Neuropathology and Braak Staging of Parkinson’s Disease

Parkinson’s disease (PD) is defined as progressive neurodegenerative disorder caused by loss of dopaminergic cells in the substantia nigra pars compacta (SNpc) [ref1][ref2]. Up until recently, the diagnosis of PD is still on clinical ground. There is no reliable laboratory or neuroimaging to confirm PD. However, the sensitivity and sensitivity of such clinical diagnosis are both 95% and 98% respectively. This value was obtained when compared to neuropathological diagnosis of PD [ref1]. Hence it is important to understand the neuropathology of PD in order to understand the difficulty in diagnosing PD accurately and why there is no reliable neuroimaging for PD.

Since PD is defined with loss of dopaminergic cell in SNpc, we should have knew by now that it is one of the neuropathological changes expected. First let’s look at the gross pathology of PD. If a transverse section is made at the level of midbrain, there will be pallor of the substantia nigra and the locus coeruleus. In some long-standing PD, there may be slight cortical atrophy and ventricular dilation which correlate with patient complicated with dementia. This, however, is not the main gross pathology of PD. [ref3][ref4]

parkinson vs normal Image above show the differences in the substantia nigra. There is loss of pigmentation in PD(left) compares to normal(right).

Such gross pathology is present in most disease presented with Parkinsonism including progressive supranuclear palsy (PSP) and multiple system atrophy. Fortunately, there are some differences among them which will help us in pathological diagnosis (will be mentioned in the next article).

Microscopic findings [ref3-ref9]
There is severe loss of the melanin-containing, tyrosine hydroxylase–immunoreactive neurons of the substantia nigra pars compacta in Parkinsonism. This results in dopaminergic denervation of the striatum. Such the neuronal loss in the substantia nigra results in reactive astrocytosis. In addition, melanin-laden macrophages and free pigment are found in the areas where neurons are loss.

The neural degeneration of ventrolateral substantia nigra, which has projection to the dorsal putamen, is seen in Parkinson’s disease with predominantly akinetic-rigid symptomatology. In tremor-predominant Parkinson’s disease, there is less severe neuronal loss of the lateral substantia nigra is seen.
Perhaps the most important of all, in addition to neuronal loss is the presence of Lewy bodies in the pathological diagnosis of PD within the surviving neuron. Lewy bodies are the hallmark of PD and dementia with Lewy bodies. These bodies are intraneuronal cytoplasmic, eosinophilic, spherical inclusions which are often surrounded by a halo. It usually ranges from 8 to 30 nm in diameter. They are made up of molecular components α-synuclein, a synaptic protein, and ubiquitin, a cellular stress protein. Lewy bodies are found in the substantia nigra, locus coeruleus, nucleus basalis of Meynert, dorsal vagal nucleus, hypothalamus, olfactory bulb, Edinger-Westphal nucleus, and raphe nuclei of patient with PD.
Density of pigmented neurons Image above show the density of of pigmented neuron in normal (A) compares with PD (B). There is reduction of pigmented neuron in PD. Note the presence of pigment-laden macrophages in (B). Image obtained from [ref3]

Another element found in the pigmented neurons of the substantia nigra is the pale bodies. Pale bodies are cytoplasmic areas of pallor. Their immunostaining characteristic is similar to Lewy bodies and has been hypothesised the pale bodies are the precursors of Lewy bodies.
lewy bodies and pale bodies Image (A) shows the presence of Lewy bodies in 2 neuron; (B) shows a neuron with lewy bodies and another adjacent neuron containing a pale body.Image obtained from [ref3]

A variant form of Lewy bodies; found most frequently in the lower cortical layers (V and VI), and most numerous in the temporal, insular, and cingulate cortices; is known as the cortical Lewy bodies. Cortical Lewy bodies, in contrast to Lewy bodies found in brainstem, do not have a distinct halo. They are eosinophilic and usually round.
Lastly but not least, is the presence of dystrophic neurites known as Lewy neurites. These neurites are immunoreactive to alpha-synuclein, ubiquitin, and neurofilament. They are found in the brains of patients with Parkinson’s disease with dementia, as well as those with dementia and Lewy bodies. Typically found in the CA2 to CA3 sector of the hippocampus, accessory cortical nuclei of the amygdala, nucleus basalis of Meynert, brainstem and olfactory bulb.
cortical lewy body Image shows the presence of cortical Lewy bodies. Note the presence of eosinophilic cytoplasmic inclusion without a halo (A) and presence of alpha-synuclein-immunostained cortical Lewy bodies (B). Image obtained from [ref3]

