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DOI 10.1007/s00702-003-0079-6 J Neural Transm (2004) 111: 47–57

Parkin mutation associated parkinsonism and cognitive decline, comparison to early onset Parkinson’s disease B. R. Benbunan1 , A. D. Korczyn1;2;3 , and N. Giladi1;3 1

Movement Disorders Unit, Department of Neurology, Tel Aviv Sourasky Medical Center, 2 Incumbent of the Heinrich Sieratzki Chair of Neurology, and 3 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Received July 2002; accepted October 1, 2003 Published online December 12, 2003; # Springer-Verlag 2003

Summary. Background: Patients with Parkinson’s disease (PD) have cognitive changes resulting, presumably, from a progressive disruption of the functional integrity of frontostriatal circuitry. Objective: To assess the cognitive state of two brothers with early onset autosomal recessive (EO-AR) parkinsonism and a large deletion in the parkin gene, and to compare it to that of patients with sporadic young onset PD (YOPD). Method: Two brothers with parkinsonism and deletion of axons 4–6 of the parkin gene (ages 51, 55 years; duration of symptoms, 22, 29 years respectively) and 4 randomly selected patients with YOPD (mean age 47.8  4.9 years; mean duration of symptoms, 11.5  1.9 years) were administered a neuropsychological battery at ‘‘on’’ state. We assessed global cognitive state using the Mini-Mental State Examination (MMSE), orientation, attention, memory, language, ideational praxis, constructive praxis and executive functions (shifting aptitude, verbal fluency, sequencing). Results: The older of the two brothers with EO-AR parkinsonism had dementia according to DSM IV criteria, and MMSE score of 24, whereas the other had normal global cognitive status with mild cognitive changes (MMSE ¼ 29). The older brother had impaired memory tasks. Storage and retrieval capacities were defective on both immediate and delayed recalls, naming, constructional praxis, selective attention, shifting aptitude and phonemic and semantic fluency were also affected. The younger brother had difficulties in retrieval on delayed recall, selective attention, phonetic fluency, shifting aptitude and sequencing. This neuropsychological profile clearly differs from that of the YOPD patients, none of whom displayed cognitive dysfunction. Conclusions: Our patients with parkin mutation performed poorly on neuropsychological tests compared to those with YOPD. This difference


B. R. Benbunan et al.

could reflect the longer disease duration or the nature of the degenerative process. Keywords: Parkin, parkinsonism, dementia, neuropsychology, young onset PD. Introduction The neuropsychological alterations associated with Parkinson’s disease (PD) have been often documented and different patterns of cognitive impairment have been identified (Pillon et al., 1996). The earliest and most evident cognitive findings are impaired executive functions and memory (Lees and Smith, 1983; Robbins et al., 1994; Pillon et al., 1995; Levin et al., 1995; Rogers et al., 1998; Muller et al., 2000; Stocchi and Brusa, 2000; Tomer et al., 2002). The term ‘‘executive functions’’ refers to the mental processes involved in goaldirected behavior. These include behavioral regulation (shifting or maintaining a behavior) and sequencing (Lezak, 1983). Regarding the memory processes, PD patients display impaired free recall of information but tend to benefit from provision of cues and show relatively spared recognition. This has led some to propose that the mechanism of memory failure may be retrieval search while the storage capacity is preserved (Helkala et al., 1988; Massman et al., 1990; Whittington et al., 2000). The neuroanatomic basis of these changes is suggested to be disruption due to the progressive dopamine deficiency of the neuronal loops connecting the basal ganglia and frontal lobes (Albin, 1989). As the disease progresses, about one third of the patients develop frank dementia (Giladi et al., 2000) due presumably to degeneration of the subcortical dopaminergic, noradrenergic and cholinergic nuclei (McRae, 1998) or to cortical lesions typical of cortical Lewy body deposition (McKeith et al., 1996) or superimposed Alzheimer’s disease or vascular changes (Jellinger, 1994). The clinical spectrum of early onset autosomal recessive (EO-AR) parkinsonism associated with mutations in the parkin gene on chromosome 6 has expanded rapidly since the discovery of the association between mutations in this gene and familial parkinsonism (Matsumine et al., 1997). However, all reports mentioned the fact that those familial patients have normal cognitive functions (Kitada et al., 2000; Lucking et al., 2000). The purpose of this study is to report the cognitive performance of two brothers with a large deletion in the parkin gene and prolonged (>20 years) symptoms and to compare it to patients with sporadic young onset PD (YO-PD) of the same age (around 50). The association of deletion in the parkin gene with cognitive decline will demonstrate for the first time that parkin mutations can cause a more global brain dysfunction and not just motor disturbances. Patients and methods Patients Two brothers with parkinsonism and deletion of axons 4–6 of the parkin gene (ages 51, 55 years; duration of symptoms 22, 29 years) and 4 male patients with YO-PD (onset under 40 years of age, mean current age, 47.8  4.9 years; mean duration of disease 11.5  1.9 years), all right-handed,

