Parkinson's - Anatomy, Pathology, Prognosis and Diagnosis

Original Editor - Bhanu Ramaswamy as part of the APPDE Project

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Introduction to Parkinson's and Parkinsonian Disorders

In keeping with current, person-focused, best practice for communicating with and about people with or without a disability, Physiopedia uses the terms "person/people with Parkinson's" (pwP) to emphasise the dignity of the person, rather than define them by their clinical diagnosis. This is a move away from the historic terms of Parkinson's Disease (PD). At times, when describing the pathophysiological process of the disease, Physiopedia may then use the term Parkinson's Disease.

Parkinson’s is the second most common but fastest rising of the progressive neurodegenerative disorders in the world. The majority of people diagnosed with Parkinson’s are aged 60 years or older. However, Parkinson's can affect people of any age group, with approximately 5 to 10 percent of pwP diagnosed before the age of 50.

Idiopathic Parkinson’s (the most common form of the condition) is characterised by the trademark symptoms of bradykinesia (must be present), and either rigidity, and/or resting tremor (between 4–6 Hz in the resting limb). Whilst Parkinson’s was previously considered a motor condition (i.e., mainly affecting movement), a variety of other non-motor symptoms have been identified, many of which precede the motor symptom-based diagnosis. These might include sensory changes (such as reduced sense of smell (i.e., hyposmia) or pain), neuropsychiatric symptoms (such as anxiety, depression, apathy, or fatigue), sleep disturbances, and autonomic symptoms (such as urinary problems or constipation).

Later in the condition, people can develop postural instability as a complication of the pathophysiology, as well as neuromuscular changes, which affect balance and strength and increase a person's likelihood of falling.

There are neurodegenerative conditions that resemble Parkinson's disease but are distinct from it. Parkinsonism describes a collection of movement symptoms that include slowness, stiffness, tremor, and balance issues. This broader category of conditions that present with parkinsonism includes both Parkinson's disease and other disorders.

Atypical parkinsonian disorders (also known as Parkinson's Plus syndromes) are a group of neurodegenerative movement disorders that resemble idiopathic Parkinson's with certain distinguishing clinical and pathophysiological features. Atypical Parkinsonian disorders represent about 10–15% of people with a Parkinsonism diagnosis. These disorders share the core motor symptoms of Parkinson's disease (tremor, rigidity, bradykinesia, postural instability) but also present with additional neurological features and typically have different disease progression patterns and response to treatment.

Clinical Anatomy

Parkinsonisn brain

Parkinson's disease is now understood as a multi-system neurodegenerative disorder extending beyond the basal ganglia. Non-typical basal ganglia circuit function drives the cardinal motor symptoms, while more widespread neurodegeneration of the cerebral cortex and brainstem results in the classical non-motor manifestations of the disease. The basal ganglia work closely in concert with cortex and cerebellum to support motor and cognitive functions. However, the degeneration of dopaminergic neurons in the substantia nigra reduces available dopamine in the striatum, making this region the most directly affected area in the disease's pathophysiology.

Cellular changes occur in the mitochondria, as well as in alpha-synuclein (a protein that misfolds and clumps in Parkinson’s, creating structures called Lewy bodies). The alpha-synuclein-based degeneration affects the peripheral autonomic nervous system and the enteric nervous system (the neurons and glial cells embedded within the walls of the gut), salivary glands and the skin.

There are changes to the structural integrity of pathways connecting lobes of the brain, as well as changes in brain volume. This is also noticeable in the cerebellum and connecting nuclei, such as the thalamus, hypothalamus and supportive connective structures, such as the limbic system, locus coeruleus and the glial cells within the brain. All of these impact how neurotransmitters (such as acetylcholine, norepinephrine, and serotonin) influence non-motor features of Parkinson’s (e.g., cognitive impairment, psychological, autonomic, and sleep disorders).

The Basal Ganglia

Overview of the basal ganglia

From the rehabilitation perspective, the basal ganglia are clinically important neurological structures due to their involvement in movement control, motor learning, executive functions, and behaviours.

The basal ganglia are a group of nuclei situated deep and centrally at the base of the forebrain. They have robust connections with the cerebral cortex, thalamus, and other areas of the brain. This vast neuronal communication system is key to their involvement in a variety of functions, including automatic and voluntary motor control, procedural learning relating to routine behaviours, and emotional functions.

