# Parkinson Disease and Movement Disorders

## Introduction

Parkinson disease is the second most common neurodegenerative disorder after Alzheimer disease, with a prevalence of 1 to 2 percent in adults aged 65 and older, rising to 3 to 4 percent in those aged 80 and above. Approximately one million Americans are currently affected. The mean age of onset is 60 years, and incidence increases steadily with advancing age, making Parkinson disease a condition of central relevance to geriatric medicine. The disease is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of alpha-synuclein-containing Lewy bodies, pathological hallmarks that underlie both the motor and non-motor manifestations of the disease.

A crucial clinical insight is that non-motor symptoms, including cognitive impairment, psychiatric disturbances, autonomic dysfunction, and sleep disorders, are frequently more disabling than the motor symptoms and may precede motor onset by years to decades. The geriatrician's approach to Parkinson disease must therefore encompass the full spectrum of the disease's manifestations rather than focusing exclusively on tremor and gait disturbance.

## Pathophysiology

The core pathophysiology of Parkinson disease involves the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, which leads to reduced striatal dopamine levels and consequent disruption of the basal ganglia motor circuits. Motor symptoms become clinically apparent when approximately 50 to 60 percent of nigral neurons and 70 to 80 percent of striatal dopamine have been lost, indicating that substantial neurodegeneration precedes clinical diagnosis by years.

The molecular pathology centers on the aggregation of misfolded alpha-synuclein protein into Lewy bodies and Lewy neurites. The Braak staging model of Parkinson disease pathology describes an ascending pattern of involvement, beginning in the medulla and olfactory bulb (stages 1-2, corresponding to the prodromal phase with constipation, anosmia, and REM sleep behavior disorder), progressing to the midbrain (stages 3-4, corresponding to clinical motor Parkinson disease), and eventually reaching the limbic system and neocortex (stages 5-6, corresponding to cognitive decline and dementia). This staging model explains the temporal sequence of symptom emergence and has significant prognostic implications.

Beyond the dopaminergic system, Parkinson disease affects multiple non-dopaminergic neurotransmitter systems, including the noradrenergic system (locus coeruleus, contributing to orthostatic hypotension and mood disorders), the serotonergic system (raphe nuclei, contributing to depression and anxiety), and the cholinergic system (nucleus basalis and pedunculopontine nucleus, contributing to cognitive impairment, gait freezing, and REM sleep behavior disorder). This widespread neurotransmitter involvement explains why many non-motor symptoms respond poorly to dopaminergic therapy.

## Diagnosis

### Cardinal Motor Features

The diagnosis of Parkinson disease rests on the identification of cardinal motor features, with bradykinesia as the essential requirement. Bradykinesia, defined as slowness of movement with progressive reduction in amplitude and speed during repetitive actions, is tested through finger tapping, hand opening and closing, pronation-supination movements, and heel tapping. The characteristic decrement in amplitude and speed with repetitive movements distinguishes parkinsonian bradykinesia from the simple slowness of other conditions.

Rest tremor, the classic 4 to 6 Hz "pill-rolling" tremor that is asymmetric, present at rest, and diminishes with voluntary action, is present in approximately 70 percent of patients at diagnosis. Notably, 30 percent of patients present without tremor (the akinetic-rigid subtype), and the absence of tremor should not delay diagnosis when bradykinesia and rigidity are present. The re-emergence of tremor during sustained posture holding (re-emergent tremor) is characteristic of Parkinson disease and distinguishes it from essential tremor. Rigidity manifests as increased resistance to passive movement, described as "cogwheel" when combined with underlying tremor or "lead-pipe" when continuous. Postural instability, assessed by the pull test demonstrating retropulsion, is typically a later feature of the disease.

### Diagnostic Criteria (MDS Clinical Diagnostic Criteria, 2015)

The Movement Disorder Society clinical diagnostic criteria for Parkinson disease require bradykinesia plus at least one of tremor or rigidity as essential features. Supportive criteria include a clear and dramatic beneficial response to dopaminergic therapy, the presence of rest tremor, and olfactory loss. Absolute exclusion criteria include cerebellar signs, supranuclear gaze palsy (suggesting progressive supranuclear palsy), cortical sensory loss, and a normal dopamine transporter scan. Red flags that argue against a diagnosis of Parkinson disease include rapid progression, early severe dysautonomia (suggesting multiple system atrophy), early frequent falls (suggesting PSP), poor levodopa response, bilateral symmetric onset, and lower body predominance (suggesting vascular parkinsonism).

