg intravenous methylprednisolone for 3 days followed by 60 mg prednisone per day. After 6 weeks her cognitive functions deteriorated. Although a university graduate, her verbal IQ was 98, performance IQ 74, with obvious deterioration in memory, learning, and graphic construction functions. Vitamins B1, B6, B12 and folic acid levels and thyroid function were normal. The cognitive deterioration was interpreted as a manifestation of pSS, and 150 mg azathioprine daily was added to the treatment. Nevertheless, after 2 months her neurological and cognitive functions had further deteriorated and magnetic resonance imaging showed aggravation of the hyperintense white matter lesions and atrophy. Azathioprine was replaced by monthly courses of cyclophosphamide (750 mg/m2). After 3 months the treatment with cyclophosphamide was abandoned because of rapid deterioration in cognitive functions and worsening of magnetic resonance imaging abnormalities. The patient died of pneumonia 2 months later. Autopsy showed old infarctions in the left and right occipital lobes and in the thalamus macroscopically. Immunohistochemistry with an antibody against amyloid-β showed extensive cerebral amyloid angiopathy (CAA) of meningocortical arteries, arteriolae, and capillaries. Neuritic plaque formation compatible with possible Alzheimer’s disease according to the CERAD criteria was observed [8]. No cellular perivascular infiltrates or vasculitis were found. After incubating normal human and murine brain with patient’s serum, perinuclear and cytoplasmic IgG deposition was seen in both cortical and cerebellar neurons, suggestive of the presence of anti-neuronal antibodies (Fig.2). Immunoperoxidase staining of human and murine brain using sera from two patients with anti-SSA antibodies showed no neuronal staining, while all sera showed nuclear staining on Hep-2 cells. Several explanations can account for the patient’s symptoms. The presence of CCA was comparable in its extent to that in patients with hereditary cerebral hemorrhage with amyloidosis of the Dutch type [7]. Furthermore, neuritic plaques were observed in numbers compatible with LETTER TO THE EDITORS J Neurol (2000) 247 :63–64