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 neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. 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 a ...

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

pars compacta The pars compacta (SNpc, SNc) is one of two subdivisions of the ''substantia nigra'' of the midbrain (the other being the pars reticulata); it is situated medial to the ''pars reticulata''. It is formed by dopaminergic neurons. It projects to th ...

, 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 (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the brai ...

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 neurons affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)) ...

Braak's theory

The staging in Parkinson's disease was described by

Heiko Braak Heiko Braak (born 16 June 1937) is a German anatomist. Braak was born in Kiel, Schleswig-Holstein, and studied medicine at the universities of Hamburg, Berlin, and Kiel. He was Professor at the Institute of Clinical Neuroanatomy, Johann Wolfgang ...

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 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 major early processing area for olfaction located behind the olfactory bulb, and in the olfactory tract (olfactory peduncle). The AON connects the olfactory pro ...

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 The raphe nuclei (, "seam") are a moderate-size cluster of nuclei found in the brain stem. They have 5-HT1 receptors which are coupled with Gi/Go-protein-inhibiting adenyl cyclase. They function as autoreceptors in the brain and decrease the ...

and

gigantocellular reticular nucleus The gigantocellular reticular nucleus (also magnocellular reticular nucleus) is the (efferent/motor) medial zone of the reticular formation of the caudal pons and rostral medulla oblongata. It consists of a substantial number of giant neurons, but ...

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 in the reticular ...

in the

pontine tegmentum The pontine tegmentum, or dorsal pons, is the dorsal part of the pons located within the brainstem. The ventral part or ventral pons is known as the basilar part of the pons, or basilar pons. Along with the dorsal surface of the medulla oblonga ...

. 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 In the human brain, the nucleus basalis, also known as the nucleus basalis of Meynert or nucleus basalis magnocellularis, is a group of neurons located mainly in the substantia innominata of the basal forebrain. Most neurons of the nucleus basali ...

, a cluster of

acetylcholine Acetylcholine (ACh) is an organic compound 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. Par ...

-rich neurons in the basal

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...

. 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 The paralimbic cortex is an area of three-layered cortex that includes the following regions: the piriform cortex, entorhinal cortex, the parahippocampal cortex on the medial surface of the temporal lobe, and the cingulate cortex just above the c ...

and

allocortex The allocortex (from Latin allo-, meaning other, and cortex, meaning bark or crust), or heterogenetic cortex, is one of the two types of cerebral cortex in the brain, together with the neocortex. In the human brain, the allocortex is the much sm ...

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, ...

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

amygdala The amygdala (; : amygdalae or amygdalas; also '; Latin from Greek language, Greek, , ', 'almond', 'tonsil') is a paired nucleus (neuroanatomy), nuclear complex present in the Cerebral hemisphere, cerebral hemispheres of vertebrates. It is c ...

and in the subnuclei of the

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

. 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 intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...

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. ''P ...

regions such as the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

, 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 sense, sensory perception, cognition, generation of motor cortex ...

involvement. This should not be confused with the degree of

senile plaque Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform everyday activities. This typically involves problems with memory, ...

involvement, which progresses differently.

References

{{reflist Parkinson's disease Alzheimer's disease