### DaT Scan (Ioflupane I-123 SPECT)

The dopamine transporter scan uses ioflupane I-123 SPECT imaging to visualize presynaptic dopamine transporter density in the striatum. Reduced uptake, characteristically asymmetric and beginning in the putamen, confirms the presence of dopaminergic degeneration and supports a diagnosis of Parkinson disease. The DaT scan differentiates degenerative parkinsonism (reduced uptake) from essential tremor, drug-induced parkinsonism, and psychogenic tremor (normal uptake), with a sensitivity of 95 to 97 percent and specificity of 80 to 85 percent. However, it does not distinguish between different forms of degenerative parkinsonism, as PD, MSA, PSP, and DLB all produce reduced DaT uptake.

<image>A clinical comparison diagram of parkinsonian syndromes. Create a table with five columns for PD, MSA, PSP, CBD, and DLB, and rows for: age of onset, early symptoms, tremor characteristics, gait pattern, eye movements, autonomic features, cognitive profile, brain MRI findings, DaT scan result, and levodopa responsiveness. Highlight distinguishing features for each syndrome: PD (asymmetric, rest tremor, levodopa-responsive); MSA (early autonomic failure, cerebellar ataxia [MSA-C] or symmetric parkinsonism [MSA-P], hot cross bun sign on MRI); PSP (early falls, vertical gaze palsy, axial rigidity, hummingbird sign on MRI); CBD (asymmetric, cortical signs like apraxia and alien limb, cortical sensory loss); DLB (fluctuations, visual hallucinations, RBD, cognitive impairment early). Use color coding to highlight the most distinguishing feature for each syndrome.</image>

## Motor Symptom Management

| Feature | Parkinson Disease | MSA | PSP | CBD | DLB |
|---------|------------------|-----|-----|-----|-----|
| Age of onset | ~60 yr | 50–60 yr | 60–70 yr | 60–70 yr | 65–80 yr |
| Symmetry | Asymmetric | Symmetric (MSA-P) | Symmetric | Asymmetric | Variable |
| Tremor | Rest tremor (4–6 Hz) | Rare | Rare | Rare; may have action tremor | Rest tremor possible |
| Early feature | Tremor, bradykinesia | Autonomic failure OR cerebellar ataxia | Falls, vertical gaze palsy | Cortical signs (apraxia, alien limb) | Visual hallucinations, fluctuations, RBD |
| Gait | Narrow-based, festination | Wide-based (MSA-C) | Wide-based, early falls | Asymmetric apraxia | Variable |
| Cognitive pattern | Late dementia (40–80%) | Mild executive dysfunction | Subcortical, apathy | Cortical (asymmetric) | Early dementia, fluctuations |
| MRI finding | Usually normal | Hot cross bun sign (MSA-C) | Hummingbird sign | Asymmetric cortical atrophy | Usually normal |
| DaT scan | Reduced (asymmetric) | Reduced | Reduced | Reduced (asymmetric) | Reduced |
| Levodopa response | Robust | Poor | Poor | Poor | Moderate; may worsen psychosis |

### Levodopa/Carbidopa — Most Effective Agent

Levodopa combined with carbidopa remains the gold standard for motor symptom control in Parkinson disease, providing the greatest magnitude of functional improvement of any available agent. Levodopa crosses the blood-brain barrier and is converted to dopamine by DOPA decarboxylase. Carbidopa inhibits peripheral decarboxylation of levodopa, reducing nausea and increasing the proportion of drug reaching the central nervous system. Treatment is typically initiated with carbidopa-levodopa 25/100, starting at half a tablet three times daily with meals, and gradually titrated to an effective dose range of 300 to 600 mg of levodopa per day in 3 to 4 divided doses. A clear and robust response to levodopa strongly supports the diagnosis of Parkinson disease.

Long-term levodopa use is complicated by motor fluctuations and dyskinesias. Wearing-off, or end-of-dose deterioration, occurs when the therapeutic effect of each levodopa dose wanes before the next dose is due, and develops in approximately 40 percent of patients by 5 years. Dyskinesias, involuntary choreiform movements most commonly occurring at peak drug levels, develop in 30 to 50 percent of patients by 5 years. On-off fluctuations represent unpredictable switches between mobile "on" states and frozen, slow "off" states.

