‘Parkinson Plus’ is a name given to a group of disorders with parkinsonian symptoms, but with additional features. While the clinical symptoms of these disorders overlap with Parkinson’s disease, the underlying neuropathology is often different and individuals may require alternate treatments. We’ve tried to provide an informative passage on each of these disorders, but for further information, please see our links for other sources.
Dementia with Lewy Bodies
Cortical Lewy bodies of dementia with Lewy bodies (DLB) are noticeably smaller and different in appearance, both with a standard H+E stain, and with an anti-synuclein staining (see figure).
Prior to the identification of Lewy bodies in demented patients, the 50% (approx.) of dementia cases not attributable to pure Alzheimer’s disease were assumed the result of vascular dementia. The discovery of Lewy bodies in the brains of demented patients by Kosaka and colleagues (1984) prompted a variety of new diagnoses i.e. dementia with Lewy bodies, diffuse Lewy body disease, Lewy body variant of Alzheimer’s disease and others. More recently, the umbrella term ‘Dementia with Lewy bodies’ has been used – distinctions between different Lewy dementias were probably due to the variable bias between research groups. As a result, today’s DLB is probably the second most common form of dementia after Alzheimer’s disease.
In DLB, patients usually initially develop Alzheimer’s like dementia symptoms or parkinsonian signs and subsequently progress to symptoms of the other condition. McKeith and colleagues (1996) defined the features of possible or probable DLB diagnoses. These are (2 needed for a probable, 1 for a possible diagnosis):
- Spontaneous development of parkinsonian motor symptoms
- Recurrent visual hallucinations
- Sharp variations in attention and alertness
Stroke or other conditions may also cause these symptoms and should be ruled out before a diagnosis of DLB is made.
Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a condition related to Parkinson’s disease, and patients present with parkinsonian symptoms, including slow movement, postural instability leading to falls, rigidity and tremor. Additional symptoms include trouble with eyesight and eye movement, as well as with breathing and swallowing. Other psychiatric symptoms may include problems with information processing, as well as planning and concept formation. Personality and behavioral changes, as well as sleep disturbances are also fairly common. Unfortunately, the treatment potential for PSP is significantly less than for PD, due to the effect the condition has on many neurotransmitters in the brain.
The pathology of the disease occurs in subcortical (under the cortex) regions of the brain – including the subthalamic nucleus, globus pallidus and the substantia nigra. As shown in the above picture, atrophy is visible in the tectum, and to a lesser extent in the pons of the midbrain region. Glial (non-neuronal cells which support neurons) and neuronal death can be seen in the diencephalon (incl. thalamus), brainstem, and basal ganglia. The characteristic microscopic feature of PSP is the ‘tufted astrocyte’ (an astrocyte is a specialized glial cell), which possess fibrous aggregates, visualized by staining for tau and ‘glial fibrillary acidic protein’ (used to distinguish glial and non-glial cells).
Along with another somewhat similar condition known as corticobasal degeration, PSP is defined as a ‘primary tauopathy’. Cells in the subcortical regions to which the pathology spreads develop ‘neurofibrillary tangles’, composed of an abnormally phosphorylated, polymerized form of the microtubule- associated protein tau. Microtubules provide a network of ‘rails’ upon which transport around the cell depends.
Tau has two forms, with different numbers of structural repeat elements in the protein. Tau in PSP (and CBD) only has four repeats, in contrast the tau present in Alzheimer’s disease is of two types, three and four-repeat. See the adjacent western blot (used for protein detection).
Multiple System Atrophy
Multiple system atrophy (MSA) is a condition which affects many areas of the brain (hence ‘multiple system’), and the associated systems in the body. Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar atrophy were three names used when symptoms were predominantly autonomic, parkinsonian, or ataxic (lack of coordination in body, speech, eyes), respectively. Onset is usually at 30-50 years of age, and more males are affected than females. Patients eventually develop symptoms of both Parkinson’s disease (e.g. slowed movement, ridity) and autonomic (linked to parts of the body not under conscious control) dysfunction, but frequently patients initially present with one or the other, leading to incorrect diagnoses of Parkinson’s disease (perhaps 10% of Parkinson’s disease diagnoses are determined to be MSA at autopsy), or pure autonomic failure.
Symptoms resulting from autonomic system failure include erectile dysfunction in males, changes in intestinal motility and urinary function, and affects on blood pressure including orthostatic hypotension (loss of blood pressure while standing- leading to symptoms of ‘getting up too quickly’- e.g dizziness, headache, clouding of vision and possibly fainting).
MSA brains show atrophy in the cerebellum, the cerebellar peduncles, the pons, and medulla, as well as the parkinsonian discoloration in the substantia nigra. The pathological hallmark of MSA are ‘glial cytoplasmic inclusions’, visible as the spots in the adjacent image. White matter in the condition shows significant demyelination (see top left slide- blue myelin stain would be widespread in a healthy individual)- the pons and cerebellum are the areas worst affected.
Symptoms may be treated with drugs in the same way as Parkinson’s disease, and response is usually good (although drugs may complicate autonomic problems), but the disease is more rapidly progressive than PD, survival is on average 5-7 years from onset. Drugs may be used to increase blood pressure, but should be used with care due to a decrease in the body’s ability to compensate.
Corticobasal degeneration (CBD) is a relatively rare disorder, which although presenting with some parkinsonism, is not misdiagnosed very often due to a distinct set of symptoms. Disease onset is late, usually after 60 years of age and the disease progresses slowly relative to related conditions. Complaints will usually be noticed unilaterally, on one side of the body intially, and later spread. Symptoms include parkinsonism as well as difficulties with speech (dysphasia), articulation (dysarthria), balance and muscle control in the face (dystonia). Myoclonus (‘jerky movement’) may develop and problems with muscle control lead to an inability to walk. ‘Alien limb’ syndrome sometimes occurs, when one limb seems to have mind of its own and move without control.
The disease causes degeneration in multiple areas of the brain, including areas of the cortex and basal ganglia (hence cortico-basal) but especially in the outer, cortical areas of the brain. Microscopic examination of brain sections reveals loss of neurons and glia (non-neuronal cells supporting neurons). Characteristic brain pathology includes ‘ballooned neurons’ (sometimes containing tau) and ‘astrocytic plaques’- see adjacent picture (astrocytes are a specialized variety of glial cell). Astrocytic plaques are composed of tau, and the brains of CBD patients have tau inclusions of various kinds in many areas including small dense bodies similar to Pick bodies or neurofibrillary tangles of Alzheimer’s disease and PSP.
Like PSP, CBD is a ‘primary tauopathy’, four-repeat tau is the predominant form. Research into the genetic bases of PSP and CBD has revealed a close similarity between them- they possess similar combinations of single nucleotide polymorphisms (variations at single ‘letters’ in the genetic code) for tau. The diseases may have a close causal relationship and may in fact be two different outcomes of the same underlying condition. Unfortunately, treatments for CBD are few and patients show little or no response to dopamine replacement therapy.
Images and additional information: Thanks to Dennis Dickson.