Parkin mutation associated parkinsonism and cognitive decline


were studied at ‘‘on’’ state. The two brothers’ clinical features have recently been published in detail together with their metabolic brain topography using PET scans (Portman et al., 2001). In summary, the older and younger brothers have developed parkinsonian signs at age 25 and 29 with mild tremor as well as rigidity. Both have responded significantly to levodopa treatment but developed motor response fluctuations and dyskinesia after few years of treatment. This clinical course was remarkable for severe freezing in the older brother and festination in the younger one. The older brother have developed slowly over a course of two to three years some psychiatric delusions and later a functionally significant dementia. A full work up for other causes of dementia like vascular changes, endocrine or metabolic disturbances was negative. The younger brother had no signs of any cognitive disturbances from the functional point of view neither psychotic features. The two patients have a sister and two brothers, who have no signs of any neurological or neurobehavioral disturbances. Similarly, no other family members had any neurological or neuropsychiatric disorders diagnosed. For comparison purposes, we searched our parkinsonism database in an alphabetical order, and selected randomly four male patients with YOPD who met the clinical criteria for PD according to the UK brain bank criteria (Hughes et al., 1993) and were 50 years old or younger with at least 10 years of symptoms. We chose a cut-off point of 10 years after failing to find patients with longer duration of symptoms (closer to the 25 years of the two brothers). We excluded patients with history of neurosurgery of any kind, severe head injury or treatment with anticholinergic drugs. The younger brother with EO-AR parkinsonism was taking amantadine. Therefore we included also a patient with YO-PD who took amantadine as well. Two YO-PD patients took antidepressive drugs but none with anticholinergic properties.

Neuropsychological assessment All tests and instructions were given in Hebrew and all patients had Hebrew as a first language. 1. Overall cognitive performance: Mini-mental State Examination (Folstein et al., 1975). 2. Orientation (Alzheimer’s Disease Assessment Scale cognitive subtest ADAScog) (Rosen et al., 1984): The components of orientation are date, month, year, day of the week, season, time of day, place and person. One point was given for each incorrect response. 3. Attention: – Stroop Color-Word Test (Neutral Condition) (Vakil et al., 1995): Patients were presented with 90 sets of 3 to 5 Xs (XXX, XXXX or XXXXX) printed in different colors and then told that they would have to name the color of each series of Xs. A color verification card was applied first as a test for color blindness and an additional card consisting of four examples served for practice. – Trail Making Test (part A) (Reitan, 1958): Patients were required to draw lines connecting 25 randomly arrayed circled numbers in numerical sequence (1-2-3, and so on). 4. Memory: – Grober and Buschke test with controlled encoding and selective reminding (Grober and Buschke, 1987; Ergis et al., 1994): In this task, encoding was controlled by asking the patient to point to and read aloud each of the 16 to-be-remembered words, presented four at a time, in response to its semantic category. All 16 items had to be retrieved at immediate cued recall before starting memory assessment, which consisted of three consecutive series of free recall and cued recall with selective reminding. These series were separated by 20second counting-backward periods, in order to obtain recall from secondary memory. Whenever a patient was unable to retrieve an item at cued recall, the correct answer was provided by the examiner. The same procedure was administered after a trial delay of 20 minutes. Following the delayed recall trial, a yes-no recognition test was administered. Five basic measures were obtained from controlled learning: Immediate Free Recall: the sum of items retrieved without cues on each immediate trial; Immediate Total Recall: the sum of free and cued recall on each immediate trial; Delayed Free Recall: the number of items


