Parkinson’s Disease: A Neuropsychiatric Triage

Parkinson’s disease is usually associated with motor problems; the neuropsychiatric problems which might be co-existent are often neglected.

Researchers have proved that it’s not the motor but the non-motor problems that affect the quality of life. It was observed that more than 60% of the patients were not asked about their sleep, dementia, depression, sexual problems etc. The reasons may be increased longevity of the patients, the effects of new drugs on disease pathology and the effects of drugs themselves on cognitive function. This raises the extremely pertinent question of whether PD should be renamed Parkinson’s Disease Complex (PDC).

Aetiopathogenesis of Parkinson’s Disease

The search for anatomical substrates dates back to James Parkinson, who postulated that the anatomical substrate was in the medulla or upper cervical cord in his famous ‘Essay on the Shaking Palsy’ in 1817 (1). However, he did not allude to the neuropsychiatric symptoms. In 1912, Fritz Heinrich Lewy and in 1919 Konstantin Tretiakoff described the Lewy bodies and the lesions in the substantia nigra, respectively. In 1962, Derek Denny-Brown (2) felt that the lesion was in the globus pallidus, with the involvement of corticospinal fibers.

Braak and colleagues (3,4) challenged the traditional view, proposing six stages of the disease, with different parts of the brain being sequentially involved.

• Stage one is the involvement of olfactory bulb, olfactory nucleus, dorsal motor nucleus of the vagus.
• Stage two is the involvement of lower brain stem, the involvement of raphe nucleus, pedunculopontine nucleus, locus coeruleus, medullary nuclei etc., leading to anosmia, constipation, sleep problems, visual hallucinations and autonomic disturbances.
• Stages three and four have typically motor consequences, topographically, substantia nigra and lesions in forebrain and deep nuclei in the midbrain are prominent. This transition from the premotor to motor disorder is clinically evident. Features like depression, cognitive impairment, and florid hallucination.
• Stages five and six are the presence of Lewy bodies in the limbic system and neocortex, respectively.

The main limitation of Braak and colleagues’ hypothesis (3,4) is that the staging is based on Lewy body distribution and not on neuronal degeneration. In 2007, Hawkes, Tradici & Braake (5) postulated a dual-hit hypothesis, by which that an unknown virus enters the nervous system through the nasal and intestinal mucosa, eventually resulting in a cascade of neurodegenerative events in the brain.

Neuropsychiatric Features of Parkinson’s Disease

The prevalent neuropsychiatric problems include sleep disturbances, dementia/cognition, depression, anxiety, apathy, psychosis, hallucination and sexual problems. (6) Sleep problems include nocturnal nonmotor symptoms, that are virtually universal. This is due to degeneration of thalamocortical pathway and sleep regulation center in the brain stem. Pedunculopontine nucleus, locus coeruleus, and retropubic nucleus are implicated in the control of REM-sleep atonia. REM sleep parasomnia, which occurs in 30% may be a pre-clinical marker. Patents have vivid dreams, vocalization, abnormal movements, turning in bed, kicking and fall from bed reported by the spouse. At this stage incidental Lewy bodies found in isolated cases, with symmetrical reduction of uptake in the substantia nigra. Excessive daytime somnolence is observed in 50% cases, again another pre-clinical marker. The causal factors are first the disease process itself, disturbed sleep and the effect of dopa agonists, orexin and dynorphin releasing neurons may have a role.

Depression occurs in 10-45% subjects, which may antedate motor features (6). Depression most probably has a biological basis and is not solely reactive. The causal factors are damage to the limbic noradrenergic and serotoninergic dopaminergic systems, catecholamines are implicated the most; low 5HTA in CSF and high plasma homocysteine and Park2 mutation. Anxiety and apathy are also involved which was mentioned by James Parkinson. This could be related to dopa-induced motor fluctuations, mostly associated with left-sided motor weakness. Another factor could be due to degeneration in corticostriatal circuits mediating goal-directed behavior, including non-dopaminergic systems (7)

40% of the patients suffer from psychosis, particularly visual hallucinations, which are classical and differentiate PD from schizophrenia (6). This correlates with the number of Lewy bodies in temporal lobe, claustrum and visual cortex. Delusions, paranoia, and delirium appear in last stages. Delirium can be due to the withdrawal of dopaminergic drugs leading to neuroleptic malignant syndrome.

There are genetic predisposition and polymorphism in cholecystokinin gene. The dramatic aspect of Parkinsonism is Dopamine Dysregulation Syndrome, a complication of dopaminergic therapy, where degeneration of nucleus accumbens and reduced intrinsic dopamine production may lead to ‘addiction’ to exogenous dopamine. Hyposexuality is the more common sexual problem in PD, resulting from dysautonomia and lower levels of testosterone in men. Hypersexuality may be associated with Dopamine Dysregulation Syndrome, manifesting as sexual fantasies and disinhibited behavior.

In Parkinsonism, dementia is not a complication but a part of the disease and occurs in 20-40% in various estimates. It is a dysexecutive syndrome with impairment in visuospatial abilities and memory in the background of hypo-responsiveness to levodopa. Patients with PD have coexistence of vascular dementia with Alzheimer’s kind of dementia. There is a possible association with APOE genotype. The hippocampal volume is found to be diminished in volumetric studies. Alpha-synuclein aggregates in limbic system and synapses. There has been an abnormal interaction between synuclein and proteins concerned with dopamine synthesis and transport such as Rab3a, Rab5, Rab8 and phospholipase C. the causal factors are cell loss in monoaminergic cells in locus coeruleus, serotonergic cells in raphe and cholinergic cells in the nucleus basalis of Meynert. Cerebral glucose metabolism is reduced, particularly in prefrontal and parietal cortical regions (8).

In conclusion, the substantia nigra is not the only region affected in PD; rather, multiple anatomical substrates and neurotransmitters are involved at different times, resulting in different clinical presentations (7). These symptoms can be broadly categorized as sensory, autonomic, cognitive-behavioral, and sleep-related, proving that, Parkinson’s Diseases is not a mere motor problem with the precise anatomical substrate; rather it is a diffuse cerebral disorder, which require a broad view and specialized clinical skills.

References

1. Parkinson, J. An Essay on the Shaking Palsy. Sherwood, Neely, and Jones, London, 1817.
2. Denny-Brown, D. The basal ganglia, and their relation to disorders of movement. Oxford University Press, Oxford, 1964.
3. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 2003;24(2):197-211.
4. Braak H, Del Tredici K. Neuroanatomy and pathology of sporadic Parkinson’s disease. Advances in Anatomy Embryology Cell Biology, 2009;201:1-119.
5. Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathology and Applied Neurobiology, 2007;33(6):599-614.
6. Ring HA, Serra-Mestres J. Neuropsychiatry of the basal ganglia. Journal of Neurology, Neurosurgery and Psychiatry, 2002;72(1):12-21.
7. Braak H, Del Tredici K. Cortico-basal ganglia-cortical circuitry in Parkinson’s disease reconsidered Experimental Neurology, 2008;212(1):226-229.
8. Brooks DJ, Pavese N. Imaging non-motor aspects of Parkinson’s disease. Progress in Brain Research, 2010;184:205-218.