Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update.

Multiple systemic atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder of undetermined aetiology characterized by a distinctive oligodendrogliopathy with argyrophilic glial cytoplasmic inclusions (GCIs) and selective neurodegeneration. GCIs or Papp-Lantos inclusions, described more than 20 years ago, are now accepted as the hallmarks for the definite neuropathological diagnosis of MSA and suggested to play a central role in the pathogenesis of this disorder. GCIs are composed of hyperphosphorylated alpha-synuclein (alphaSyn), ubiquitin, LRRK2 (leucin-rich repeat serine/threonine-protein) and many other proteins, suggesting that MSA represents an invariable synucleinopathy of non-neuronal type, a specific form of proteinopathies. The origin of alphaSyn deposition in GCIs is not yet fully understood, but recent findings of dysregulation in the metabolism of myelin basic protein (MBP) and p25alpha, a central nervous system-specific protein, also called TPPP (tubulin polymerization promoting protein), strengthened the working model of MSA as a primary glial disorder and may explain frequent alterations of myelin in MSA. However, it is unknown whether these changes represent an early event or myelin dysregulation occurs further downstream in MSA pathogenesis. The association between polymorphisms at the SNCA gene locus and the risk for developing MSA also points to a primary role of alphaSyn in its pathogenesis, while in a MBP promoter-driven alphaSyn transgenic mouse model gliosis accompanied the neurodegenerative process originating in oligodendrocytes. Because alphaSyn represents a major component in both oligodendroglial and neuronal inclusions in MSA, some authors suggested both a primary oligodendrogliopathy and a neuronal synucleinopathy, but current biomolecular data and animal models support a crucial role of the Papp-Lantos inclusions and of aberrant alphaSyn accumulation as their main constituent, causing oligodendroglial pathology, myelin disruption and, finally, neuronal degeneration in MSA. The relationship between oligodendrocytes involved by Papp-Lantos inclusions and those in degenerating neurons in the course of MSA needs further elucidation.

What determines the molecular composition of abnormal protein aggregates in neurodegenerative disease?

Abnormal protein aggregates, in the form of either extracellular plaques or intracellular inclusions, are an important pathological feature of the majority of neurodegenerative disorders. The major molecular constituents of these lesions, viz., beta-amyloid (Abeta), tau, and alpha-synuclein, have played a defining role in the diagnosis and classification of disease and in studies of pathogenesis. The molecular composition of a protein aggregate, however, is often complex and could be the direct or indirect consequence of a pathogenic gene mutation, be the result of cell degeneration, or reflect the acquisition of new substances by diffusion and molecular binding to existing proteins. This review examines the molecular composition of the major protein aggregates found in the neurodegenerative diseases including the Abeta and prion protein (PrP) plaques found in Alzheimer's disease (AD) and prion disease, respectively, and the cellular inclusions found in the tauopathies and synucleinopathies. The data suggest that the molecular constituents of a protein aggregate do not directly cause cell death but are largely the consequence of cell degeneration or are acquired during the disease process. These findings are discussed in relation to diagnosis and to studies of to disease pathogenesis.

A quantitative study of the pathological changes in white matter in multiple system atrophy.

The density and spatial distribution of the vacuoles, glial cell nuclei and glial cytoplasmic inclusions (GCI) were studied in the white matter of various cortical and subcortical areas in 10 cases of multiple system atrophy (MSA). Vacuolation was more prevalent in subcortical than cortical areas and especially in the central tegmental tract. Glial cell nuclei widespread in all areas of the white matter studied; overall densities of glial cell nuclei being significantly greater in the central tegmental tract and frontal cortex compared with areas of the pons. The GCI were present most consistently in the external and internal capsules, the central tegmental tract and the white matter of the cerebellar cortex. The density of the vacuoles was greater in the MSA brains than in the control brains but glial cell density was similar in both groups. In the majority of areas, the pathological changes were distributed across the white matter randomly, uniformly, or in large diffuse clusters. In most areas, there were no spatial correlations between the vacuoles, glial cell nuclei and GCI. These results suggest: (i) there is significant degeneration of the white matter in MSA characterized by vacuolation and GCI; (ii) the central tegmental tract is affected significantly more than the cortical tracts; (iii) pathological changes are diffusely rather than topographically distributed across the white matter; and (iv) the development of the vacuoles and GCI appear to be unrelated phenomena.

