Siblings/children of PSPers have motor+other deficits(’01)

(I did a search and couldn’t find any previous post about this 2001 study.)

Remember how we’ve been told that PSP doesn’t run in families except in rare cases…. I learned about this disturbing 2001 article during the October ’08 PSP/CBD webinar presented by Dr. Golbe, an expert in PSP. Another MD (Timothy Hain) described this article as follows: “Relatives of patients with PSP tend to score more abnormally on screening tests for Parkinsonism (Baker and Montgomery, 2001), supporting either a genetic factor or exposure to a common environmental toxin.”

Note that fewer than 1% of those diagnosed with PSP have a family member with PSP. The percentage for PD is much higher: 20-25%. (Those numbers are also from the Golbe webinar. I’ve posted my notes to Golbe’s webinar here on the Forum.)

So maybe first-degree relatives don’t get PSP but have some sort of motor, olfactory, and affective deficits….? (FDRs = siblings and children) The 2001 article states: “In any case, what is clear is that many of the FDR testing in the abnormal range in the current study are unlikely to go on to develop PSP, suggesting that the PD Battery may be detecting an asymptomatic carrier state or subclinical form of the disease.”

After you’ve had a chance to read over the rest of this post, please let me know if you have a different take on things or if you’ve understood more of it than I have!

Here’s the abstract of the 2001 article:

Neurology. 2001 Jan 9;56(1):25-30.
Performance on the PD test battery by relatives of patients with progressive supranuclear palsy.
Baker KB, Montgomery EB Jr.
Departments of Neurology and Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH.

OBJECTIVE: To determine whether there is a greater prevalence of asymptomatic first-degree relatives (FDR) of patients with progressive supranuclear palsy (PSP) performing abnormally on the PD test battery (PD Battery) compared to sex- and age-matched normal control (NC) individuals. The PD Battery incorporates tests of motor function, olfaction, and mood. It has high specificity and sensitivity in distinguishing mildly affected PD patients from NC individuals in previous studies.

METHODS: This test battery and regression analysis-derived scoring equations were applied to asymptomatic FDR.

RESULTS: Twenty-three FDR and 23 NC individuals were tested. Of the FDR, 39% scored in the abnormal range, whereas none of the NC individuals achieved abnormal scores. This difference was significant. Further analysis demonstrated that the two groups differed significantly on a measure of simple reaction time.

CONCLUSIONS: The proportion of FDR who demonstrated abnormal performance on the PD Battery was greater than NC individuals. Thus, the PD Battery may detect the asymptomatic carrier state or risk for PSP or a subclinical effect of a shared environmental exposure.

PubMed ID#: 11148231 (see for abstract only)

Dr. Golbe had one slide on this paper in his presentation: (the info wasn’t presented in this way but the facts are correct)

Performance on the PD test battery by [asymptomatic] relatives of patients with [sporadic] progressive supranuclear palsy

FDR of patients with PSP
23 studied (7 sons, 13 daughters, 1 brother, 2 sisters)
Mean age = 43.5 years
Abnormal score on battery of motor, olfactory and affective test = 9 people (39.1%)
Median reaction time on a reaction time task = 380 ms

23 gender-matched individuals
Mean age = 44.3 years
Abnormal score on battery of motor, olfactory and affective test = 0
Median reaction time on a reaction time task = 305 ms

I exchanged email with the lead author Dr. Baker. I asked if this study had been reproduced since 2001. He said: “Unfortunately, I have no follow-up information to what is published in that report as we were unable to get funding for a larger scale project and our research has since been directed elsewhere.”

The remainder of this email is the Discussion section of the 2001 article, which I acquired.


Some abbreviations used in this excerpt from the article:
FDR = first-degree relatives
NC = normal controls
BDI = Beck Depression Inventory

“Discussion. The FDR of patients with PSP had a significantly higher prevalence of abnormalities on the PD Battery than did NC subjects without a family history of movement disorders. Consistent with this was the finding that the performance of the two groups was significantly different across all three subtests of the battery. It is impossible to know at this point which, if any, of the FDR might go on to develop PSP at some point in the future. The increasing number of familial cases being reported in the literature suggests that there may be some increase in risk, but just how much is not clear. There was no family history of PSP beyond the single index case for each of the FDR participating in this study. In any case, what is clear is that many of the FDR testing in the abnormal range in the current study are unlikely to go on to develop PSP, suggesting that the PD Battery may be detecting an asymptomatic carrier state or subclinical form of the disease.”

“Investigations into the factors responsible for PSP, whether focused on genetics or environmental toxins, are complicated by the late onset and rarity of the disease as well as the limited reliability of historical information from families. Moreover, similar to what has been observed in PD, there may be a familial form of PSP that differs genetically from the more typical and seemingly sporadic form of the disease. Indeed, the pattern of inheritance suggested by reports in the literature has been mixed, with both recessive and dominant patterns observed. Other familial case reports are not sufficiently complete to allow a confident determination to be made. However, a recent investigation examining the frequency of tau polymorphisms in PSP patients with no family history of the disease showed evidence of linkage disequilibrium between PSP and the tau marker using a recessive as opposed to a dominant model of inheritance. Although certainly complicated by the factors mentioned previously, this study provides some evidence that the more sporadic variety of PSP may be recessively inherited with variable penetrance.”

