What are the potential PD subtypes, and how do they differ clinically and/or genetically?

As anyone who knows me knows, this is something I'm fascinated by.

The existence of subtypes...even if not 100% pure categorizations...could greatly influence how we approach the search for biomarkers as well as how we tackle clinical trials.

I have to believe we start with clinical presentation and back into differing biology/pathology. But of course genetics also provide a clear clue, and to that end the LRRK2 cohorts we're working to develop could shed some light on a "subtype."

Each person's PD is clearly very different, but if you were to try to determine some true subtypes, based on clinical presentation but trying to get to pathological differences, what would you do?

With gene identification we have an opportunity to perform “genotype-phenotype” correlations and determine if specific mutations are associated with particular subtypes. For the most part, the G2019S mutation in LRRK2 has been described as causing “typical”  “PD”. Some studies suggest, however, that LRRK2  motor and non-motor features may be milder (Healy 2008).  Also several studies (including our own LRRK2 G2019S PD population) have confirmed that the usual male predominance is lost, with equal frequencies of men and women. We also found that although the average age onset is not significantly different from non-LRRK2, a higher proportion have onset <50 years. 

So although this mutation does not appear to be associated with a uniform distinct PD subtype, it does produce a clinical spectrum that lends itself to detailed analyses that may help tease apart factors (environment, other genes) that influence expression  (eg slowly progressive  tremor predominant vs rapid progression with dementia)

Together with my colleagues at Baylor we first proposed two major subtypes of PD, tremor-dominant and postural-instability-gait-difficulty (PIGD) in 1985 and this observation was confirmed when we analyzed the clinical features of the 800 PD patients enrolled in the DATATOP study (Jankovic et al, 1990). In that study we defined the mean tremor score as the mean of the sum of the baseline tremor (UPDRS part II) and tremor scores (UPDRS part III) for face, right and left hand, right and left foot, and right and left hand action tremor. The mean PIGD score was defined as the sum of an individual's baseline falling, freezing, walking, gait and postural stability UPDRS scores divided by five.

Patients were categorized as having tremor-dominant PD if the ratio of the mean tremor score to the mean PIGD score was 1.5 or higher and as PIGD dominant if the ratio was 1 or lower.  We and others subsequently found that presentation with bradykinesia and the PIGD type of PD seems to be associated with more rapidly progressive course than if PD patients have tremor at the onset of their disease. Using different rating scales Van Rooden et al recently confirmed these initial findings and identified four distinct motor patterns: tremor-dominant, bradykinetic-rigid, and two types of axial patterns: A. rise, gait, postural instability (similar to PIGD) and B. freezing, speech, and swallowing, the latter related to complications of dopaminergic therapy (van Rooden et al., 2009).  The more favorable course of the tremor-dominant form of PD is also supported by various PET scan studies showing slower rate in decline of various dopaminergic indices in patients with the tremor-dominant form of PD (Jankovic, 2005). The tremor-dominant form of PD is associated with a more frequent family history of tremor, raising the possibility of overlap between PD and ET in a subset of cases, a notion that is gaining more and more support (Shahed and Jankovic, 2007). Axial impairment observed in patients with the PIGD subtype, often associated with cognitive impairment, is probably mediated predominantly by nondopaminergic systems. In addition to these subtypes PD population can be separated into young- and late-onset disease.  It is not clear what the subdivision of sporadic PD means and whether the different subtypes have distinct pathogenesis or if they represent a continuum.  With the better understanding of the genetic forms of PD (e.g. LRRK2) and the different clinical and pathological subtypes despite common gene mutations will provide insight into the role of environmental factors in determining the penetrance and the phenotype.

If we use as a model those neurodegenerative diseases caused by single gene mutations, such as FTDP-17 (tau gene mutations), FTLD-TDP (progranulin gene mutations), LRRK2 mutations, APP mutations, etc, it is evident that even though the cause of disease may be identical, caused by the same point mutation, the clinical presentation can vary widely, from cognitive impairment to behavioral changes to motor syndromes including parkinsonism.  This would seem to point to the importance of genetic background or environment as a critical modifying feature.  There also can be substantial inter-individual differences in brain histopathology amongst people carrying the same point mutation, as demonstrated in mutations of APP, PS2, prion protein and familial British and Danish dementia, where the same point mutation may cause only amyloidosis predominating in plaques, amyloidosis predominating in amyloid angiopathy or amyloidosis plus neurofibrillary tangles and/or Lewy bodies.  So we might expect that idiopathic, sporadic PD, which is a multifactorial disorder to start with, would have equal or greater clinical and pathological variability than these simpler conditions.  Sorting out the relative contributions of genetic background vs environment may be an important task that could be helped by the genome-wide association studies (GWAS) approach combined with detailed  epidemiological studies.  A recent Brazilian study of homozygous twins with the G2019S LRRK2 mutation (Munhoz et al, 2008) was interesting in that both twins developed right asymmetric PD with an identical age of onset at age 60.  However, in this situation both genetic background and environmental differences were minimized.  In idiopathic, sporadic PD, twin studies have found concordance for PD is uncommon to rare (Rajput et al, 1997; Tanner et al, 1999; Wirdefeldt et al, 2008), with a recent Swedish study of 50,000 twin pairs finding concordance for PD in only three twin pairs.  These studies suggest that for idiopathic, sporadic PD, environmental influences are the dominant cause of clinical variability. 

katie:  first thing i would do is apply the subtype information to clinical trials.   if we tried the right drug on the right patients, we would be more successful with drug development/ novel therapeutics.