Akiko Imamura

MR imaging of brainstem atrophy in progressive supranuclear palsy.

BackgroundTo enhance the sensitivity and specificity of the clinical diagnosis of progressive supranuclear palsy (PSP), neuroradiological parameters established in pathologically proven cases are needed.MethodsWe examined brainstem atrophy in five pathologically confirmed PSP patients (three men, mean age at death 77 years, range 64–84 years). Time interval between symptom onset and MRI ranged from 1 to 5 years, and between MRI and death from 33 to 52 months. Only one patient had clinical diagnosis of PSP at the time of MRI. Control group consisted of 19 age- and gendermatched healthy subjects. Seventeen morphometric parameters of the midbrain and pons were measured on T1-weighted midsagittal and T2-weighted axial MRI scans with Image Analyzer. Measurements of superior cerebellar peduncle (SCP) width were performed on PSP autopsy specimens.ResultsMean SCP width on MRI in PSP (2.7 ± 0.8 mm, 95%CI: 2.1–3.3) was smaller than in controls (3.7 ± 0.5 mm, 95%CI: 3.5–3.9). Mean SCP width at autopsy was 8% smaller than mean SCP width on MRI. Midsagittal midbrain area in PSP (99.1 ± 6.9 mm2, 95%CI: 90.5–107.6) was smaller than in controls (141.0 ± 18.1 mm2, 95%CI: 132.2–149.7). Midbrain/pons area ratio in PSP was 1:5 and in controls was 1:4 (p < 0.01). Repeat MRI 17 months later in one PSP case revealed 30% decrease of SCP width.ConclusionsMR imaging with quantitative analysis may be useful in the diagnosis of early PSP and in monitoring disease course.

Medications used to treat Parkinson’s disease and the risk of gambling

Recent case–series studies indicated that a medication used to treat Parkinson’s disease (PD), in particular Pramipexole, is associated with gambling. A case–series study cannot test this hypothesis; therefore, we need to design a case–control or cohort study to test the aforementioned hypothesis. Typical of a case–control design, we sampled on the dependent variable, which we defined as incident gambling in PD. A research neurologist, who was kept uninformed of the case–control status, retrospectively measured the exposure of interest (i.e. medications used to treat PD) by using the medical database system of Mayo Clinic Jacksonville. Eleven patients with PD without history of gambling, but had newly developed gambling, were matched by age and sex to the control group of 37 PD patients without gambling at a ratio of one case to at least three controls. Disease duration, age, and sex did not differ between cases and controls. Combined therapy with Pramipexole and levodopa did not increase the risk of gambling as compared to monotherapy with Pramipexole (OR, 0.15; 95% CI, 0.01–1.26). Treatment with Pramipexole was associated with increased risk of gambling and this association approached significance (OR, 3.6; 95% CI, 0.9–14.9). Patients with PD who newly developed gambling behavior were more likely to have been taking Pramipexole than other anti‐PD medication. However, the association between Pramipexole and gambling behavior is not necessarily etiologic.

Corticobasal syndrome with Alzheimer's disease pathology

We read with great interest the article by Chand et al. entitled ‘‘Alzheimer’s disease presenting as corticobasal syndrome’’ in which a patient diagnosed clinically with corticobasal syndrome had pathology of Alzheimer’s disease (AD) at autopsy. Just recently, we have encountered a patient with the same clinical and pathological disparity. A 59-year-old, right handed woman presented with the right alien hand. Head MRI revealed mild generalized cerebral atrophy. SPECT study showed right temporal glucose hypometabolism. EEG demonstrated right temporal intermittent slowing. She was seen by us 2 years later complaining of some memory difficulties, right hand tremor, and general body bradykinesia. Her Mini-Mental State Exam (MMSE) score was 22 of 30. She had right hand rigidity and apraxia. Formal neuropsychological testing revealed evidence of a mild to moderate frontal subcortical dysfunction, characterized by marked bradyphrenia and visual processing deficits, as well as mild inattention and naming deficits. In contrast, the patient’s verbal memory functioning was normal for her age, with 100% retention of initially learned narrative information over a 30-min delay. Delayed free recall of a word list was mildly impaired, but improved to the normal range with cueing and recognition testing. MRI showed no significant change from previous study. She was placed on levodopa/carbidopa 25 of 100 three times a day with the recommendation of further upward titration of her dose if needed by her primary physician. When seen a year later, she was wheelchair bound and required assistance in all daily living activities. She reported that her right hand had ‘‘its own mind.’’ She had severe right hand rigidity and dystonia. Myoclonic jerks were seen. The MMSE was 13 of 30. Levodopa and donepezil provided no benefit. On examination performed 2 years later, there was severe right hand tremor, rigidity, and myoclonus with dystonic posturing. Frontal lobe release signs and gegenhalten were noted. A year later, she became mute. Rigidity and myoclonus became generalized. She lost a significant amount of weight because of dysphagia. She died 8 years after the disease onset and a brain autopsy was performed. Her brain weighed 800 g and had superior parietal lobule atrophy. There was normal pigmentation of substantia nigra and locus ceruleus. The neocortex had neuronal loss and diffuse gliosis, especially in superficial cortical layers, that was most marked in the frontal and parietal lobes. Many senile plaques (SP), neurofibrillary tangles (NFT), and neuropil threads were noted on thioflavin-S fluorescent microscopy. The hippocampus had only mild patchy neuronal loss with some NFT, Hirano bodies, and granulovacuolar degeneration. The entorhinal cortex had moderate to marked neuronal loss and NFT in layer II. The amygdala had many SP and NFT with atrophy, spongiosis, and gliosis. The Braak NFT stage was VI. The basal nucleus of Meynert and hypothalamus had NFT. There was SP in the striatum and globus pallidus. The thalamus and subthalamic nucleus were unremarkable. Substantia nigra had only mild focal neuronal loss and a few NFT. Immunohistochemistry for phospho-tau failed to reveal the dense thread pathology in gray and white matter in cortical and subcortical areas that is typical of corticobasal degeneration. No ballooned neurons were detected in the cortex. There were only a few thorn shaped astrocytes in basal structures, but no cortical astrocytic plaques. The final pathological diagnosis was AD, Braak stage IV, with relative hippocampal sparing. There are only a few reports of AD clinically presenting with the corticobasal syndrome. All 7 cases, including 6 reported in the literature and our patient (average age at death: 60 6 4 years; 4 men and 3 women), presented with typical clinical features and fulfilled the proposed research criteria of corticobasal syndrome. Pathologically, all cases had SP and NFT consistent with AD, but not corticobasal degeneration. Unlike the patient described by Chand et al., our patient did not demonstrate significantly impaired memory early in the course of illness. Although impairment was noted in other cognitive domains, the observed pattern (e.g., bradyphrenia, retrieval difficulties, and inattention) was more consistent with that of patients with subcortical disease. As suggested by Chand et al., the presenting clinical features of our patient suggest an atypical distribution of Alzheimer pathology early in the disease course, with unusual phenotypic expression. This clinical–pathological disparity is puzzling and requires further study of potential factors that may influence AD presentation.