Lewy neurites Images above shows the Lewy neurites immunostained with alpha-synuclein antibody in hippocampus. Image obtained from [ref3]


Neuropathological staging of Parkinson’s disease (Braak Staging)
. [ref5][ref10]
Based on autopsy findings in PD patients, Braak et al. reported that the intracerebral formation of Lewy inclusion bodies and Lewy neurites has a topographically predictable progression. Hence the Braak staging is created with 6 stages based on the presence of Lewy bodies and Lewy neurites. The pre-symptomatic phase of PD patient usually falls within Stage 1, 2 & 3; while symptomatic phase falls into the stage 3, 4, 5 & 6.

The stages are described as below:
1. Stage 1 (Medulla oblongata)
Lesions initially occur in the dorsal glossopharyngeal/vagal motor nucleus and frequently in the anterior olfactory nucleus. This explained the reason in some pre-symptomatic PD victims has loss of sense of smell. There may also have involvement of intermediate reticular zone. Along with this stage is the Lewy pathology in the enteric nervous system, which explained gastrointestinal symptoms in pre-symptomatic phase. The pathology in the anterior olfactory nucleus expands less readily into related areas than that expanding from the brain stem which takes an upward course.

2. Stage 2 ( Medulla oblongata + pontine tegmentum)
This include the pathology of stage 1 with s lesions in caudal raphe nuclei, gigantocellular reticular nucleus, and coeruleus–subcoeruleus complex.

3. Stage 3 (Midbrain)
Pathology of stage 2 plus midbrain lesions, particularly in the pars compacta of the substantia nigra.

4. Stage 4 (basal prosencephalon and mesocortex)
Pathology of stage 3 with lesion at prosencephalon. Cortical involvement is confined to the temporal mesocortex (transentorhinal region) and allocortex (CA2-plexus). The neocortex is however, unaffected.

5. Stage 5 (Neocortex)
Stage 5 and above involved the neocortex. Its lesion include those of stage 4 plus lesions in high order sensory association areas of the neocortex and prefrontal neocortex.

6. Stage 6 (Neocortex)
Pathology of stage 5 plus lesions in first order sensory association areas of the neocortex and premotor areas, occasionally mild changes in primary sensory areas and the primary motor field.

braak staging of PD Image above shows the progression of PD-related intraneuronal pathology. The depth of colour correlate with the density of Lewy pathology. The white arrow indicates the gradual involvement of related structures. Relevant abbr; dm, dorsal motor nucleus of the glossopharyngeal and vagal nerves; co, coeruleus–subcoeruleus complex; sn, substantia nigra;mc, anteromedial temporal mesocortex; fc, first order sensory association areas, premotor areas, as well as primary sensory and motor fields; hc, high order sensory association areas and prefrontal fields. Image obtained from [ref7].

However there is criticism of Braak staging mentioned that although it reflects the topographical sequence of Lewy body distribution, there has not been an attempt to correlate Lewy body and neurite density with loss of neurons and synaptic connections.

References
1. Jenkins, Mary E. eds. Neurology: an evidence-based approach. New York, NY: Springer; 2012
2. National Institute for Health and Clinical Excellence. Parkinson’s disease: Diagnosis and management in primary and secondary care. NICE clinical guideline 35. National Collaborating Centre for Chronic Conditions. 2006.
3. Richard A. Prayson. Neuropathology: a volume in the series foundation in diagnostic pathology. Philadelphia, PA: Elsevier Saunders; 2012.
4. Dennis W. Dickson. Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harbor Perspective in Medicine. 2012. Doi: 10.1101/cshperspect.a009258.
5. Heiko Braak and Kelly D. Tredici. Eds. Neuroanatomy and pathology of sporadic Parkinson’s Disease. Springer-Verlag Berlin Heidelberg; 2009.
6. Catherine Haberland. Ed. Clinical neuropathology: text and color atlas. New York, NY: Demos Medical Publishing; 2007.
7. Heiko Braak et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging. 2003; 24:197-211
8. A. Michotte. Recent developments in the neuropathological diagnosis of Parkinson’s disease and parkinsonism. Acta neurol. Baelg. 2003; 103:155-158.
9. Maria Grazia Spillantini et al. Alpha-synuclein in Lewy bodies. Nature. 1997; 388:839-840
10. David J. Brooks. Examining Braak’s Hypothesis by Imaging Parkinson’s Disease. Movement Disorders. 2010; 25(1):S83–S88.

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