Parkinson’s Disease and Braak stages

The progression of Parkinson’s Disease (PD) is generally slow, taking place over years (often many years).^1,2 While diagnosis tends to occur with the onset of motor symptoms, this can be preceded by a long prodromal phase of 15 years or more.^1,2,3 This prodromal phase is typically characterized by a range of non-motor symptoms, including sleep disorders, hyposmia, constipation, and depression.^3,4 One of the most common symptoms is ‘REM sleep behavior disorder,’ in which affected individuals can become physically, even violently, active during the REM (rapid eye movement) stage of sleep.^2,3

At a pathophysiological level, PD is characterized by the loss of neurons in specific regions of the brain and the spreading of Lewy pathology.⁵ The widely used scheme proposed by Braak and colleagues categorizes PD into stages of neuropathological changes, specifically Lewy pathology, roughly aligned with PD symptoms.^6,7,8 While the Braak staging scheme is a valuable model for conceptualizing PD progression and has fundamentally changed the thinking about disease pathogenesis and its treatment^6,7,9, in reality, patients vary considerably in the extent to which they conform to this model.⁸

Stage 1. (Dorsal motor nucleus of the vagus nerve and olfactory bulb) and Stage 2. (Gain setting nuclei)

The first two stages involve early α-synuclein deposition associated with the appearance of prodromal non-motor symptoms in the domains of olfaction (smell), autonomic function (e.g., constipation), and sleep (e.g., REM sleep behavior disorder).⁸

Stage 3. (Substantia nigra, amygdala)

As the disease progresses, other aspects of brain function may become impaired, causing further sleep dysregulation and depression in some individuals, as well as early/prodromal motor features.⁸

Stage 4. (Mesocortex, thalamus)

Stage 4 is typically the point at which clinical diagnosis occurs since this stage involves the appearance of clinically apparent motor symptoms, such as resting tremor, bradykinesia, and muscle rigidity.⁸

Stage 5. (Neocortex, higher-order association areas)

Stage 5 is characterized by poor balance, increased susceptibility to falls, and the onset of cognitive impairment.⁸

Stage 6. (Neocortex, primary and secondary areas)

By Stage 6, the patient is likely to be significantly physically disabled, and cognitive decline may well have progressed to PD dementia.⁸