A critical clinical point, established by the LEAP trial, is that levodopa should not be delayed based on concerns about accelerating motor complications. The trial demonstrated that earlier versus later initiation of levodopa does not increase the risk of motor complications when compared at matched disease duration, dispelling the long-held but evidence-unsupported practice of withholding levodopa to "save it for later." For patients with advanced fluctuating disease, enteral levodopa delivered as a continuous jejunal infusion via PEG-J tube (Duopa) provides more stable drug levels.

### Dopamine Agonists

Pramipexole (0.125 to 1.5 mg three times daily), ropinirole (0.25 to 8 mg three times daily), and the rotigotine transdermal patch (2 to 8 mg per 24 hours) are less potent than levodopa and are associated with several significant adverse effects. Impulse control disorders, including pathological gambling, compulsive shopping, and hypersexuality, affect 15 to 20 percent of patients. Daytime somnolence, peripheral edema, and hallucinations are additional concerns. In elderly patients aged 70 and older, the risk of neuropsychiatric complications, particularly hallucinations and confusion, is substantially higher, and dopamine agonists should be used cautiously in this age group. Ergot-derived agonists (bromocriptine, cabergoline) should be avoided due to the risk of cardiac valvular fibrosis.

### MAO-B Inhibitors

Rasagiline at 1 mg daily, selegiline at 5 mg twice daily, and safinamide at 50 to 100 mg daily provide mild symptomatic benefit as monotherapy and serve as useful adjuncts to levodopa for reducing off-time. The SETTLE trial demonstrated that safinamide reduces off-time by 1.4 hours per day. Selegiline is metabolized to amphetamine derivatives, which may cause insomnia, and evening dosing should be avoided.

### COMT Inhibitors

Entacapone, administered at 200 mg with each dose of levodopa, extends the duration of levodopa's effect and is used to manage wearing-off, with diarrhea occurring in approximately 10 percent of patients. Opicapone at 50 mg daily at bedtime offers the convenience of once-daily dosing with fewer gastrointestinal effects. Tolcapone is the most potent COMT inhibitor but carries a risk of hepatotoxicity requiring liver function test monitoring. COMT inhibitors typically increase levodopa on-time by 1 to 2 hours per day.

### Anticholinergics (Trihexyphenidyl, Benztropine)

Anticholinergic agents have a very limited role in elderly Parkinson disease patients. While they can provide modest tremor relief, they are designated in the Beers Criteria as agents to avoid in patients aged 65 and older due to their substantial adverse effect profile, including cognitive impairment, confusion, hallucinations, constipation, urinary retention, and dry mouth.

### Amantadine

Amantadine is primarily used for the management of levodopa-induced dyskinesias. The extended-release formulation (Gocovri) at 137 to 274 mg at bedtime is specifically approved for this indication. Standard amantadine at 100 to 300 mg daily also provides a mild antiparkinsonian effect. Side effects include livedo reticularis, peripheral edema, hallucinations, and confusion, all of which are more problematic in the elderly. Renal dose adjustment is required.

### Surgical Therapies

Deep brain stimulation, targeting either the subthalamic nucleus or the globus pallidus internus, is the primary surgical intervention for Parkinson disease. It is indicated for motor fluctuations and dyskinesias that are refractory to optimal medical therapy in patients who remain levodopa-responsive. DBS reduces off-time by 4 to 6 hours per day, dyskinesia by 50 to 70 percent, and medication requirements by 30 to 50 percent. Contraindications include atypical parkinsonism, dementia (a relative contraindication), severe psychiatric disease, and advanced age, though age is considered on a case-by-case basis as benefit tends to diminish after age 70. The EARLYSTIM trial demonstrated that DBS was superior to best medical therapy even in patients with early motor fluctuations, challenging the prior practice of reserving DBS for advanced disease. Focused ultrasound thalamotomy, targeting the VIM thalamus, is a non-invasive FDA-approved option for tremor-predominant Parkinson disease, though it is limited to unilateral treatment.

## Non-Motor Symptom Management

### Cognitive Impairment and Dementia

Parkinson disease dementia develops in 40 to 80 percent of patients over the disease course, representing a 6-fold increased risk of dementia compared with the general population. Rivastigmine is the only FDA-approved medication for PDD and provides modest cognitive improvement, with mean MMSE scores improving by 1 to 2 points compared with placebo. Cholinesterase inhibitors may worsen tremor, though this effect is usually minimal and tolerable.

