D. Del Turco

The intralaminar nuclei assigned to the medial pain system and other components of this system are early and progressively affected by the Alzheimer's disease-related cytoskeletal pathology.

The intralaminar nuclei of the human thalamus are integrated into the ascending reticular activating system and into limbic, oculomotor and somatomotor loops. In addition, some of them also represent important components of the medial pain system. We examined the occurrence and severity of the Alzheimers disease (AD)-related cytoskeletal pathology and beta-amyloidosis in the seven intralaminar nuclei (central lateral nucleus, CL; central medial nucleus, CEM; centromedian nucleus, CM; cucullar nucleus, CU; paracentral nucleus, PC; parafascicular nucleus, PF; subparafascicular nucleus, SPF) in 27 autopsy cases at different stages of the cortical neurofibrillary pathology (cortical NFT/NT-stages I-VI) and beta-amyloidosis (cortical phases 1-4). The CEM, CL, PF, and SPF are slightly affected at stage II (corresponding to preclinical AD). They are markedly involved at stages III and IV (i.e. incipient AD) and severely affected at stages V and VI (i.e. clinical AD). In the PC and CU, the cytoskeletal pathology is mild at stage III, marked at stage IV, and severe at stages V-VI, whereas the CM is only mildly affected at stages IV-VI. In all of the intralaminar nuclei, deposits of the protein beta-amyloid occur for the first time during the final phase of cortical beta-amyloidosis. Functionally, the cytoskeletal pathology encountered in the intralaminar nuclei may contribute to the memory and affective symptoms, attention deficits, and dysfunctions related to horizontal saccades and smooth pursuits seen in AD patients. Equally important, however, are the findings that the cytoskeletal pathology developing within the intralaminar nuclei assigned to the medial pain system (CEM, CL, CU, PC, PF) as well as within other components of this system begins already during the preclinical or incipient phases of AD. Given this fact, the question arises as to whether non-discriminative aspects mediated by the medial pain system could be employed to identify individuals in the very earliest stages of AD.

Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance

Although the vestibular complex represents an important component of the neural circuits crucial for the maintenance of truncal and postural stability, and it is integrated into specialized oculomotor circuits, knowledge regarding the extent of the involvement of its nuclei and associated fibre tracts in cases with spinocerebellar ataxia type 3 (SCA3) is incomplete. Accordingly, we performed a pathoanatomical analysis of the vestibular complex and its associated fibre tracts in four clinically diagnosed and genetically confirmed SCA3 patients with the aim of providing more exact information as to the involvement of the vestibular system in this disorder. By means of unconventionally thick serial sections through the vestibular nuclei stained for lipofuscin pigment and Nissl material, we could show that all five nuclei of this complex (interstitial, lateral, medial, spinal, and superior vestibular nuclei) are subject to neurodegenerative processes in SCA3, whereby examination of thick serial sections stained for myelin revealed that all associated fibre tracts (ascending tract of Deiters, juxtarestiform body, lateral and medial vestibulospinal tracts, medial longitudinal fascicle, vestibular portion of the eighth cranial nerve) underwent atrophy and demyelinization in all four of the patients studied. The reported lesions can help to explain the truncal and postural instability as well as the impaired optokinetic nystagmus, vestibulo‐ocular reaction, and horizontal gaze‐holding present in SCA3 cases.

Damage to the reticulotegmental nucleus of the pons in spinocerebellar ataxia type 1, 2, and 3

Background: The reticulotegmental nucleus of the pons (RTTG) is among the precerebellar nuclei of the human brainstem. Although it represents an important component of the oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuits, the RTTG has never been considered in CAG repeat or polyglutamine diseases. Methods: Thick serial sections through the RTTG of 10 patients with spinocerebellar ataxias (SCAs) assigned to the CAG repeat or polyglutamine diseases (2 SCA-1 patients, 4 SCA-2 patients, and 4 SCA-3 patients) were stained for neuronal lipofuscin pigment and Nissl material. Results: The unconventionally thick tissue sections revealed the hitherto overlooked involvement of the RTTG in the degenerative processes underlying SCA-1, SCA-2, and SCA-3, whereby in one of the SCA-1 patients, in two of the SCA-2 patients, and in all of the SCA-3 patients, the RTTG underwent a conspicuous loss of its nerve cells. Conclusions: Neurodegeneration may not only affect the cranial nerve nuclei (i.e., oculomotor and abducens nuclei) of SCA-1, SCA-2 and SCA-3 patients integrated into the circuits, subserving accuracy of horizontal saccades and the generation of horizontal smooth pursuits, but likewise involves the premotor networks of these circuits. This may explain why the SCA-1, SCA-2, and SCA-3 patients in this study with a heavily damaged reticulotegmental nucleus of the pons developed dysmetric horizontal saccades and impaired smooth pursuits during the course of the disease.

