Filippo Gullotta

Neuropathological Diagnostic-criteria for Creutzfeldt-jakob-disease (cjd) and Other Human Spongiform Encephalopathies (prion Diseases)

Neuropathological diagnostic criteria for Creutzfeldt‐Jakob disease (CJD) and other human transmissible spongiform encephalopathies (prion diseases) are proposed for the following disease entities: CJD ‐ sporadic, iatrogenic (recognised risk) or familial (same disease in 1st degree relative): spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; or encephalopathy with prion protein (PrP) immuno‐reactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types). Gerstmann‐Sträussler‐Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multicentric PrP plaques. Familial fatal insomnia (FFI) (in member of a family with PRNP178 mutation): thalamic degeneration, variable spongiform change in cerebrum. Kuru (in the Fore population).

Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease

Abstract Creutzfeldt-Jakob disease (CJD) and Alzheimer’s disease (AD) share clinical, neuropathological, and pathogenetic features. To investigate eventual mutual influences, we screened prominently affected neocortex from 110 neuropathologically proven CJD patients for Alzheimer-type pathology with anti-β/A4, Bielschowsky and anti-tau (immuno)stains. The neuropathological classification of Alzheimer-type pathology was made according to the CERAD criteria. Results were controlled by comparison with Alzheimer-type changes in sections from the same cortical areas in 110 sex- and age-matched non-demented control patients. For comparison, the control patients were also classified according to the CERAD neuropathology criteria as if they had been demented. Alzheimer-type tissue changes as in definite and probable CERAD AD occur in 10.9% of the CJD patients and 19.1% of control patients (P = 0.11). The median age of CJD and control patients with CERAD AD is 72 and 68 years, respectively, which differs significantly from the median ages of 64 and 63 years, respectively, in the non-AD/CJD and non-AD control patients. Since CERAD criteria include “presence of other neuropathological lesions likely to cause dementia”, an AD diagnosis in CJD patients (all of whom are demented) is solely based on densities of neuritic plaques. Similar Alzheimer-type changes in even higher frequency, however, are also present in elderly non-demented controls. Thus, the coexistence of Alzheimer-type pathology in CJD most likely represents an age-related change. Deposits of prion protein (PrP) frequently accumulate at the periphery of β/A4 plaques. The presence of β/A4 amyloid in the brain may influence PrP morphogenesis.

Dysembryoplastic neuroepithelial tumour of the cerebellum

A case of dysembryoplastic neuroepithelial tumour of the cerebellum occurring in a 28-year-old woman is presented. The lesion extended from the cortex of the inferior vermis upwards into the white matter. Histologically, it exhibited areas of microcystic cerebellar astrocytoma and glial regions with hamartomatous blood vessels as well as areas with oligodendrocyte-like cells (OLC) with a delicate, fibrillary stroma lying in a mucinous, often microcystic matrix. The OLC showed prominent rosette formation and immunohistochemical features suggesting neuronal, i.e. granule cell, differentiation.

Cell death mechanisms in multiple system atrophy.

The presence and distribution of apoptotic cell death in multiple system atrophy (MSA) and morphologically related diseases were investigated by means of a modified terminal deoxynucleotidyl transferase-mediated nick end labeling method, comparing their distribution with that of glial cytoplasmic inclusions, immunohistochemically demonstrated bcl-2 protein, bax protein, CD95, TNFα, and p53-protein expression, as well as activated microglia. Apoptosis occurred almost exclusively in oligodendrocytes in multiple system atrophy and its general distribution was comparable to the already known oligodendroglial pathology in this disorder. Additionally, in about a quarter of glial cytoplasmic inclusions, there was upregulation of bcl-2-protein and coexpression with ubiquitin, suggesting a final attempt of involved cells to counteract apoptotic cell death. Bax protein was also demonstrated in oligodendroglial cells. A significant neuronal apoptosis was not observed in MSA; these cells might be destroyed secondarily to oligodendroglial apoptosis by necrosis or other forms of programmed cell death. These results emphasize the central role of oligodendroglial pathology in multiple system atrophy, making this disease unique among neurodegenerative diseases.

Ubiquitin in Motor Neuron Disease: Study at the Light and Electron Microscope

Several neurodegenerative diseases, including motor neuron disease (MND), are characterized by formation of abnormal cytoskeleton-derived inclusions which contain ubiquitin (Ubq). We have studied the distribution of Ubq in 26 cases of MND with light and electron microscopic immunocytochemistry. Ubiquitin-positive inclusions were found in neurons of anterior horns in most cases of amyotrophic lateral sclerosis (ALS) but were not present in other forms of MND. Ubiquitin immunoreactivity was observed in 10–15 nm intraneuronal filaments, which were not stained by antibodies to neurofilaments, and on dense bodies of dystrophic neurites throughout the neuropil of anterior horns and pyramidal tracts. Data analysis showed a trend toward lower percentage of Ubq-positive neurons in cases with longer duration of illness or lower number of neurons. A high percentage of Ubq-positive inclusions occurred in cases with an aggressive clinical course, suggesting that ubiquitination takes place at early stages of the disease.

Age‐related ubiquitin deposits in dystrophic neurites: an immunoelectron microscopic study

Widespread neuritic dystrophy is a hallmark of Alzheimers disease (AD) and, in a less severe form, of brain ageing in various mammalian species. By immunohistochemistry, diffuse dot‐like staining for ubiquitin (Ubq), a polypeptide involved in the degradation of abnormal and shortlived proteins, has been associated with human brain ageing. The nature of the Ubq deposits was investigated by immunogold electron microscopy on autopsy samples from aged human and dog brains. Most of the dot‐like staining was localized to the white matter and corresponded to myelinated dystrophic neurites filled by Ubq‐labelled lysosomal dense bodies. They did not contain paired helical filaments or multilamellar bodies. A minority of Ubq deposits was represented by amorphous densities in focal enlargements of the myelin sheaths, Our findings show that the spectrum of Ubq changes in ageing brain is wider than formerly recognized, and support the hypothesis that a defective regulation of the lysosomal system might be involved in the pathogenesis of structural abnormalities both in the ageing brain and in Alzheimers disease.