B. R. Benbunan et al. free-recalled in delayed trial; Delayed Total Recall: the sum of free and cued items on the delayed trial; Recognition: the number of correct responses. – Word recall (ADAScog subtest): Patients read 10 high-imagery words and were told to recall the words aloud. Three trials of reading and recall were given. The score equals the mean number of words not recalled on three trials. – Word-recognition (ADAScog subtest): Patients read aloud 12 high-imagery words. These words were then randomly mixed with 12 words the patient had not seen. Patients were asked to indicate whether or not the word was shown previously. Then two more trials of reading the original words and recognition were given. The score equals the mean number of incorrect responses for three trials.

5. Language – Commands (ADAScog subtest): Receptive speech was assessed on the patient’s ability to carry out one to five-step commands. The score equals the number of commands incorrectly performed. – Naming (ADAScog subtest): Patients were asked to name 5 body parts and 12 objects, whose frequency values are high, medium or low. The score equals the number of incorrect responses. 6. Praxis – Constructional Praxis (ADAScog subtest): Patients were requested to copy four geometric forms. The score equals the number of forms incorrectly copied. – Ideational Praxis (ADAScog subtest): Patients were instructed to pretend to send a letter to themselves. Five steps are required. The score equals the number of steps incorrectly performed. 7. Executive functions – Shifting Aptitude: Stroop Color-Word Test (Interference Condition): Patients were presented with 90 color words, each of which is printed in a color other than the one spelled by the letters. The task was to name the color of the letters and to inhibit the strong tendency to read the word that they spell. The time to complete each task was recorded. First, a color verification card was applied as a test for color blindness and an additional card consisting of four examples, one from each condition, served as practice cards. Trail Making Test (part B): Patients were asked to connect consecutively 13 numbers and 12 letters by alternating between the two sequences (from 1 to A to 2 to B to 3 to C, and so on). The score was the time in seconds that was required by the patient to draw the connecting lines. Mental Regulation (Zec et al., 1999): – Category Fluency: Patients were asked to generate within 60 seconds as many animals as they could think of. – Phonemic Fluency: Patients were asked to generate in one minute as many words as they could think of beginning with the Hebrew equivalent of the English letter ‘‘M’’. For both fluency measures, the score recorded was the total number of correct responses. – Sequencing: Sequential Visual Alternations Task [Dementia Rating Scale (DRS) subtest] (Mattis, 1988): Patients were asked to copy a design that contained ‘‘squared waves’’ and ‘‘triangular waves’’ alternated 10 times. To receive one point the production should have the same number of ‘‘squared waves’’ and ‘‘triangular waves’’, in the same sequence as the stimulus card. Sequential Motor Alternations Task (DRS subtest): Patients were asked to make a sequence of three consecutive hand movements (fist, side, flat). Disruption of the proper sequence and a tendency to repeat the same movement indicated a failure of this test. One point was given for five consecutive correct alternations.

Parkin mutation associated parkinsonism and cognitive decline


Results All patients were cooperative and completed the study successfully. None was colorblind. The YOPD patients had a shorter disease duration (mean, 11.5 years) than the EO-AR patients (mean 25.5, p20 years) disease duration on the neuropsychological disturbances but it could give us the opportunity to eliminate the effect of long term parkinsonism (>10 years) at the age of 50 as an independent cause for cognitive decline. It could also give us the opportunity to compare the neuropsychological performance among the two groups of patients. Acknowledgements We thank Prof. Mizuno and Dr. Hattori for the genetic testing of the two brothers with AR-YO parkinsonism.

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