The following table shows how the basal ganglia and related nuclei can broadly be categorised.

	Function	Involved nuclei
Input (afferent) nuclei	Receives incoming information from other parts of the brain, mainly from the cortex, thalamus, and brainstem The appropriate functioning of the basal ganglia system requires dopamine, a chemical neurotransmitter, to be released at the input nuclei.	The striatum, which consists of (1) caudate nucleus, (2) putamen, and (3) the accumbens nucleus
Output (efferent) nuclei	Sends information from the basal ganglia to the rest of the brain via the thalamus	Globus pallidus pars interna Substantia nigra pars reticulata
Intrinsic nuclei	Facilitates communication within the basal ganglia itself to process information and modulate the activity of the input and output nuclei These nuclei are interconnected and contribute to the direct and indirect pathways of the basal ganglia	Globus pallidus pars externa Subthalamic nucleus Substantia nigra pars compacta

Information from our cortex and thalamus enters the striatum to be processed further within the basal ganglia system. The output nuclei (GPi and SNr) project mainly to the thalamus (ventral nuclei), which, in turn, project back to the cerebral cortex (mainly the frontal lobe).

Basal ganglia pathways

The functional organisation of the basal ganglia is often described as a system of loops in which activity is sent to the basal ganglia from different areas of the brain, modulated and returned to facilitate (or inhibit) motor activity. The main loops are functionally subdivided into motor, associative, and limbic/emotional domains according to their interaction with brain regions they engage with. In addition to the role of the basal ganglia in motor control, we now understand functions such as attention and time estimation, implicit learning and habit formation, and reward-related behaviour and emotions.

The basal ganglia mechanism can be simplified into two pathways:

1. A direct pathway which is considered excitatory and hence facilitates movement to occur—i.e., promotes voluntary movement in specified muscles, and
2. An indirect pathway, which is considered inhibitory to movement and inhibits movement into other muscles that do not contribute to the required movement.

The ability to select and execute movement whilst suppressing unwanted movement brought about through the association with other cortical areas ensures smoothly orchestrated movement control and motor behaviour.

Pathology

A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson's. B. Localisation of the cluster of significant volume reduction in Parkinson's compared with people without the disease. The significant cluster located in the medulla oblongata/pons is superimposed as a red blob on the mean normalized anatomical scan of all participants.

The term ‘idiopathic’ is still applied to most cases of Parkinson’s, meaning that the cause is largely unknown. This makes it difficult to ascertain where or when pathological changes start. It is usually only post-mortem that a true diagnosis can be made based on (1) a loss of pigmented dopamine neurons and (2) the presence of Lewy bodies. Such a clear understanding is, however, problematic and impractical for those still alive.

Multiple environmental factors may contribute to an individual developing Parkinson's, particularly in aeging populations living in industrialised societies. Environmental toxicants including certain pesticides and air pollution can affect mitochondrial functioning. These environmental exposures can lead to mitochondrial dysfunction characterised by impaired complex I function, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and bioenergetic deficiency. The resulting mitochondrial dysfunction contributes to protein misfolding and aggregation, inflammatory responses, oxidative stress, and ultimately dopaminergic neuron death. This dysfunction is characterised by reactive oxygen species generation, decreased mitochondrial complex I enzyme activity, and ATP depletion.

In the late 1990s, the first of many monogenic forms of Parkinson’s was found (i.e., caused by a single gene mutation), allowing scientists over the past three decades to unravel changes to the biological mechanisms impacting mitochondrial regulation, cell membrane structure, and the effect on the pathways governing our immune response. The younger the person at age of onset, the more likely genetic factors play a role in the aetiology of Parkinson’s.

The role of gut microbiota has also increasingly come under scrutiny since histological studies of the brains of people with Parkinson’s post-mortem led Braak’s team to conceive a staging model. The model, which emphasised the sequential progression of Lewy pathology starting in the bowel with a ‘slow virus’ entering the central nervous system after passing through the intestinal mucosa, was not without controversy when first published. It was stipulated that interactions between the enteric nervous system, the parasympathetic nerves frequently affected by α-syn pathology, and the intestinal microbiota provide a possible cause of the spread of disease to the brain via the vagus nerve and to other non-nigral regions like the locus coeruleus, pedunculopontine nucleus and Meynert’s nucleus in the basal forebrain.

