Cutis laxa in hereditary gelsolin amyloidosis.

BACKGROUND: Hereditary gelsolin amyloidosis (AGel amyloidosis) is an age-associated systemic disease with global distribution, caused by a G654A or G654T gelsolin gene mutation. Cutis laxa is a principal clinical manifestation of this disease. However, only few data on the dermatological involvement are available, and the pathogenesis of this amyloidosis-associated form of cutis laxa has remained unknown. OBJECTIVES: To elucidate the pathomechanism of this less well-known genodermatosis. METHODS: We performed systematic clinical, histological, immunohistochemical and ultrastructural skin biopsy studies in 12 patients with a G654A gelsolin gene mutation. For comparison, skin specimens from 10 control subjects were analysed. RESULTS: All patients had clinically characteristic cutis laxa, and frequently other signs of symptomatic skin disease such as increased fragility and risk for intracutaneous bleeding. All patients showed cutaneous deposition of gelsolin amyloid (AGel), mainly attached to basement membranes or basal laminae of various cutaneous structures, dermal nerves and blood vessel walls, and elastic fibres, particularly in the lower reticular dermis. AGel often encircled the elastic fibres, and colocalized with amyloid P component (AP), an elastic fibre microfibrillar sheath-associated protein. Fragmentation and loss of elastic fibres, epidermal atrophy, and reduction of dermal appendages were also common. Antibodies to wild-type gelsolin bound to S-100-positive epidermal dendritic cells, a previously unrecognized immunoreaction. Patients had fewer gelsolin-positive dendritic cells than controls. CONCLUSIONS: Widespread skin involvement with AGel deposition and elastic fibre involvement are essential pathological features in AGel amyloidosis, and contribute to the characteristic cutis laxa, dramatic in old age. Codistribution of AGel and AP, with demonstrated specific binding affinity for amyloid fibrils, suggests that elastic fibre-associated AP acts as a matrix for cutaneous amyloid deposition in AGel amyloidosis.

The normal population distribution of PRNP codon 129 polymorphism.

OBJECTIVES: The common prion protein gene (PRNP) codon 129 polymorphism modifies the susceptibility to and the phenotype of prion diseases. However, no truly representative normal population-based data, or data stratified according to age or gender are available on the distribution of this polymorphism. MATERIAL AND METHODS: Allelic variation of codon 129 in three Finnish populations representing different age groups, and among Finnish, British and Irish blood donors were examined. RESULTS: The PRNP codon 129 genotype distribution in the total Finnish sample was 49% for methionine-methionine (MM), 42% for methionine-valine (MV) and 9% for valine-valine (VV), for the UK blood donors 42% for MM, 47% for MV and 11% for VV, and for the Irish blood donors 34% for MM, 56% for MV, and 10% for VV. CONCLUSIONS: The genotype frequencies were almost identical in all three Finnish populations of different ages, with no gender differences, and did not differ from corresponding figures for the Finnish blood donors. However, the PRNP codon 129 genotype distribution in Finland differed significantly from that of the British and the Irish blood donors and the previously published blood donor data on other Western Europeans and Americans.

Status epilepticus induces changes in the expression and localization of endogenous palmitoyl-protein thioesterase 1.

Kainic acid (KA)-induced experimental epilepsy, a model of excitotoxicity, leads to selective neuronal death and synaptic restructuring. We used this model to investigate the effects of neuronal hyperactivation on palmitoyl-protein thioesterase 1 (PPT1), the deficiency of which causes drastic neurodegeneration. Immunological stainings showed that epileptic seizures in adult rats led to a progressive and remarkable increase of PPT1 in limbic areas of the brain. Within 1 week, the maximal expression was observed in CA3 and CA1 pyramidal neurons of the hippocampus. In the surviving pyramidal neurons, PPT1 localized in vesicular structures in cell soma and neuritic extensions. After seizures, colocalization of PPT1 with synaptic membrane marker (NMDAR2B) was enhanced. Further, synaptic fractionation revealed that after seizures PPT1 was readily observed on the presynaptic side of synaptic junction. These data suggest that PPT1 may protect neurons from excitotoxicity and have a role in synaptic plasticity.

Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.

OBJECTIVE: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. BACKGROUND: Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. METHODS: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. RESULTS: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. CONCLUSION: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.

Association of lipoprotein lipase Ser447Ter polymorphism with brain infarction: a population-based neuropathological study.

BACKGROUND: Variants of the lipoprotein lipase (LPL) gene have been shown to influence serum lipid levels, risk of coronary heart disease and, as found recently, risk of clinical ischaemic cerebrovascular disease. Here we tested for an association between brain infarction and two common polymorphisms of the LPL gene, Ser447Ter and Asn291 Ser. METHOD: To avoid ascertainment and selection bias involved in many association studies, we compared the distribution of these polymorphisms in neuropathologically verified patients (n = 119) vs controls (n = 133) derived from a prospective, population-based study (the Vantaa 85+ study). RESULTS: The LPL Ter447 variant was negatively associated with neuropathologically verified brain infarcts (P = 0.006), and even more strongly with small brain infarcts (P = 0.004). In addition, we found that the Ter447 variant was associated with higher serum HDL chblesterol (P = 0.004) and lower triglyceride levels (P= 0.003), and that it was negatively associated with pathologically verified severe coronary artery disease (P=0.001) in the Vantaa 85+ study sample. The Asn291Ser polymorphism was not significantly associated with brain infarction. CONCLUSION: The Ter447 variant of LPL is associated with decreased risk of brain infarction and coronary artery disease in our very elderly population.

Hippocampal lesions in the neuronal ceroid lipofuscinoses.

Epilepsy is a common manifestation in all childhood-onset forms of neuronal ceroid lipofuscinosis. In order to document hippocampal lesions and their relationship to epilepsy we studied autopsy specimens from the hippocampi of a series of patients with the infantile (CLN1), classic late infantile (CLN2), Finnish variant late infantile (CLN5), and juvenile (CLN3) neuronal ceroid-lipofuscinosis as well as Northern epilepsy (CLN8), using a battery of histological and immunocytochemical staining methods. Despite striking differences in the overall degree of neocortical neuronal storage and loss, these genetically heterogeneous forms of neuronal ceroid lipofuscinosis showed a common lesional pattern in the hippocampi: a relative sparing of the CA1 sector and severe involvement of the neighbouring CA2 sector, with intermediate degrees of involvement of the CA3 and CA4 sectors. These findings distinguish the hippocampal pathology associated with the neuronal ceroid lipofuscinoses from classical 'mesial temporal sclerosis' and show that the selective lesional pattern in the neuronal ceroid lipofuscinoses is not a secondary anoxic-ischaemic phenomenon. It is rather a consequence of the primary metabolic defects and may be directly involved in the causation of the epileptic discharges.

Congenital ovine neuronal ceroid lipofuscinosis--a cathepsin D deficiency with increased levels of the inactive enzyme.

We recently showed that a form of neuronal ceroid lipofuscinosis (NCL) in white Swedish landrace sheep is caused by a missense mutation in the cathepsin D gene resulting in complete inactivation of the enzyme. Despite the lack of cathepsin D activity, the brains of the cathepsin D deficient sheep showed strongly increased staining for cathepsin D in immunohistochemistry. By Western blotting, a 5-10 fold increase in the level of cathepsin D was confirmed. These results indicate that the missense mutation in congenital NCL sheep results in the synthesis of an inactive yet stable cathepsin D.

Amphoterin includes a sequence motif which is homologous to the Alzheimer's beta-amyloid peptide (Abeta), forms amyloid fibrils in vitro, and binds avidly to Abeta.