Brainstem atrophy on routine MR study in pallidopontonigral degeneration

Sirs, Pallidopontonigral degeneration (PPND) is an autosomal dominant inherited disorder which belongs to the spectrum of frontotemporal dementia linked to chromosome 17 (FTDP-17). It is caused by the N279K mutation in the gene encoding the microtubule-associated protein tau on chromosome 17 [3, 11]. Clinically, PPND is characterized by early and prominent parkinsonism with mild cognitive and behavioral changes, with some differences in clinical presentation between four branches of the PPND kindred [9, 11, 13]. Pathologically, PPND presents with neuronal loss and gliosis, most pronounced in the globus pallidus, pontine and mesencephalic tegmentum and substantia nigra [7, 13]. Immunohistochemistry reveals extensive neuronal and glial tau pathology [7, 8]. Routine magnetic resonance (MR) scanning performed in PPND patients reveals bilateral cortical atrophy, ventricular enlargement, narrowing of the substantia nigra pars compacta and atrophy of the pontine tegmentum [4]. Arvanitakis et al. [1] stressed prominent temporal atrophy in five affected PPND subjects; this was also seen in one asymptomatic N279K mutation carrier who converted to affected status 8 months after the MR study. In some FTDP-17 cases with the MAPT mutation, atrophy of the midbrain and pons was observed at autopsy [14]. Our previous pathological and MR studies confirmed profound brainstem atrophy in progressive supranuclear palsy (PSP) [10, 12]. Because PPND shares some clinical and pathological features with other atypical parkinsonian disorders [1, 8, 9], we decided to examine whether brainstem atrophy is also a feature of PPND and, if so, whether this feature may facilitate the differential diagnosis of PPND. We examined six pathologically confirmed PPND patients [three males, symptom duration 7 ± 3 years, age at death (AAD) 53 ± 5 years] and a historical series [10] of five pathologically confirmed PSP patients [three males, symptom duration 6 ± 2 years, AAD 77 ± 8 years]. The control group consisted of 25 healthy subjects, age and gender-matched to the PPND patients. The time interval between MR imaging and death was 50 ± 13 months in the PPND group and 45 ± 8 months in the PSP group. Six morphometric parameters of the midbrain (MB) and pons were measured on T1-weighted midsagittal and axial MR scans with Image Analyzer software. The technique of MR scanning and image analysis have been described in detail earlier [10]. The Mann–Whitney test was applied. A P value\0.05 was considered to be significant. Results of the study are summarized in Table 1. Midsagittal midbrain (MB) area and the MB area/pons area ratio were significantly smaller in PPND patients than in the controls (Fig. 1a, b), with the PSP cases showing even more pronounced midbrain atrophy. Other measurements did not differ between the PSP and PPND patients. Mean J. L. Slowinski K. J. Schweitzer A. Imamura R. J. Uitti A. J. Strongosky Z. K. Wszolek (&) Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, USA e-mail: wszolek.zbigniew@mayo.edu

LRRK2 (Leucine-Rich Repeat Kinase 2) Gene on PARK8 Locus in Families with Parkinsonism

It is estimated that about 10% to 30% of Parkinson’s disease (PD) cases are familial [1]. Eleven PD loci/mutations have already been identified [2] (Table 1). The PARK8 locus on chromosome 12p11.2-q13.1 was first found in 2002 in a large Japanese kindred known as the Sagamihara family [3]. The linkage analysis studies performed by our group on 21 caucasian families showed probable linkage to this locus in 10 kindreds [4]. In late April of 2004, we found the first mutation in the leucine-rich repeat kinase 2 (LRRK2) gene in family D (western Nebraska). Two weeks later the second mutation in this gene for family A (German-Canadian) [5] was discovered. Other groups have confirmed our discovery in a number of other families [6–9].