Involvement of areas linked with the basal ganglia affects noradrenergic, glutamatergic, serotonergic and adenosine pathways, as well as the dopaminergic pathways, creating the diverse symptoms of Parkinson’s that vary over the years. With regards to the influences of these changes on the basal ganglia, Parkinson’s is characterised by the degeneration of dopamine neurons in the substantia nigra, resulting in a loss of axons which project to the striatum along the nigrostriatal pathway. This creates a reduction in available neurotransmitter dopamine, and once the levels of striatal dopamine are reduced beyond 70%, the primary motor symptoms upon which a diagnosis of Parkinson’s is decided emerge (i.e., bradykinesia with tremor and/or, rigidity). This impacts the basal ganglia’s response to external input, distorting the roles of the putamen, subthalamic nucleus, and globus pallidus internus in the selection or filtering of incoming signals. The default position is inhibitory and, overall, reduces the excitatory response, making movement more difficult.

However, Parkinson’s rarely presents as a single condition, particularly as pathogenesis parallels natural aging changes in our nervous and musculoskeletal systems. For example, cognitive impairment worsens, and cardiac disease or metabolic syndromes, such as Type 2 diabetes, develop secondary to increased sedentary behaviour. The consequence of falling may be physical injury to soft tissue or bone fracture, psychological fear, slowing movement and increasing disability, which are independent risk factors of morbidity. Links of anecdotal reports of the longer-term effects of the Corona virus-19 (Covid-19) impacting Parkinson’s risk are under investigation.

Increasing emphasis is being placed on the development of biomarkers to detect changes early in the disease course and monitor these over time through imaging, permitting in vivo monitoring of changes in pathology and progression of the condition.

Prognosis

Prior to the 1960s when Levodopa was introduced, around a quarter of people diagnosed with Parkinson's were expected to die within 5 years of onset, the likelihood rising to at least nine-tenths of people dying within 15 years of their diagnosis. Levodopa therapy altered this mortality rate, extending a person’s longevity – probably through the relief of many symptoms, as there is no clear evidence that levodopa can halt the progressive nature of Parkinson’s.

It is widely accepted that the following clinical features may help predict the rate of progression of Parkinson's disease:

1. Older age at onset and initial rigidity/hypokinesia can be used to predict (1) a more rapid rate of motor progression in those with newly diagnosed Parkinson's disease and (2) earlier development of cognitive decline and dementia.
2. Initially presenting with tremor may predict a more benign disease course and longer therapeutic benefit from levodopa.
3. A faster rate of motor progression may also be predicted if the patient is male, has associated comorbidities, and has postural instability/gait difficulty
4. Older age at onset, dementia, and decreased responsiveness to dopaminergic therapy may predict earlier nursing home placement and decreased survival.

Modifiable factors, like regular physical activity, a healthy diet, restorative sleep, and social engagement, can also play a significant role in maintaining quality of life and potentially slowing disease progression.

Diagnosis

The diagnosis of Parkinsonism has been divided into three clinical stages:

1. Pre-clinical stage: neuropathological changes can be predicted or detected early through biomarkers such as blood tests, saliva and/or genetic markers. In this stage, people with risk factors could be identified and triaged for early intervention.
2. Prodromal Parkinson’s: this stage is characterised by the presence of symptoms such as a decreased sense of smelling (hyposmia), low mood/ depression, bowel symptoms and/or sleep changes. Symptoms can be experienced 15 – 20 years before the onset of the motor symptoms.
3. Clinical Parkinson’s: symptoms defined by dopamine-responsive motor features; bradykinesia (with a large scale of sensory-motor changes symptoms and symptoms and fatigue), tremors and /or rigidity.

There are varied criteria to distinguish Idiopathic Parkinson’s from Parkinsonism, but the specificity and sensitivity of its characteristics make it hard in some cases to clearly establish that it is Parkinson’s and not one of the related atypical conditions. In most people, the diagnosis of Idiopathic Parkinson’s is based on clinical findings, and it may take a few months to years before one of the Atypical conditions becomes more obvious. Step 2 in the shaded section below provides more detail on how Parkinson’s is confirmed once other investigations or conditions are excluded.

The widely accepted clinical criteria for the diagnosis of Parkinson's, introduced by the United Kingdom Parkinson's Society Brain Bank Diagnostic Criteria for Parkinson’s Disease, have now been superseded by the International Parkinson’s and Movement Disorder Society (MDS) clinical diagnostic criteria.