Many of the proteins associated with amyloidoses have been found to share structural and sequence similarities, which are believed to be responsible for their capability to form amyloid fibrils. Interestingly, some proteins seem to be able to form amyloid-like fibrils although they are not associated with amyloidoses. This indicates that the ability to form amyloid fibrils may be a general property of a greater number of proteins not associated with these diseases. In the present work, we have searched for amyloidogenic consensus sequences in two current protein/peptide databases and show that many proteins share structures which can be predicted to form amyloid. One of these potentially amyloidogenic proteins is amphoterin (also known as HMG-1), involved in neuronal development and a ligand for the receptor for advanced glycation end products (RAGE). It contains an amyloidogenic peptide fragment which is highly homologous to the Alzheimer's amyloid beta-peptide. If enzymatically released from the native protein, it forms amyloid-like fibrils which are visible in electron microscopy, exhibit apple green birefringence under polarized light after Congo red staining, and increases thioflavin T fluorescence. This fragment also shows high affinity to Abeta as a free peptide or while part of the native protein. Our results support the hypothesis that the potential to form amyloid is a common characteristic of a number of proteins, independent of their relation to amyloidoses, and that this potential can be predicted based on the physicochemical properties of these proteins.

Cases of Alzheimer's disease due to deletion of exon 9 of the presenilin-1 gene show an unusual but characteristic beta-amyloid pathology known as 'cotton wool' plaques.

The pattern of deposition of amyloid beta protein (Abeta) was investigated, using the monoclonal antibodies BA27 and BC05 detecting the C-terminal species Abeta40 and Abeta42(43), in six cases of Alzheimer's disease (AD) due to deletions in exon 9 of PS-1 gene. These cases are characterized histologically by the presence of very large rounded plaques within the frontal cortex, known as 'cotton wool' plaques, composed of both Abeta40 and Abeta42(43) that are relatively free from neuritic changes and glial cell components, and usually devoid of a compact amyloid core. In the cerebellum the plaques are almost entirely of a compact type, again composed of Abeta40 and Abeta42(43), with only few diffuse Abeta42(43) containing plaques. The area fraction of Abeta40, and the ratio between Abeta40 and Abeta42(43), in frontal cortex was significantly higher than that seen in other cases of AD due to different PS-1 mutations, or in cases of sporadic AD, all of similar APO E genotype. The area fractions of Abeta42(43), however, did not significantly differ between these three groups. The unusual nature of the Abeta deposition in these cases may reflect the uniqueness of the mutation, which results in a failure to constitutively cleave the PS-1 holoprotein into its active form, and the effect this might have on APP trafficking and catabolism.

Prevalence of Alzheimer's disease in very elderly people: a prospective neuropathological study.

BACKGROUND: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. OBJECTIVE: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. METHODS: A population-based sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. RESULTS: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p < 0.001) association between the APOE epsilon4 allele and AD: Sixty-three percent of APOE epsilon4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. CONCLUSIONS: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.

CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts.

BACKGROUND: Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a genetically heterogeneous disease characterized by a combination of systemic bone cysts and dementia. OBJECTIVE: The authors present a neurologic, neuroradiologic, and neuropathologic analysis of a series of PLOSL patients in which the diagnosis has been confirmed by molecular genetic methods. METHODS: Clinical, neurophysiologic, and imaging follow-up data on eight patients as well as autopsy samples of three patients were analyzed in this study. All eight patients were homozygous for a loss-of-function mutation in the DAP12 gene. RESULTS: In most patients, the disease debuted with pain in ankles and wrists after strain during the third decade, followed by fractures caused by cystic lesions in the bones of the extremities. Frontal lobe syndrome and dementia began to develop by age 30, leading to death by age 40. Neuroimaging disclosed abnormally high and progressively increasing bicaudate ratios and calcifications in the basal ganglia as well as increased signal intensities of the white matter on T2-weighted MR images even before the appearance of clinical neurologic symptoms. Three patients who had undergone autopsies showed an advanced sclerosing leukoencephalopathy with frontal accentuation, widespread activation of microglia, and microvascular changes. CONCLUSIONS: Although PLOSL in most patients manifests by bone fractures, some patients do not show any osseous symptoms and signs before the onset of neurologic manifestations. Consequently, patients with frontal-type dementia of unknown origin should be investigated by x-ray of ankles and wrists. The current results suggest early basal ganglia involvement in PLOSL.