Spatial topography of the neurofibrillary tangles in cortical and subcortical regions in progressive supranuclear palsy.

OBJECTIVE: To study the topography of neurofibrillary tangles (NFT) in cortical and subcortical areas in progressive supranuclear palsy (PSP). METHODS: Pattern analysis was carried out on tau-positive NFT in eight PSP cases. RESULTS: Of the areas studied, NFT were randomly distributed in 68%, regularly distributed in 3%, and clustered in 29%. A regular distribution of clusters was more frequent in cortical than subcortical areas. CONCLUSION: NFT topography in subcortical areas was similar to inclusions in the synucleinopathy multiple system atrophy (MSA) but in cortical areas was comparable to other tauopathies.

Expression of cellular prion protein in the frontal and occipital lobe in Alzheimer's disease, diffuse Lewy body disease, and in normal brain: an immunohistochemical study.

Cellular prion protein (PrP(c)) is a glycoprotein expressed at low to moderate levels within the nervous system. Recent studies suggest that PrP(c) may possess neuroprotective functions and that its expression is upregulated in certain neurodegenerative disorders. We investigated whether PrP(c) expression is altered in the frontal and occipital cortex in two well-characterized neurodegenerative disorders--Alzheimer's disease (AD) and diffuse Lewy body disease (DLBD)--compared with that in normal human brain using immunohistochemistry and computerized image analysis. The distribution of PrP(c) was further tested for correlation with glial reactivity. We found that PrP(c) was localized mainly in the gray matter (predominantly in neurons) and expressed at higher levels within the occipital cortex in the normal human brain. Image analysis revealed no significant variability in PrP(c) expression between DLBD and control cases. However, blood vessels within the white matter of DLBD cases showed immunoreactivity to PrP(c). By contrast, this protein was differentially expressed in the frontal and occipital cortex of AD cases; it was markedly overexpressed in the former and significantly reduced in the latter. Epitope specificity of antibodies appeared important when detecting PrP(c). The distribution of PrP(c) did not correlate with glial immunoreactivity. In conclusion, this study supports the proposal that regional changes in expression of PrP(c) may occur in certain neurodegenerative disorders such as AD, but not in other disorders such as DLBD.

Overlap between neurodegenerative disorders.

Neurodegenerative disorders are characterized by the formation of distinct pathological changes in the brain, including extracellular protein deposits, cellular inclusions, and changes in cell morphology. Since the earliest published descriptions of these disorders, diagnosis has been based on clinicopathological features, namely, the coexistence of a specific clinical profile together with the presence or absence of particular types of lesion. In addition, the molecular profile of lesions has become an increasingly important feature both in the diagnosis of existing disorders and in the description of new disease entities. Recent studies, however, have reported considerable overlap between the clinicopathological features of many disorders leading to difficulties in the diagnosis of individual cases and to calls for a new classification of neurodegenerative disease. This article discusses: (i) the nature and degree of the overlap between different neurodegenerative disorders and includes a discussion of Alzheimer's disease, dementia with Lewy bodies, the fronto-temporal dementias, and prion disease; (ii) the factors that contribute to disease overlap, including historical factors, the presence of disease heterogeneity, age-related changes, the problem of apolipoprotein genotype, and the co-occurrence of common diseases; and (iii) whether the current nosological status of disorders should be reconsidered.

Spatial patterns of alpha-synuclein positive glial cytoplasmic inclusions in multiple system atrophy.

