K. Del Tredici

Idiopathic Parkinson's disease : possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen

Summary. The progressive, neurodegenerative process underlying idiopathic Parkinsons disease is associated with the formation of proteinaceous inclusion bodies that involve a few susceptible neuronal types of the human nervous system. In the lower brain stem, the process begins in the dorsal motor nucleus of the vagus nerve and advances from there essentially upwards through susceptible regions of the medulla oblongata, pontine tegmentum, midbrain, and basal forebrain until it reaches the cerebral cortex. With time, multiple components of the autonomic, limbic, and motor systems become severely impaired. All of the vulnerable subcortical grays and cortical areas are closely interconnected. Incidental cases of idiopathic Parkinsons disease may show involvement of both the enteric nervous system and the dorsal motor nucleus of the vagus nerve. This observation, combined with the working hypothesis that the stereotypic topographic expansion pattern of the lesions may resemble that of a falling row of dominos, prompts the question whether the disorder might originate outside of the central nervous system, caused by a yet unidentified pathogen that is capable of passing the mucosal barrier of the gastrointestinal tract and, via postganglionic enteric neurons, entering the central nervous system along unmyelinated praeganglionic fibers generated from the visceromotor projection cells of the vagus nerve. By way of retrograde axonal and transneuronal transport, such a causative pathogen could reach selectively vulnerable subcortical nuclei and, unimpeded, gain access to the cerebral cortex. The here hypothesized mechanism offers one possible explanation for the sequential and apparently uninterrupted manner in which vulnerable brain regions, subcortical grays and cortical areas become involved in idiopathic Parkinsons disease.

Cognitive status correlates with neuropathologic stage in Parkinson disease

Objective: To study the association of cognitive status with the stages of a published neuropathologic staging procedure for sporadic Parkinson disease (PD) in a cohort of 88 patients with PD from a single neurologic unit. None had received the clinical diagnosis of dementia with Lewy bodies (DLB). Methods: The authors assessed Lewy neurites/bodies (LNs/LBs) immunoreactive for α-synuclein semiquantitatively in sections from 18 brain regions. In silver-stained sections and sections immunostained for tau and β-amyloid protein, the authors semiquantitatively evaluated comorbidities potentially contributing to cognitive decline, e.g., Alzheimer disease (AD), argyrophilic grain disease (AGD), and cerebral vascular disease. The authors analyzed four Mini-Mental State Examination (MMSE) subgroups ranging from marginally impaired cognition to severe dementia using nonparametric tests. Results: It was possible to assign all patients to one of the PD stages. MMSE scores correlated with neuropathologic stages (p < 0.005) and this association showed a linear trend (p < 0.025). Median MMSE test scores for women were lower than those for men. Cognitively impaired individuals displayed higher stages of AD-related neurofibrillary pathology (p < 0.05) and β-amyloid deposition (p < 0.05) than cognitively unimpaired persons. MMSE scores did not correlate significantly with AGD, disease duration, age at disease onset, or age at death. Hoehn and Yahr scores, however, correlated with PD stages (p < 0.0005) and MMSE scores (p < 0.0005). Conclusions: The decrease in median Mini-Mental State Examination scores between PD stages 3 to 6 indicates that the risk of developing dementia increases with disease progression. In some individuals, however, cognitive decline can develop in the presence of mild Parkinson disease–related cortical pathology and, conversely, widespread cortical lesions do not necessarily lead to cognitive decline.

Parkinson's disease: a dual‐hit hypothesis

Accumulating evidence suggests that sporadic Parkinsons disease has a long prodromal period during which several non‐motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissners plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinsons disease is pathogenic access to the brain through the stomach and nose – hence the term ‘dual‐hit’.

Parkinson’s disease: the thalamic components of the limbic loop are severely impaired by α-synuclein immunopositive inclusion body pathology

The Parkinsons disease (PD)-related inclusion body pathology comprises Lewy bodies (LBs) as well as Lewy neurites (LNs). The distribution and severity of this pathology were investigated in the thalamus of 12 autopsy cases with clinically diagnosed and neuropathologically confirmed PD. The LBs and LNs were visualized by immunoreactions against the protein alpha-synuclein. In the human thalamus during PD, a specific and highly stereotypical distribution pattern of LBs and LNs evolves. As in cortical and other subcortical regions, the components of human thalamus assigned to the limbic loop bear the brunt of the PD-related pathology. In contrast, the thalamic components integrated into the striatal and cerebellar loops as well as the primary sensory nuclei of the thalamus show at best a mildly developed pathology. Damage to the thalamic components of the limbic loop nuclei may contribute not only to the cognitive, emotional, and autonomic symptoms of PD but to the somatomotor and oculomotor dysfunctions as well.

Involvement of precerebellar nuclei in multiple system atrophy

H. Braak, U. Rüb and K. Del Tredici (2003) Neuropathology and Applied Neurobiology 29, 60–76 
Involvement of precerebellar nuclei in multiple system atrophy

The evolution of Alzheimer's disease-related cytoskeletal pathology in the human raphe nuclei.