### Psychosis

| Antipsychotic | Dose | D2 Blockade | Use in PD | Key Consideration |
|--------------|------|-------------|-----------|-------------------|
| Pimavanserin | 34 mg daily | None (5-HT2A inverse agonist) | FDA-approved for PD psychosis | Does not worsen motor symptoms |
| Quetiapine | 12.5–75 mg | Low | Widely used off-label | Most commonly used; low D2 affinity |
| Clozapine | 6.25–50 mg | Low | Refractory psychosis only | Most effective; requires CBC monitoring (agranulocytosis 1–2%) |
| **Haloperidol** | **AVOID** | **High** | **CONTRAINDICATED** | **Severely worsens parkinsonism** |
| **Risperidone** | **AVOID** | **Moderate-High** | **CONTRAINDICATED** | **Worsens motor symptoms** |
| **Olanzapine** | **AVOID** | **Moderate** | **CONTRAINDICATED** | **Worsens motor symptoms** |

Visual hallucinations occur in 40 to 60 percent of Parkinson disease patients over the course of the disease. Initially, hallucinations are often non-threatening with preserved insight (so-called "benign hallucinations"), but may progress to threatening hallucinations with loss of insight and frank delusions, including paranoid and jealousy themes. Management begins with ruling out delirium, infection, and medication effects, then systematically reducing or eliminating medications in order of their risk-to-benefit ratio: anticholinergics first, then amantadine, then dopamine agonists, then MAO-B inhibitors, and finally cautious reduction of levodopa.

Pimavanserin at 34 mg daily is the only FDA-approved treatment for Parkinson disease psychosis. As a selective 5-HT2A inverse agonist, it has no dopamine D2 receptor blockade and therefore does not worsen motor symptoms, a critical advantage over conventional antipsychotics. Quetiapine at 12.5 to 75 mg is widely used off-label due to its low D2 receptor affinity. Clozapine at 6.25 to 50 mg is the most effective antipsychotic for Parkinson disease psychosis but requires regular complete blood count monitoring due to a 1 to 2 percent risk of agranulocytosis, limiting its use to refractory cases. All other antipsychotics, including haloperidol, risperidone, and olanzapine, must be strictly avoided in Parkinson disease patients because they severely worsen parkinsonism through D2 receptor blockade.

### Depression and Anxiety

Depression affects 40 to 50 percent of Parkinson disease patients and should be treated with SSRIs (sertraline, escitalopram) or SNRIs (venlafaxine). Pramipexole may possess antidepressant properties and can serve dual purpose in depressed PD patients who also require motor symptom augmentation. Anxiety affects 30 to 40 percent of patients and may be related to dopaminergic off periods, in which case optimization of dopaminergic therapy rather than addition of anxiolytics may be the most effective intervention. CBT and SSRIs remain the mainstays of anxiety treatment.

### Autonomic Dysfunction

Autonomic dysfunction is a major source of morbidity in Parkinson disease. Orthostatic hypotension is managed with midodrine, droxidopa, and fludrocortisone, along with timing adjustments of dopaminergic medications. Constipation, affecting 60 to 80 percent of patients, requires fiber supplementation, osmotic laxatives, exercise, and potentially lubiprostone. Urinary symptoms should be treated with mirabegron or vibegron rather than anticholinergic bladder medications, which would exacerbate cognitive impairment. Sialorrhea (drooling), which results from reduced spontaneous swallowing rather than excess saliva production, is treated with botulinum toxin injections to the salivary glands or glycopyrrolate. Sexual dysfunction may be addressed with sildenafil, with prior assessment for orthostatic hypotension.

### Sleep Disorders

REM sleep behavior disorder in Parkinson disease is managed with melatonin at 3 to 12 mg as first-line therapy and clonazepam at 0.25 to 0.5 mg as second-line, along with safety measures. Excessive daytime sleepiness is addressed through sleep hygiene optimization, with modafinil having limited evidence for this indication. Insomnia management follows the same CBT-I-first approach as in non-PD populations, with avoidance of benzodiazepines.