In cases of multiple system atrophy (MSA), glial cytoplasmic inclusions (GCI) were distributed randomly or present in large diffuse clusters (>1,600 microm in diameter) in most areas studied. These spatial patterns contrast with those reported for filamentous neuronal inclusions in the tauopathies and alpha-synucleinopathies.

A quantitative study of the pathological changes in cortical neurons in sporadic Creutzfeldt-Jakob disease.

The frequency of morphological abnormalities in neuronal perikarya was studied in the cerebral cortex in cases of sporadic CJD (sCJD) and in elderly control patients. Three hypotheses were tested, namely that the proportion of neurons exhibiting abnormal morphology was increased: (i) in sCJD compared with control patients; (ii) in sCJD, in areas with significant prion protein (PrP) deposition compared with regions with little or no PrP deposition; and (iii) when neurons were spatially associated with a PrP deposit compared with neurons between PrP deposits. Changes in cell shape (swollen or atrophic cell bodies), nuclei (displaced, indistinct, shrunken or absent nuclei; absence of nucleolus), and cytoplasm (dense or pale cytoplasm, PrP positive cytoplasm, vacuolation) were commonly observed in all of the cortical areas studied in the sCJD cases. The proportion of neurons exhibiting each type of morphological change was significantly increased in sCJD compared with age-matched control cases. In sCJD, neuronal abnormalities were present in areas with little PrP deposition, but at significantly lower frequencies compared with areas with significant densities of PrP deposits. Abnormalities of cell shape, nucleus and the presence of cytoplasmic vacuolation were increased when the neurons were associated with a PrP deposit, but fewer of these neurons were PrP-positive compared with neurons between deposits. The data suggest significant neuronal degeneration in the cerebral cortex in sCJD in areas without significant PrP deposition and a further phase of neuronal degeneration associated with the appearance of PrP deposits.

Olfactory bulb in multiple system atrophy.

Olfactory dysfunction is a characteristic clinical sign in Parkinson's disease (PD); it is also present in multiple system atrophy (MSA). The pathological basis of hyposmia or anosmia in PD is well known: the olfactory bulb (OB) contains numerous Lewy bodies and severe neuronal loss is present in the anterior olfactory nucleus (AON). We established that glial cytoplasmic inclusions (GCIs) are present in all the OBs from MSA cases. Their presence in the OB is diagnostic for MSA. Additionally, neuronal loss is present in the AON in MSA. These pathological changes might be responsible for the olfactory dysfunction seen in MSA.

Glyceraldehyde 3-phosphate dehydrogenase and endothelin-1 immunoreactivity is associated with cerebral white matter damage in dentatorubral-pallidoluysian atrophy.

DRPLA is a rare neurodegenerative disorder caused by CAG triplet elongation on chromosome 12p. In addition to neurodegeneration of both the dentatorubral and pallidoluysian systems, there is cerebral white matter damage, especially in older cases. Intracellular accumulation of DRPLA protein is widespread in the central nervous system, and DRPLA protein has been shown to immobilize glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which regulates glycolysis and controls mRNA of tissue-type plasminogen activator (tPA) in tissue restoration. However, little is known about the pathogenesis regarding the formation of cerebral white matter damage in DRPLA. Therefore, the pathology of this damage was investigated by examining markers of glycolysis and related processes. Nine clinically and pathologically confirmed DRPLA cases were used in the present study. CAG triplet elongation on chromosome 12p was confirmed in all cases where tissue was available for genotyping (seven cases). PAS and immunohistochemistry with antibodies to GFAP, GAPDH and endothelin-1 were used to demonstrate astrocytosis. The polysaccharides storage state with PAS-positive astrocytes was detected in seven cases. GAPDH- and endothelin-1-positive endothelium and astrocytes were observed in two cases with GFAP-positivity. Based on the biochemical process together with the present results, GAPDH and endothelin-1 immunoreactivity is associated with this damage and the mismetabolism of polysaccharides caused by CAG triplet elongation on chromosome 12p may contribute to the formation of the cerebral white matter damage in DRPLA.

