Michail E. Kalaitzakis

The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of α-synuclein staging

Aims: It has been proposed that alpha‐synuclein (αSyn) pathology in Parkinsons disease (PD) spreads in a predictable caudo‐rostral way with the earliest changes seen in the dorsal motor nucleus of the vagus nerve (DMV). However, the reliability of this stereotypical spread of αSyn pathology has been questioned. In addition, the comparative occurrence of αSyn pathology in the spinal cord and brain has not been closely studied. Methods: In order to address these issues, we have examined 71 cases of PD from the UK Parkinsons Disease Society Tissue Bank at Imperial College, London. The incidence and topographic distribution of αSyn pathology in several brain regions and the spinal cord were assessed. Results: The most affected regions were the substantia nigra (SN; in 100% of cases) followed by the Nucleus Basalis of Meynert (NBM) in 98.5%. Fifty‐three per cent of cases showed a distribution pattern of αSyn compatible with a caudo‐rostral spread of αSyn through the PD brain. However, 47% of the cases did not fit the predicted spread of αSyn pathology and in 7% the DMV was not affected even though αSyn inclusions were found in SN and cortical regions. We also observed a high incidence of αSyn in the spinal cord with concomitant affection of the DMV and in a few cases in the absence of DMV involvement. Conclusions: Our results demonstrate a predominant involvement of the SN and NBM in PD but do not support the existence of a medullary induction site of αSyn pathology in all PD brains.

Striatal β-Amyloid Deposition in Parkinson Disease With Dementia

Dementia is common in Parkinson disease (PD), although its anatomic and pathologic substrates remain undefined. Recently, striatal abnormalities in Lewy body diseases have been described, but their clinical relevance is not clear. Thirty PD cases from the United Kingdom Parkinsons Disease Society Tissue Bank were grouped as demented (PDD; n = 16) and nondemented (PD; n = 14) based on a review of clinical records. The extent of &agr;-synuclein, tau, and amyloid &bgr; peptide (A&bgr;) deposition in the caudate nucleus, putamen, and nucleus accumbens was assessed. All cases showed severe dopaminergic striatal terminal denervation based on tyrosine hydroxylase immunohistochemistry. &agr;-synuclein and tau deposition in the striatum were rare in both groups, but the A&bgr; burden was significantly greater in the striatum of PD cases with dementia than present in the nondemented PD group. Striatal A&bgr; deposition was type-independent of Alzheimer disease changes in the cortex and was minimal in nondemented PD cases. We conclude that A&bgr; deposition in the striatum strongly correlates with dementia in PD.

Dementia and visual hallucinations associated with limbic pathology in Parkinson's disease

The pathological basis of dementia and visual hallucinations in Parkinsons disease (PD) is not yet fully understood. To investigate this further we have conducted a clinico-pathological study based on 30 post-mortem PD brains. PD cases were stratified into groups according to clinical characteristics as follows: (1) cognitively intact (n=9); (2) cases with severe dementia and visual hallucinations (n=12); (3) cases with severe dementia and no visual hallucinations (n=4); and (4) cases with severe visual hallucinations and no dementia (n=5). The extent of alpha-synuclein (alphaSyn), tau and amyloid beta peptide (Abeta) deposition was then examined in the CA2 sector of the hippocampus and in neocortical and subcortical areas known to subserve cognitive function. We find that dementia in PD is significantly associated with alphaSyn in the anterior cingulate gyrus, superior frontal gyrus, temporal cortex, entorhinal cortex, amygdaloid complex and CA2 sector of the hippocampus. Abeta in the anterior cingulate gyrus, entorhinal cortex, amygdaloid complex and nucleus basalis of Meynert is also associated with dementia as is tau in the CA2 sector of the hippocampus. alphaSyn burden in the amygdala is strongly related to the presence of visual hallucinations but only in those PD cases with concomitant dementia. Statistical analysis revealed that alphaSyn burden in the anterior cingulate gyrus could differentiate demented from non-demented PD cases with high sensitivity and specificity. We conclude that alphaSyn in limbic regions is related to dementia in PD as well as to visual hallucinations when there is an underlying dementia.

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin–proteasome system, play an important role in the pathogenesis of Parkinson’s disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin–proteasomal system (UPS) genes in Parkinson’s disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson’s-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by “gene shaving” clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson’s disease. Our quantitative results also suggest that Parkinson’s disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well.

The morbid anatomy of dementia in Parkinson's disease.

Dementia in Parkinson’s disease (PD/PDD) is a common complication with a prevalence of up to 50%, but the specific changes underlying the cognitive decline remain undefined. Neuronal degeneration resulting in the dysfunction of multiple subcortical neurochemical projection systems has been described along with Lewy body-type pathology in cortical and limbic regions. Advanced alpha-synuclein (αSyn) pathology is not necessarily sufficient for producing dementia and concomitant Alzheimer’s disease (AD) change has also been proposed as a possible substrate of PDD. A lack of consensus in the extant literature likely stems from clinical heterogeneity and variable reliability in clinical characterisation as well as other historical and methodological issues. The concurrent presence of abnormally deposited αSyn, amyloid-β and tau proteins in the PDD brain and the interaction of these molecules in a linked pathological cascade of AD and PD-related mechanisms may prove important in determining the underlying pathological process for the development of dementia in PD and this concept of combined pathologies awaits further investigation.