Step 1: Diagnosis of Parkinsonism – made through recording history and observing symptoms:

• Bradykinesia (a slowness of movement paired with a reduction in movement amplitude and/or speed) and at least one of the following:
• Muscular rigidity (described as ‘lead-pipe’ for the quality of stiffness in all directions. Where a tremor is present, e.g., in the hand or foot, the examiner may describe the rigidity as ‘cog-wheeling’ when testing the wrist or ankle respectively, as the tremor combined with rigidity makes the movement more ratchet like)
• 4–6 Hz resting tremor

N.B. In the past, postural instability (not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction) was a marker of Parkinson’s. It remains so if it occurs later in the condition, but it is no longer a diagnostic criterion.

Step 2: Features must be checked to exclude Parkinson’s as the cause of Parkinsonism or raise red flags, which must be further investigated. Whilst some of these are recorded in the history of the person awaiting diagnosis, there are some that only become obvious 18 months to 3 years following a diagnosis of Parkinson’s.

• History of repeated strokes with stepwise progression of Parkinsonian features
• History of repeated head injury
• History of definite encephalitis
• Neuroleptic treatment at onset of symptoms
• >1 affected relatives
• Sustained remission
• Strictly unilateral features after 3 years
• Supranuclear gaze palsy
• Cerebellar signs, including early falls (within a year of symptom onset)
• Early severe autonomic involvement
• Early severe dementia with disturbances of memory, language and praxis
• Babinski's sign
• Presence of a cerebral tumour or communicating hydrocephalus on computed tomography scan
• Negative response to large doses of levodopa (if malabsorption is excluded)
• 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure

Step 3: Features that support a diagnosis of Parkinson’s (three or more required for diagnosis of definite Parkinson’s disease)

• History of prodromal symptoms – anosmia or hyposmia (reduced sense of smell); low mood/ depression; constipation and rapid-eye-movement (REM) sleep behaviour disorder may predict the development of motor Parkinson’s
• Unilateral onset
• Rest tremor present
• Progressive disorder (slower in those with Young Onset Parkinson’s and those with tremor-dominant phenotype)
• Persistent asymmetry affecting the side of onset most
• Excellent (70–100%) response to levodopa
• Severe levodopa-induced chorea
• Levodopa response for ≥5 years
• Clinical course of ≥10 years
• In recent years, attempts to define Parkinson’s genetically have become possible with the discovery of monogenic forms of the condition. Currently known genetic causes of Parkinson's account for approximately 10% of cases.

See the video below by Stanford Medicine on diagnosing Parkinson's:

Role of Neuroimaging in the Diagnosis of Parkinson’s

In certain cases, when a more definite cause of a person’s symptoms needs to be established, they will be sent for neuroimaging (i.e., investigation by use of a brain scan). These cannot diagnose Parkinson’s with 100% accuracy, but support the clinical diagnosis of Parkinson's. The imaging acts to observe brain structures and functions to compare against ‘normal’ data or to enable differentiation between other Parkinsonian conditions; the scans may also be used to assess disease progression over time.

Whilst newer forms of molecular and cellular imaging are being developed to discover changes in the brain earlier than motor symptoms appear through biomarker detection (to diagnose and target the causes of Parkinson’s), the current most widely used scans in clinical practice are magnetic resonance imaging (MRI), single‐photon emission computed tomography (SPECT), and positron emission tomography (PET).

PET scanning is a nuclear imaging technique and relies on the decay characteristics of positron‐emitting radionuclides. A tracer compound (i.e., one labelled with a positron‐emitting radionuclide) is injected into the person and given time to distribute across the body. As it decays, the radionuclide ejects a positron. The surrounding tissue stops the activity by combining the positron with an electron, with the final effect of producing a pair of gamma photons. These gamma photons can be tracked as a function of time to enable the evaluation of how well different parts of the body are functioning and identify potential abnormalities.

Clinically, in the case of suspected Parkinsonism, the radioactive tracers bind to dopamine receptors or transporters, thus enabling quantification of the dopamine activity in different brain regions, indicating changes in dopamine release or receptor availability. This aids the diagnosis process and monitoring of disease progression.