Motor neuron disease with pallido-luysio-nigral atrophy

SummaryA case of motor neuron disease (MND) with pallido-luysio-nigral atrophy (PLNA) is reported. The 45-year-old male patient presented with lower motor neuron symptoms and signs of basal ganglia disturbance. He died after a progressive course of 7 months. Neuropathological examination revealed motor neuron loss at all spinal cord levels with sparing of Onufs nucleus. Nerve cell loss and gliosis were also present in substantia nigra, globus pallidus, and subthalamic nucleus. The presence of ubiquitin-positive inclusions, a hallmark of most variants of MND, confirms this case as an example of MND. At immunoelectron microscopy the granules were distributed on filamentous material. The combination of clinically apparent PLNA with MND has only been described twice previously. The relationship of this syndrome to other forms of MND and its nosological placement are discussed.

Paragangliom der Cauda equina

ZusammenfassungWir berichten über ein Paragangliom der Cauda equina bei einem 48jährigen Patienten. Klinisch imponieren diese langsam intradural-extramedullär wachsenden, meist benignen und von einer bindegewebigen Kapsel umgebenen Geschwülste durch Lumbalgien, Parästhesien und Paresen sowie gelegentlich durch Inkontinenz. Paragangliome der Cauda equina zeichnen sich histomorphologisch durch monomorphe Zellen (Hauptzellen) in typischer „Zellballen”-anordnung mit lobulärer Architektur und feinem Bindegewebsnetz aus Hüllzellen (Sustentakularzellen) aus, z.T. liegt eine ganglionäre Differenzierung vor. Wegen ihrer Ähnlichkeit zum häufigeren Ependymom werden sie mitunter fehldiagnostiziert, so daß ihre Inzidenz wahrscheinlich höher ist als bislang angenommen. Immunhistochemisch exprimieren sie neuronspezifische Enolase, Chromogranin und andere neuronale Marker sowie Neuropeptide (Hauptzellen) und S-100-Protein (Sustentakularzellen) bei weitgehend fehlender Reaktion für GFAP. Das Paragangliom der Cauda equina ist eine seltene Entität, von der bislang erst 80 Fälle in der Literatur beschrieben worden sind und an der gerade aufgrund ihres sporadischen Auftretens bei der Differentialdiagnose von Raumforderungen in diesem Bereich oft nicht gedacht wird.SummaryWe report on a case of paraganglioma of the cauda equina in a 48-year-old man. These slow-growing, mostly benign and encapsulated intradural–extramedullar tumours are clinically characterized by lumbago, paraesthesia and motor deficits as well as occasi-onally by incontinence. Paragangliomas of the cauda equina show monomorphous (main) cells arranged in a typical cell cluster pattern, demonstrating a lobular architecture and a fine net of connective tissue formed by so-called sustentacular cells; some tumours show focal ganglionic differentiation. Because of their morphological similarity to the more common ependymomas, paragangliomas of the cauda equina are sometimes misdiagnosed so that their incidence is likely to be higher than previously estimated. Immunohistochemistry findings are positive for neuron-specific enolase, chromogranin and other neuronal markers as well as neuropeptides (main cells) and S-100 protein (sustentacular cells) while widely lacking reactivity for GFAP. Paragangliomas of the cauda equina represent a rare entity, of which only 80 cases have been described in the literature. Because they only occur sporadically, they are often not included in the differential diagnosis of mass lesions of the region of the cauda equina.

Paraneoplastische limbische Enzephalitis

ZusammenfassungBerichtet wird über den Fall eines 69jährigen Mannes mit einer unklaren depressiven Symptomatik und Gewichtsabnahme in Verbindung mit Appetitlosigkeit, Ageusie und Anosmie. Der Patient verstarb an einer Bronchopneumonie, und die neuropathologische Untersuchung ergab den Befund einer sog. limbischen Enzephalitis. Die paraneoplastische Genese des Krankheitsbildes wurde dann a posteriori durch den Nachweis eines klinisch unbekannten, lokal indolent wachsenden kleinzelligen Bronchialkarzinoms bestätigt. Der Fall illustriert die schwierige klinische Diagnose einer paraneoplastischen limbischen Enzephalitis und unterstreicht die Notwendigkeit einer engen Zusammenarbeit von Pathologen und Neuropathologen in der Aufklärung derartiger Fälle.SummaryWe report on a 69-year old male patient who presented with vague depressive symptoms and loss of weight accompanied by lack of appetite, ageusia and anosmia. The patient died of bronchial pneumonia, and neuropathological examination revealed a so-called limbic encephalitis. The paraneoplastic origin of this case was later confirmed by discovery of a clinically inapparent, indolently growing small cell lung cancer. This case illustrates the difficult clinical diagnosis of paraneoplastic limbic encephalitis and the need for a close cooperation of pathologists and neuropathologists in the clarification of such cases.

Multifactorial genesis of neuroradiological “leucoencehalopathies”

Three cases of neuroradiologically diagnosed “leucoencephalopathy” are reported. Histopathological examination disclosed Binswangers encephalopathy in Case 1, congophilic angiopathy with secondary leucoencephalopathy in Case 2, and HIV encephalopathy with secondary white matter changes in Case 3. These three cases demonstrate the unspecificity of neuroradiological findings in “leucoencephalopathy”.