Controversies over the staging of α-synuclein pathology in Parkinson’s disease

Parkinson’s disease (PD) is a complex disorder the aetiopathogenesis of which has remained enigmatic almost 200 years after its initial description by James Parkinson. It is now accepted that the neuropathological changes deWning PD are by no means conWned to the substantia nigra pars compacta but that other central and peripheral nervous tissues show degenerative changes as well, which result in dysfunction in a variety of neurotransmitter systems. The papers by Polymeropoulos et al. (15) and Kruger et al. (11), demonstrating that -synuclein ( Syn) gene mutations can cause PD, and the discovery that the encoded protein, which is natively unfolded and still of unknown physiological function, constitutes a major component of Lewy bodies (LBs) and Lewy neurites (LNs) by Spillantini et al. [16], provided the cornerstone for a molecular deWnition of the disease and placed Syn at the centre of PD research interests. Although molecular work is in progress to unravel the mechanisms by which Syn is abnormally deposited in the PD brain, an important issue explored recently and attracting much attention is the natural history of Syn deposition, that is, how Syn pathology progresses within the PD brain [2]. Aiming at a precise patho-architectonic analysis, Braak et al. in 2003 devised a staging system according to which Syn pathology progresses in a systematic fashion and proposed six distinct stages of PD. According to this design, the earliest pathology is to be observed in the dorsal motor nucleus of the vagus nerve (DMV) (stage 1) from where Syn pathology is thought to proceed in a rostral direction via the pons (stage 2) to the midbrain (stage 3) and thence to the basal forebrain and mesocortex (stage 4), Wnally spreading to/involving the neocortex (stages 5–6). However, a certain percentage of incidental and PD cases from diVerent research centres in Europe and the US have been shown/found not to comply with/follow this predicted caudo-rostal pattern [1, 10, 13, 14]. While the observations as such which are documented in the Braak et al., 2003 publication raise little objection, principal methodological considerations make it very unlikely that they provide a reliable and accurate picture of the progression of PD pathology from its earliest stages. Certainly, highlighting the multiple-system and widespread nature of neurodegeneration throughout the central nervous system in PD is important and F. Lewy’s classical work may be cited in this context. The complexity and variety of clinical symptoms found in PD are the reXection of an anatomically wide-ranging disease process. This view is also in agreement with animal studies, which have demonstrated that lesions restricted to the substantia nigra or dopamine pathways alone do not accurately model PD. The review by Meredith et al. in this journal supports this view [12]. Regarding the PD-staging system proposed by Braak, some critical issues need to be considered:

Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other Parkinsonian syndromes

Recent neuropathological studies have described widespread amyloid-β peptide (Aβ) deposition in the striatum of patients with Lewy body disorders, particularly in Parkinsons disease with dementia (PDD) and dementia with Lewy bodies (DLB). However, positron emission tomography (PET) studies using the [(11)C]PIB ligand, binding to Aβ deposits, detects significant striatal pathology only in DLB and not in PDD. Employing immunohistochemistry, we examined striatal Aβ deposition in the caudate nucleus and putamen of 52 PD, 41 PDD, 14 DLB, 7 multiple system atrophy (MSA) and 14 progressive supranuclear palsy (PSP) cases in relation to the presence of dementia. PD, MSA and PSP cases showed little or no Aβ pathology in the striatum. In contrast, both PDD and DLB cases demonstrated significantly greater Aβ deposition in the striatum when compared to PD, MSA and PSP groups. We conclude that striatal Aβ pathology is common in both PDD and DLB and may reflect the development of dementia in these conditions. More detailed examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging.

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

The identification of mutations that cause familial Parkinson’s disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be up-regulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly(ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.

Neuronal pentraxin II is highly upregulated in Parkinson’s disease and a novel component of Lewy bodies

Neuronal pentraxin II (NPTX2) is the most highly upregulated gene in the Parkinsonian substantia nigra based on our whole genome expression profiling results. We show here that it is a novel component of Lewy bodies and Lewy neurites in sporadic Parkinson’s disease (PD). NPTX2 is also known as the neuronal activity-regulated protein (Narp), which is secreted and involved in long-term neuronal plasticity. Narp further regulates AMPA receptors which have been found to mediate highly selective non-apoptotic cell death of dopaminergic neurons. NPTX2/Narp is found in close association with alpha-synuclein aggregates in both substantia nigra and cerebral cortex in PD but unlike alpha-synuclein gene expression, which is down-regulated in the Parkinsonian nigra, NPTX2 could represent a driver of the disease process. In view of its profound (>800%) upregulation and its established role in synaptic plasticity as well as dopaminergic nerve cell death, NPTX2 is a very interesting novel player which is likely to be involved in the pathway dysregulation which underlies PD.

Disturbed sleep in Parkinson's disease: anatomical and pathological correlates.

Abnormal sleep is a common feature of Parkinsons disease (PD) and prodromal disorders of sleep are frequent (e.g. restless legs syndrome and rapid eye movement sleep behaviour disorder). However, the exact pathological basis of disturbed sleep remains as yet undefined.