Braak staging refers to two methods used to classify the degree of pathology in

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. These methods are used both in research and for the clinical diagnosis of these diseases and are obtained by performing an autopsy of the brain.

Parkinson's disease

The main pathological characteristic of

is cell death in the

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...

. In particular, this death occurs in the ventral part of the

pars compacta The pars compacta (SNpc) is a portion of the ''substantia nigra'', located in the midbrain. It is formed by dopaminergic neurons and located medial to the pars reticulata. Parkinson's disease is characterized by the death of dopaminergic neurons ...

, with up to 70% of the cells affected by the time the patient dies. The mechanisms by which the brain cells are lost are varied. One mechanism consists of an abnormal accumulation of the protein

alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...

bound to ubiquitin in the damaged cells. This protein accumulation forms inclusions called

Lewy bodies Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias ( Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and ...

Braak's theory

The staging in Parkinson's disease was described by Heiko Braak in 2003. Braak and colleagues state that Parkinson's disease begins when a foreign agent enters the body via the nose or gastrointestinal system and travels into the central nervous system (CNS). The presence of Lewy bodies in the enteric and peripheral nervous systems supports their claim. This Lewy body pathology selectively travels through the CNS, targeting thin and largely unmyelinated neurons. Braak et al., therefore, developed a staging system that characterizes disease progression. This system is divided into six different stages, with each stage being attributed to abnormal pathology in particular neurological structures. In terms of symptomatology, the type and severity of symptoms is correlated to progression through the Braak stages. Early stages are characterized by non-motor symptoms, such as a lessened sense of smell or constipation. Motor symptoms are often displayed around the mid-stage state, and cognitive symptoms arise as later Braak stages are reached. Braak and colleagues further state that the disease begins in the enteric nervous system and gains entry to the CNS through the vagus nerve.

Stage 1

The disease begins in structures of the lower brainstem and the olfactory system. In particular, the

dorsal motor nucleus of the vagus nerve The dorsal nucleus of vagus nerve (or posterior nucleus of vagus nerve or dorsal vagal nucleus or nucleus dorsalis nervi vagi or nucleus posterior nervi vagi) is a cranial nerve nucleus for the vagus nerve in the medulla that lies ventral to the f ...

in the

medulla oblongata The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involun ...

and

anterior olfactory nucleus The anterior olfactory nucleus (AON; also called the anterior olfactory cortex) is a portion of the forebrain of vertebrates. It is involved in olfaction and has supposedly strong influence on other olfactory areas like the olfactory bulb and the ...

are affected. Lewy neurites, thread-like alpha-synuclein aggregates, are more prevalent than globular Lewy bodies in this stage.

Stage 2

In addition to the pathology observed in Stage 1, Stage 2 is characterized by additional lesions in the raphe nuclei and

gigantocellular reticular nucleus The gigantocellular reticular nucleus (Gi) is a subregion of the medullary reticular formation. As the name indicates, it consists mainly of so-called giant neuronal cells. This nucleus has been known to innervate the caudal hypoglossal nucleus, ...

of the medulla oblongata. The disease then moves up the brainstem, traveling from the medullary structures to the

locus ceruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system. The locus coeru ...

in the

pontine tegmentum Pontine may refer to: * Having to do with the pons, a structure located in the brain stem (from ''pons'', "bridge") * Pontine Marshes, a region of Italy near Rome * Pontine Islands The Pontine Islands (, also ; it, Isole Ponziane ) are an ar ...

. Similar to Stage 1, Lewy neurites outnumber Lewy bodies.

Stage 3

At the beginning of Stage 3, the disease has entered the substantia nigra and Lewy body lesions begin to form in the pars compacta. The latter half of this stage involves disease progression into the basal nucleus of Meynert, a cluster of

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

-rich neurons in the basal

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the Anatomical terms of location#Directional terms, rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hin ...

. Further, structures affected in Stages 1 and 2 begin to develop more Lewy bodies.

Stage 4

Stage 4 is characterized by severe dopaminergic cell destruction in the pars compacta. There is also

mesocortex Mesocortex (also called juxtallocortex) is the transitional areas of the cerebral cortex, formed at borders between true isocortex and true allocortex (either paleocortex or archicortex). Parts of mesocortex that lie closer to the true isocortex an ...

and

allocortex The allocortex or heterogenetic cortex, and neocortex are the two types of cerebral cortex in the brain. The allocortex is the much smaller area of cortex taking up just 10 %, the neocortex takes up the remaining 90 %. It is characterized by havi ...

involvement; the

neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, sp ...

remains unaffected. In particular, pathology can be observed in the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...

and in the subnuclei of the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

. There is significant damage done to the anterior olfactory nucleus.

Stage 5

The disease has started to invade the neocortex and spreads into the structures of the temporal, parietal, and frontal lobes. Cell death can be observed in the substantia nigra, the dorsal motor nucleus of the vagus nerve, the gigantocellular reticular nucleus, and the locus ceruleus.

Stage 6

The disease has fully invaded the neocortex, affecting the motor and sensory areas in the brain. The disease is at its most severe.

Alzheimer's disease

Staging in Alzheimer's disease was described by Braak in 1991. Braak stages I and II are used when

neurofibrillary tangle Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is kn ...

involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there is also involvement of

limbic The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''Ps ...

regions such as the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...

, and V and VI when there is extensive

neocortical The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, sp ...

involvement. This should not be confused with the degree of

senile plaque Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of mi ...

involvement, which progresses differently.

References

{{reflist Parkinson's disease Alzheimer's disease