Studies of homogenous populations: CLN5 and CLN8.

Finland and the Finns have been the subject of numerous genetic and genealogical studies, owing to enrichment of certain rare hereditary disorders in the Finnish population. Two types of NCL have so-far been found almost exclusively in Finland: Finnish variant late infantile NCL, vLINCL (CLN5), and the Northern epilepsy syndrome or Progressive epilepsy with mental retardation, EPMR (CLN8). The first symptoms of Finnish vLINCL are concentration problems or motor clumsiness by 3 to 6 years of age, followed by mental retardation, visual failure, ataxia, myoclonus, and epilepsy. Northern epilepsy, the newest member of the NCL family with the most protracted course, is characterized by the onset of generalized seizures between 5 and 10 years of age and subsequent progressive mental retardation. Visual problems are slight and late, while myoclonus has not been observed. Both the Finnish vLINCL and Northern epilepsy are pathologically characterized by intraneuronal cytoplasmic deposits of autofluorescent granules which are Luxol fast blue-, PAS-, and Sudan black B-positive in paraffin sections. In Northern epilepsy the intraneuronal storage process and neuronal destruction are generally of mild degree but highly selective and, in contrast to other forms of childhood onset NCL, the cerebellar cortex is relatively spared. By electron microscopy the storage bodies mainly contain rectilinear complex type and fingerprint profiles in Finnish vLINCL and structures resembling curvilinear profiles in Northern epilepsy. Mitochondrial ATP synthase subunit c is the main stored protein in both disorders. Both the DCLN5 and CLN8 genes encode putative membrane proteins with yet unknown functions. Furthermore, a well studied spontaneously occurring autosomal recessive mouse mutant, motor neuron degeneration (mnd) mouse, is a homolog for CLN8.

Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype.

Variant Alzheimer disease (varAD) is clinically characterized by the combination of presenile dementia with spastic paraparesis and is caused by certain mutations of the presenilin 1 (PS-1) gene. We now present the unusual neuropathological phenotype of varAD as seen in 5 affected members of the original Finnish family with a genomic deletion encompassing exon 9 of the PS-1 gene. Their primary and association cortices and hippocampus showed a profusion of eosinophilic, roundish structures with distinct borders termed "cotton wool" plaques (CWPs). The CWPs were immunoreactive for Abeta42/43 but weakly or not at all for Abeta40 isoforms of the amyloid beta peptide (Abeta). They were devoid of a congophilic core, and fibrillar amyloid could not be identified within them by electron microscopy. Confocal microscopy showed reduced density of axons within individual CWPs and only few CWP-related PHF-tau-positive dystrophic neurites. CWPs were particularly numerous in the medial motor cortex representing the lower extremities, and degeneration of the lateral corticospinal tracts was observed at the level of the medulla oblongata and the spinal cord. In addition to the predominant CWPs, variable numbers of diffuse and cored plaques were found in the cerebral cortex. Diffuse and non-neuritic cored amyloid plaques but no CWPs occurred in the cerebellum. In conclusion, varAD in this Finnish family is distinct from classic AD because of the degeneration of lateral corticospinal tracts, predominance of CWPs devoid of fibrillar amyloid cores in the cerebral cortex, and presence of non-neuritic amyloid plaques in the cerebellum.

Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations.

We describe 3 new families affected by Alzheimer's disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large "cotton wool" plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin-1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Abeta42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid-beta concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimer's disease and have implications for the pathogenesis of the disease in general.

Human prion diseases.