Patients with a novel neurofilamentopathy: dementia with neurofilament inclusions.

We report a new disease, dementia with neurofilament inclusions, characterized clinically by early-onset dementia with frontal lobe signs, focal atrophy of the frontal and temporal lobes, and microscopically by the presence in many brain regions of intraneuronal, cytoplasmic, neurofilament inclusions. The neuronal inclusions are immunoreactive to all three molecular weight neurofilament subunits: heavy (NF-H), light, and medium subunits, including the phosphorylated and non-phosphorylated forms of NF-H. Prion protein and beta-amyloid deposits were absent. The inclusions do not contain tau or alpha-synuclein protein aggregates known to characterize many neurodegenerative disorders. In addition to delineating a new disease entity, the identification of intraneuronal, cytoplasmic, neurofilament inclusions extends the molecular classification of neurodegenerative diseases and implicates new mechanisms of neurodegeneration in diseases affecting the human brain.

Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration ('reaction' hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.

Creutzfeldt-Jakob disease with amyotrophy and demyelinating polyneuropathy.

OBJECTIVE: To report the clinical and neuropathological features in a patient with Creutzfeldt-Jakob disease with amyotrophy and demyelinating polyneuropathy. DESIGN: Case report. PATIENT AND RESULTS: A 62-year-old man had progressive numbness of the left foot, unsteady gait, diminished deep reflexes, fasciculations, and tactile hypesthesia on the feet. Cerebrospinal fluid, electroneurography, and electromyography were suggestive of chronic inflammatory demyelinating polyneuropathy. He was treated with plasmapheresis, corticosteroids, and immunglobulins, with minimal improvement. After 2 months, severe amyotrophy, polyneuropathy, cerebellar signs, and dementia developed, and he died 8 months after onset of the disease. Autopsy and prion protein immunohistochemistry proved typical Creutzfeldt-Jakob disease. No mutation was found in the prion protein gene, and the codon 129 polymorphism was methionine-valine. In the ventral horn, the loss of the motoneurons was accompanied by prion protein immunoreactivity. The peripheral nerves were segmentally demyelinated but free of prion protein deposition. CONCLUSIONS: The view that peripheral neuropathy and amyotrophy may occasionally be an integral part of Creutzfeldt-Jakob disease is supported by our case, which showed these abnormalities simultaneously. These symptoms, when prominent, may cause problems in differential diagnosis.

Laminar distribution of the pathological changes in the cerebral cortex in variant Creutzfeldt-Jakob disease (vCJD).

To determine the pattern of cortical degeneration in cases of variant Creutzfeldt-Jakob disease (vCJD), the laminar distribution of the vacuolation ("spongiform change"), surviving neurones, glial cell nuclei, and prion protein (PrP) deposits was studied in the frontal, parietal and temporal lobes. The vacuolation exhibited two common patterns of distribution: either the vacuoles were present throughout the cortex or a bimodal distribution was present with peaks of density in the upper and lower cortical laminae. The distribution of the surviving neurones was highly variable in different regions; the commonest pattern being a uniform distribution with cortical depth. Glial cell nuclei were distributed largely in the lower cortical laminae. The non-florid PrP deposits exhibited either a bimodal distribution or exhibited a peak of density in the upper cortex while the florid deposits were either uniformly distributed down the cortex or were present in the upper cortical laminae. In a significant proportion of areas, the density of the vacuoles was positively correlated with either the surviving neurones or with the glial cell nuclei. These results suggest similarities and differences in the laminar distributions of the pathogenic changes in vCJD compared with cases of sporadic CJD (sCJD). The laminar distribution of vacuoles was more extensive in vCJD than in sCJD whereas the distribution of the glial cell nuclei was similar in the two disorders. In addition, PrP deposits in sCJD were localised mainly in the lower cortical laminae while in vCJD, PrP deposits were either present in all laminae or restricted to the upper cortical laminae. These patterns of laminar distribution suggest that the process of cortical degeneration may be distinctly different in vCJD compared with sCJD.