“If we assume an autosomal recessive mode of transmission, then 25% or approximately 6 of the 23 FDR tested in the current study would be expected to carry the putative gene or be at risk. Alternatively, an autosomal dominant pattern suggests that 50% or approximately 12 of the 23 subjects should be at risk. The actual prevalence of abnormalities in the FDR tested was 39% or 9 of 23, a figure that falls about midway between the different models. The absence of false positives in the matched NC group, although worthy of note, does not bear a significant impact on this finding. Within the larger database of 120 NC individuals from which the matched subjects were selected, the total false positive rate is 9%. Although there is no correlation between age and PD score in that group, the false positive rate for individuals under 52 years of age is only 3.1%. Given that 20 of the 23 FDR of PSP patients were 51 years of age or younger, it is not surprising that the NC sample should be without false positives. Even if we were to allow for a 9% false positive rate in NC individuals, this would predict that only 1 of the 11 FDR without the gene would have a false positive abnormality using the dominant model or 2 of 17 using the recessive model. Thus, the PD Battery would have accurately identified 66% (8 of 12) under the autosomal dominant model and 42% (7 of 17) using the autosomal recessive model—much higher than the rather conservative 9% false positive rate in the NC sample. Finally, a sex-linked inheritance pattern does not seem likely; however, the power of the performed test was insufficient to completely rule out such a pattern in this small sample.”

“The observed difference in olfactory function between the two groups is of interest given the lack of olfactory findings in patients with PSP. Reports in the literature have shown that the odor identification ability of patients with PSP is comparable to normal control subjects and significantly better than patients with idiopathic PD. However, in reviewing both reports it is clear that there is a marked trend toward reduced olfactory function in the patients with PSP. Neither set of authors reported the results of subsequent power analysis, leaving open the possibility of a type II error in their results. That is to say, the possibility exists that the null hypothesis, which in this case would state that there is no difference between the groups, may have been falsely accepted. The higher rate of smoking in the FDR group is of some concern given the potential impact of smoking on the sense of smell. However, the PDscore reflects performance on all three subtests and abnormal performance on any single subtest of the battery will not result in an abnormal score. The observed difference on the BDI is not surprising, given previous reports of psychiatric symptoms, including depression-like symptoms, in patients with PSP.”

“Reaction time was observed to be significantly longer in the FDR group as compared to the NC group across all tasks. If we assume the possibility of a subclinical disease state or an asymptomatic carrier state in PSP, there is both theoretical and empirical evidence that coincides with this finding. Previous studies have suggested that motor initiation utilizes physiologic mechanisms separate from those underlying motor execution. These studies have suggested that the anterior striatum, consisting of the head of the caudate nucleus and the anterior putamen, may be more involved in motor initiation, whereas the posterior striatum is more involved in motor execution. PET and SPECT have shown preservation of dopamine in the anterior striatum relative to posterior striatum of PD compared to PSP patients. Several groups have demonstrated that reaction time is delayed in patients with PSP, even in those with relatively mild disease. All of this suggests that reaction time may be of some value in further improving the identification of PSP as well as the asymptomatic carrier state or subclinical form of the disease.”

“There was an observed trend in the current study for extension movements to be more affected than flexion movements in the FDR group. This is consistent with observations in experimental animal studies. Denny­Brown showed that nonhuman primates became immobile in a flexed posture following large lesions of the globus pallidus. Similarly, injections of muscimol, a gamma-aminobutyric acid (GABA) agonist that inactivates the globus pallidus, have been shown to produce a greater slowing of extension movements compared to flexion movements on a wrist flexion and extension task similar to that used in the current study. Finally, recordings of neuronal activity changes made in nonhuman primates and correlated with wrist flexion and extension movements before and following induction of parkinsonism using n-methyl-4-phenyl-1,2,3,6-tetrahyrdopyridine (MPTP) showed that greater changes in neuronal activity following MPTP were associated with the wrist extension task than with the flexion task.”

“One possible explanation for the greater impairment of extension movements may be that there is a greater representation or dedication of neurons to flexion motor control in the basal ganglia. This greater representation could explain the predominance of flexion after stimulation and may convey increased resistance to degradation of performance
of flexion movements. Thus, flexion is relatively well preserved, resulting in a flexor bias such as flexed posture. Also, there would be greater impairment of extension movements with disease.”

“The results of the current study are of considerable interest regardless of whether the pathogenesis of PSP involves genetic or environmental factors. In either case, the PD Battery, either in its present form or with the addition of reaction time data, could help advance research into the cause of PSP. If the cause is genetic, then the PD Battery may be able to detect the asymptomatic carrier state or risk. Comparing the genetic makeup of the FDR scoring in the abnormal range with that of the unaffected parents or siblings who score in the normal range could lead to the identification of a shared genetic makeup that could cause or facilitate PSP. Likewise, if the cause is environmental, the PD Battery may be able to detect preclinical or subclinical involvement. As such, comparing the environmental exposure of FDR who score in the abnormal range with those who do not may help to identify potential causative agents. Further, the presumably earlier detection would be closer to the time of exposure, thereby facilitating the discovery of causative environmental factors.”

Here’s some info on the “PD Battery” and the “PDscore”:

“PD Battery. The PD Battery incorporates tests of motor function, olfaction, and mood, and has been described previously. Briefly, the motor task consists of rapid wrist flexion and extension movements made to one of two types of targets in response to an auditory “go” signal. Olfactory function was measured by the University of Pennsylvania Smell Identification Test (UPSIT, Sensonics, Inc. Haddonfield, NJ). Finally, mood state was assessed using the BDI. Results from the test battery were combined in a logistic regression analysis into an equation that yielded a score (PDscore) between 0 and 1.0 for each individual.”