The term 'prion diseases' refers to a group of neurodegenerative disorders thought to be caused by prions, pathogenic agents with novel modes of replication and transmission. Prion diseases are characterized by long incubation periods ranging from months to years and are invariably fatal once clinical symptoms have appeared. They are also called transmissible spongiform encephalopathies (TSE), on account of the predominant neuropathological change observed in the central nervous system. The most important members of this group are Creutzfeldt-Jakob disease (CJD) of man displaying sporadic, inherited and infectious forms, bovine spongiform encephalopathy (BSE, 'mad cow disease') of cattle, and scrapie of sheep. Despite their rarity, human prion diseases have recently been covered extensively in the media because of the likely connection between a new variant of human CJD (vCJD) and BSE and the possibility of contamination of human blood and blood products by the vCJD agent. This short review discusses the basic biological properties of prions, followed by a presentation of the clinical and pathological features of the most important human prion diseases.

Cardiovascular risk factors and Alzheimer's disease: a genetic association study in a population aged 85 or over.

Increasing evidence suggests a relation between vascular disorders and late-onset Alzheimer's disease (AD). We performed an association analysis of low-density lipoprotein receptor-related protein (LRP), lipoprotein lipase (LPL), and angiotensin converting enzyme (ACE) genes, known to be involved in vascular disorders, and AD. Genotyping was carried out in 113 patients with clinically defined Alzheimer's disease (NINCDS-ADRDA criteria) and 203 non-demented controls in a prospective, population-based study of people aged 85 years or over (Vantaa 85+ Study). Corresponding analysis was performed on 121 neuropathologically verified AD patients (CERAD criteria) and 75 controls derived from the same study population. We did not find significant associations between the polymorphisms studied and AD. However, analysis of the LPL polymorphism showed a weak trend (uncorrected P-value 0.095) towards protection against neuropathologically defined AD. Our study is based on very elderly Finns. Therefore, further studies are warranted in other populations.

Apolipoprotein E includes a binding site which is recognized by several amyloidogenic polypeptides.

Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is a risk factor for late-onset Alzheimer's disease (AD). Biochemically apoE is present in AD plaques and neurofibrillary tangles of the AD brain. There is a high avidity and specific binding of apoE and the amyloid beta-peptide (A beta). In addition to AD apoE is also present in many other cerebral and systemic amyloidoses, Down's syndrome and prion diseases but the pathophysiological basis for its presence is still unknown. In the present study we have compared the interaction of apoE with A beta, the gelsolin-derived amyloid fragment AGel(183-210) and the amyloidogenic prion fragments PrP(109-122) and PrP(109-141). We show that, similar to A beta, also AGel and PrP fragments can form a complex with apoE, and that the interaction between apoE and the amyloidogenic protein fragments is mediated through the same binding site on apoE. We also show that apoE increases the thioflavin-T fluorescence of PrP and AGel and that apoE influences the content of beta-sheet conformation of these amyloidogenic fragments. Our results indicate that amyloids and amyloidogenic prion fragments share a similar structural motif, which is recognized by apoE, possibly through a single binding site, and that this motif is also responsible for the amyloidogenicity of these fragments.

A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration.

The neuronal ceroid lipofuscinoses (NCLs) constitute a group of neurodegenerative storage diseases characterized by progressive psychomotor retardation, blindness and premature death. Pathologically, there is accumulation of autofluorescent material in lysosome-derived organelles in a variety of cell types, but neurons in the central nervous system appear to be selectively affected and undergo progressive death. In this report we show that a novel form of NCL, congenital ovine NCL, is caused by a deficiency in the lysosomal aspartyl proteinase cathepsin D. A single nucleotide mutation in the cathepsin D gene results in conversion of an active site aspartate to asparagine, leading to production of an enzymatically inactive but stable protein. This results in severe cerebrocortical atrophy and early death, providing strong evidence for an important role of cathepsin D in neuronal development and/or homeostasis.

No association between TAU haplotype and Alzheimer's disease in population or clinic based series or in familial disease.

We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.