<image>A non-motor symptoms management guide for Parkinson disease. Create a body system diagram showing a human figure with labeled regions indicating non-motor symptoms and their treatments. BRAIN: cognitive impairment (rivastigmine), depression (SSRIs), anxiety (SSRIs, CBT), psychosis (pimavanserin, quetiapine — with RED cross over haloperidol), sleep disorders (melatonin for RBD, CBT-I for insomnia). EYES: visual hallucinations (pimavanserin). MOUTH: sialorrhea (botulinum toxin, glycopyrrolate). CARDIOVASCULAR: orthostatic hypotension (midodrine, droxidopa, fludrocortisone). GI: constipation (fiber, PEG, lubiprostone), dysphagia (SLP evaluation, texture modification). GU: urinary urgency (mirabegron — NOT oxybutynin), sexual dysfunction (sildenafil). SKIN: seborrheic dermatitis, hyperhidrosis. GENERAL: fatigue (exercise, optimize sleep), pain (optimize PD treatment, analgesics), weight loss (nutrition optimization). Include a note: "Non-motor symptoms often cause MORE disability than motor symptoms and should be actively assessed and treated at every visit."</image>

## Other Movement Disorders in Elderly

### Essential Tremor (ET)

Essential tremor is the most common movement disorder, with a prevalence of 5 to 10 percent in individuals aged 65 and older. It manifests as a bilateral action and postural tremor primarily affecting the hands, head, and voice, worsening with intentional movement, and characteristically improving with alcohol ingestion. Distinguishing essential tremor from Parkinson disease relies on several key features: essential tremor is an action tremor rather than a rest tremor, is bilateral rather than asymmetric, is not accompanied by bradykinesia, and produces a normal DaT scan. Treatment includes propranolol at 40 to 320 mg (avoiding use in patients with asthma or bradycardia), primidone at 25 to 750 mg, topiramate, and gabapentin. Refractory essential tremor can be treated with DBS targeting the VIM thalamus or focused ultrasound thalamotomy.

### Drug-Induced Parkinsonism

Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson disease. Causative agents include antipsychotics (especially typical antipsychotics), metoclopramide, prochlorperazine, and valproic acid. Features that distinguish drug-induced parkinsonism from PD include bilateral symmetric involvement, typical absence of rest tremor, development within weeks to months of drug exposure, and a normal DaT scan (when there is no underlying PD). Management centers on discontinuation of the offending agent if possible, though symptoms may take months to resolve fully.

### Normal Pressure Hydrocephalus (NPH)

Normal pressure hydrocephalus presents with the classic triad of gait apraxia (a magnetic, shuffling gait), dementia, and urinary incontinence. Diagnosis requires neuroimaging demonstrating ventriculomegaly (Evans index greater than 0.3) and clinical improvement following high-volume lumbar puncture (removal of 30 to 50 mL of cerebrospinal fluid). Treatment with ventriculoperitoneal shunt placement produces gait improvement in 70 to 80 percent of well-selected patients, making NPH one of the few potentially reversible causes of both gait disorder and cognitive decline in the elderly.

## Key Clinical Pearls

- Do NOT delay levodopa treatment — the LEAP trial showed no benefit to delayed initiation; levodopa remains the most effective motor symptom treatment at any disease stage
- Pimavanserin is the only FDA-approved treatment for PD psychosis — it has NO D2 blockade and does not worsen motor symptoms; NEVER use haloperidol in PD
- Non-motor symptoms (depression, constipation, RBD, orthostatic hypotension, cognitive decline) often cause more disability than motor symptoms — actively screen for and treat them at every visit
- REM Sleep Behavior Disorder (RBD) may precede PD motor symptoms by 10-20 years — it is the strongest prodromal marker for synucleinopathy
- DaT scan differentiates degenerative parkinsonism from essential tremor and drug-induced parkinsonism, but does NOT distinguish PD from MSA, PSP, or DLB
- Impulse control disorders (gambling, shopping, hypersexuality) affect 15-20% of patients on dopamine agonists — screen at every visit and reduce agonist dose if present
- Avoid anticholinergics (trihexyphenidyl, benztropine) in elderly PD patients — cognitive harm outweighs tremor benefit

## References
1. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. *Mov Disord*. 2015;30(12):1591-1601.
2. Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. *JAMA*. 2020;323(6):548-560.
3. Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized delayed-start trial of levodopa in Parkinson's disease (LEAP). *N Engl J Med*. 2019;380(4):315-324.
4. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. *Lancet*. 2014;383(9916):533-540.
5. Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson's disease — an evidence-based medicine review. *Mov Disord*. 2019;34(2):180-198.