Extended pathoanatomical studies point to a consistent affection of the thalamus in spinocerebellar ataxia type 2

The involvement of the thalamus during the course of the currently known polyglutamine diseases is still a matter of debate. While it is well‐known that this diencephalic nuclear complex undergoes neurodegeneration in some polyglutamine diseases such as Huntingtons disease (HD), it has remained unclear whether and to what extent the thalamus is also involved in spinocerebellar ataxia type 2 (SCA2) patients. Encouraged by our recent post‐mortem findings in one German SCA2 patient and the results of a recent nuclear magnetic resonance (NMR) study, we extended our pathoanatomical analysis to serial thick sections stained for lipofuscin granules and Nissl substance through the thalami of four additional German and Cuban SCA2 patients. According to this analysis the thalamus is consistently affected by the destructive process of SCA2. In particular, during our study we observed a consistent involvement of the lateral geniculate body, the lateral posterior, ventral anterior, ventral lateral, ventral posterior lateral, and ventral posterior medial thalamic nuclei as well as the extraterritorial reticular nucleus. In four of the SCA2 cases studied additional damage was seen in the inferior and lateral nuclei of the pulvinar, whereas in the minority of the patients a subset of the limbic nuclei of the thalamus (i.e. anterodorsal, anteroprincipal, laterodorsal, fasciculosus, mediodorsal, central lateral, central medial, cucullar, and paracentral nuclei, medial nucleus of the pulvinar) underwent neurodegeneration. These interindividual differences in the distribution pattern of thalamic neurodegeneration indicate that the thalamic nuclei differ in their proclivities to degenerate in SCA2 and may suggest that they become involved at different phases in the evolution of the underlying degenerative process.

Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3).

The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.

Guidelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patient.

U. Rüb, E. R. Brunt, D. Del Turco, R. A. I. de Vos, K. Gierga, H. Paulson and H. Braak (2003) Neuropathology and Applied Neurobiology 29, 1–13 u2028Guildelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patient

Accumulation of phosphorylated IκBα and activated IKK in nodes of Ranvier

Aims: Nuclear factor‐kappaB (NF‐κB) is an ubiquitously expressed transcription factor that modulates inducible gene transcription crucial for the regulation of immunity, inflammatory processes, and cell survival. In the mammalian nervous system, constitutive NF‐κB activation is considered to promote neuronal cell survival by preventing apoptosis. Increasing evidence suggests a critical role for NF‐κB activation in acute and chronic neurodegenerative diseases. Recently, a striking enrichment of phosphorylated IκBα (pIκBα) and activated IKappaB Kinase (IKK), two key components of the NF‐κB activation pathway, was demonstrated in the axon initial segment (AIS) of neurons. As the AIS shares fundamental features with nodes of Ranvier (NR), we examined whether pIκBα and activated IKK are also enriched in NR. Methods: Double‐immunofluorescence labelling was performed with vibratome sections of the rodent central and peripheral nervous system. Sections were analysed using confocal laser scanning microscopy and preembedding electron microscopy. Results: Here we report a remarkable accumulation of pIκBα and activated IKK in NR in the central and peripheral nervous system. Immunolabelling for both proteins extended from NR into the adjacent paranode. pIκBα predominantly accumulated within the cytoplasm and was associated with fasciculated microtubules. This association was confirmed by electron microscopy. By comparison, activated IKK preferentially clustered beneath the cytoplasmic membrane. Conclusion: In conclusion, the coincident accumulation of pIκBα and activated IKK in AIS and NR suggests that these specific axonal compartments contribute to neuronal NF‐κB activation.