SPECT scanning also requires a tracer compound to be injected into the person under investigation, and when looking for a possible Parkinson’s diagnosis, it uses radioactive tracers that bind to dopamine transporters (DaTs) (hence the term DatScan). However, the radionuclides in this case emit single gamma photons. A series of 2D projection images of tracer distribution in the body are acquired by one or more gamma cameras from multiple angles. These projection images are then assembled to produce a 3D image that reveals the integrity of the presynaptic dopaminergic system. In Parkinson's, reduced tracer uptake in the striatum indicates a loss of dopamine neurons.

Clinically, SPECT scans, particularly DaTscans, are valuable for diagnosing and differentiating between Parkinsonian disorders and other movement disorders. They can also help assess the severity and progression of the disease.

MRI is different to the other types of scans as it uses the behaviour of atomic nuclei with a non‐zero spin in a strong magnetic field to generate images. When trying to ascertain Parkinson’s, it is usual to use functional MRI (fMRI). This method relies on the detection of dopamine levels indirectly by measuring changes in blood flow and oxygenation associated with neural activity.

Each scan modality has its uses, as well as limitations, depending on things like the availability of and proximity to the tracers and equipment. The cost and staffing resources required for the different scans mean they are more often used in research than for clinical investigation.

Value of Accurate Diagnosis

Establishing an accurate diagnosis in individuals with suspected Parkinson's disease is crucial for prognosis and treatment planning. This is particularly important for those with younger-onset disease, as people diagnosed with young-onset Parkinson's disease have a longer survival and slower progression of symptoms over time, staying functional and cognitively intact for a longer duration. Establishing an accurate diagnosis in individuals with suspected Parkinson's is essential for selecting appropriate treatment strategies and setting realistic expectations for therapeutic outcomes. The distinction between true Parkinson's and other parkinsonian conditions fundamentally determines treatment response and prognosis.

Finding appropriate and reliable biomarkers to facilitate earlier diagnosis is proving to be pivotal in this area. The development of reliable biomarkers for earlier Parkinson's disease diagnosis represents a critical frontier in neurological medicine. These diagnostic advances extend far beyond current symptomatic management approaches. Rather than solely focusing on restoring dopaminergic function or preventing further cell death in established disease, the search for preclinical Parkinson's disease markers is becoming increasingly important because pathogenesis-targeted neuroprotective strategies are being developed for future use in at-risk populations, even before the clinical onset of disease.

Related Pages

• Parkinsons Disease
• Parkinsons Clinical Presentation
• Physiotherapy - Referral and Assessment
• Physiotherapy - Management and Interventions
• Key Evidence and resources

Additional Resources

Get to Know More About the Basal Ganglia

For the visuo-auditory learners, there are several YouTube videos, including voiced presentations to provide an overview of the mechanisms of the basal ganglia motor circuit:

Optional Reading:

• Lanciego JL, Luquin N, Obeso JA. Functional neuroanatomy of the basal ganglia. Cold Spring Harbor perspectives in medicine. 2012 Dec 1;2(12):a009621.
• Rocha GS, Freire MA, Britto AM, Paiva KM, Oliveira RF, Fonseca IA, Araújo DP, Oliveira LC, Guzen FP, Morais PL, Cavalcanti JR. Basal ganglia for beginners: the basic concepts you need to know and their role in movement control. Frontiers in systems neuroscience. 2023 Aug 3;17:1242929.

Clinical Resources:

• Parkinson's Disease: Challenges, Progress, and Promise (National Institute of Neurological Disorders and Stroke) this site is regularly updated and contains useful clinical information

Get to Know More About the Pathophysiology of Parkinson’s

For auditory-visual learner you may want to check out:

• This link to overview the Pathophysiology of Parkinson's from Khan Academy
• This YouTube video discusses the pathology of both motor and non-motor symptoms of Parkinson's

Optional Reading:

• Jankovic J, Tan EK. Parkinson’s disease: Etiopathogenesis and treatment. Journal of Neurology, Neurosurgery & Psychiatry. 2020 Aug 1;91(8):795-808.

Clinical Resources:

• Living Well with Parkinson's (National Institute of Neurological Disorders and Stroke) this site is regularly updated and contains useful clinical information
• Jankovic J, Tan EK. Parkinson’s disease: Etiopathogenesis and treatment. Journal of Neurology, Neurosurgery & Psychiatry. 2020 Aug 1;91(8):795-808.