The cross‐sectional analyses currently available show that the Alzheimers disease (AD)‐related cytoskeletal alterations within the human brain affect variously susceptible areas of the cerebral cortex in a uniform sequence with very little interpatient variability. This sequence has been divided for research and comparative purposes into six stages (cortical NFT/NT‐stages I–VI). Among the subcortical nuclei affected in AD are those belonging to the raphe system. Efforts were focused on the lesions present in these nuclei to see in which of the six stages the AD‐related cytoskeletal anomalies begin and whether a correlation exists between the AD‐related pathology developing within the cerebral cortex and the cytoskeletal damage that occurs in the nuclei of the raphe system. To this end, serial sections from the brainstems of 27 post‐mortem cases with stages I–VI of cortical cytoskeletal lesions were examined. The cytoskeletal pathology was visualized using the modified silver iodide–Gallyas staining technique and the antibody AT8. The latter is directed specifically against the abnormally phosphorylated cytoskeletal protein tau. The dorsal raphe nucleus manifests the cytoskeletal lesions early on (stages I–II). The central and linear raphe nuclei, by contrast, do so initially in stages III–IV, and the caudal raphe nuclei register the first changes in stages V–VI. In stages V and VI, the dorsal raphe nucleus displays the most severe cytoskeletal pathology within the raphe system, followed by the central and linear raphe nuclei, whereas the cytoskeletal anomalies in the caudal raphe nuclei are slight. The developing damage within the nuclei of the raphe system correlates with the stages I–VI and, furthermore, progresses in the oral raphe nuclei in close connection with the evolution of the pathological process in cortical projection destinations of these nuclei. As the source of the ascending serotonergic system, the involvement of the oral raphe nuclei may be partially responsible for the early manifestation of the non‐cognitive and emotional deficiencies possibly traceable to dysfunctions within the ascending serotonergic system.

Critical appraisal of brain pathology staging related to presymptomatic and symptomatic cases of sporadic Parkinson’s disease

Clinical Parkinsons disease (PD) is a well-characterised syndrome that benefits significantly from dopamine replacement therapies. A staging procedure for sporadic PD pathology was developed by Braak et al. assuming that the abnormal deposition of alpha-synuclein indicates the intracellular process responsible for clinical PD. This paradigm has merit in corralling patients with similar cellular mechanisms together and determining the potential sequence of events that may herald the clinical syndrome. Progressive pathological stages were identified--1) preclinical (stages 1-2), 2) early (stages 3-4, 35% with clinical PD) and 3) late (stages 5-6, 86% with clinical PD). However, preclinical versus early versus late-stage cases should on average be progressively older at the time of sampling, a feature not observed in the cohort analysed. In this cohort preclinical cases would have developed extremely late-onset PD compared with the other types of cases analysed. While the staging scheme is a valuable concept, further development is required.

The autonomic higher order processing nuclei of the lower brain stem are among the early targets of the Alzheimer's disease-related cytoskeletal pathology

Abstract. The nuclei of the pontine parabrachial region (medial parabrachial nucleus, MPB; lateral parabrachial nucleus, LPB; subpeduncular nucleus, SPP) together with the intermediate zone of the medullary reticular formation (IRZ) are pivotal relay stations within central autonomic regulatory feedback systems. This study was undertaken to investigate the evolution of the Alzheimers disease-related cytoskeletal pathology in these four sites of the lower brain stem. We examined the MPB, LPB, SPP and IRZ in 27 autopsy cases and classified the cortical Alzheimer-related cytoskeletal anomalies according to an established staging system (neurofibrillary tangle/neuropil threads [NFT/NT] stages I–VI). The lesions were visualized either with the antibody AT8, which is immunospecific for the abnormally phosphorylated form of the cytoskeletal protein tau, or with a modified Gallyas silver iodide stain. The MPB, SPB, and IRZ display cytoskeletal pathology in stage I and the LPB in stage II, whereby bothstages correspond to the preclinical phase of Alzheimers disease (AD). In stages III–IV (incipient AD), the MPB and SPP are severely affected. In all of the stage III–IV cases, the lesions in the LPB and IRZ are well developed. In stages V and VI (clinical phase of AD), the MPB and SPP are filled with the abnormal intraneuronal material. At stages V–VI, the LPB is moderately involved and the IRZ shows severe damage. The pathogenesis of the AD-related cytoskeletal lesions in the nuclei of the pontine parabrachial region and in the IRZ conforms with the cortical NFT/NT staging sequence I–VI. In the event that the cytoskeletal pathology observed in this study impairs the function of the nerve cells involved, it is conceivable that autonomic mechanisms progressively deteriorate with advancing cortical NFT/NT stages. This relationship remains to be established, but it could provide insights into the illusive correlation between the AD-related cytoskeletal pathology and the function of affected neurons.

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.

The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology

Argyrophilic grain disease (AGD) constitutes a neurodegenerative disorder that occurs in the brains of the elderly and affects 5% of all patients with dementia. τ protein‐containing lesions known as argyrophilic grains and located predominantly in limbic regions of the brain characterize this disease. Dementia is encountered in only a subset of cases that display the morphological pattern of AGD. The aim of this study is to determine the role of concurrent Alzheimers disease (AD)‐related pathology for the development of dementia in AGD patients. A total of 204 post‐mortem brains from 30 demented and 49 nondemented AGD patients, 39 AD patients, and from 86 nondemented controls without AGD were staged for AD‐related neurofibrillary tangles (NFTs) as well as amyloid β‐protein (Aβ) deposition. To identify differences in AD‐related pathology between demented and nondemented AGD cases, and to differentiate the pattern of AD‐related changes in demented and nondemented AGD cases from that seen in AD and nondemented controls, we  statistically  compared  the  stages of Aβ and NFT distribution among these groups. Using a logistic regression model, we showed that AGD has a significant effect on the development of dementia beyond that attributable to AD‐related pathology (P < 0.005). Demented AGD cases showed lower stages of AD‐related pathology than did pure AD cases but higher stages than nondemented AGD patients. AGD associated dementia was seen in the presence of NFT (Braak)‐stages II–IV and Aβ‐phases 2–3, whereas those stages were not associated with dementia in the absence of AGD. In conclusion, AGD is a clinically relevant neurodegenerative entity that significantly contributes to the development of dementia by lowering the threshold for cognitive deficits in the presence of moderate amounts of AD‐related pathology.