Search

Almost half of the nigral neurons are already lost during the preclinical period of Parkinson's disease (PD), and then the speed of neuronal loss is slowly attenuated during the subsequent progression. We sought to establish long-term temporal trajectory models for the dopaminergic input to the striatal subregions and a 4D-temporal trajectory model for the dopamine transporter positron emission tomography (PET).We selected 83 patients in PD spectrum who underwent dopamine transporter PET scan twice and 71 age-matched healthy controls. We created temporal trajectories of specific binding ratios of the striatal subregions by integrating function between baseline values and their annual change rates and also created 4D-temporal trajectory model by applying the same method for each striatal voxel. Using the PET data of additional 100 PD patients, we estimated an individual time point in the 4D-temporal trajectory model for the validation.Degenerative loss of striatal dopaminergic input first appeared in the posterior dorsal putamen in the more affected side at 14.4 years before the clinical onset, and subsequently in the posterior ventral and anterior putamen, and finally in the caudate. The time delay between the initiation of dopaminergic loss in the more and less affected posterior dorsal putamen was 6.1 years. The estimated individual time points within the entire disease course were correlated with the motor severity.Our temporal trajectory model demonstrated a sequential loss of dopaminergic input in the striatal subregions in PD and may be beneficial for the evaluation of individual status of disease progression.

Purpose A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are tau PET–negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET–positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. Methods We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. Results Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan. Conclusion We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.

Background The clinical features of Alzheimer’s disease (AD) vary substantially depending on whether the onset of cognitive deficits is early or late. The amount and distribution patterns of tau pathology are thought to play a key role in the clinical characteristics of AD, which spreads throughout the large-scale brain network. Here, we describe the differences between tau-spreading processes in early- and late-onset symptomatic individuals on the AD spectrum. Methods We divided 74 cognitively unimpaired (CU) and 68 cognitively impaired (CI) patients receiving 18F-flortaucipir positron emission tomography scans into two groups by age and age at onset. Members of each group were arranged in a pseudo-longitudinal order based on baseline tau pathology severity, and potential interregional tau-spreading pathways were defined following the order using longitudinal tau uptake. We detected a multilayer community structure through consecutive tau-spreading networks to identify spatio-temporal changes in the propagation hubs. Results In each group, ordered tau-spreading networks revealed the stage-dependent dynamics of tau propagation, supporting distinct tau accumulation patterns. In the young CU/early-onset CI group, tau appears to spread through a combination of three independent communities with partially overlapped territories, whose specific driving regions were the basal temporal regions, left medial and lateral temporal regions, and left parietal regions. For the old CU/late-onset CI group, however, continuation of major communities occurs in line with the appearance of hub regions in the order of bilateral entorhinal cortices, parahippocampal and fusiform gyri, and lateral temporal regions. Conclusion Longitudinal tau propagation depicts distinct spreading pathways of the early- and late-onset AD spectrum characterized by the specific location and appearance period of several hub regions that dominantly provide tau.

BackgroundStudies of secondary movement disorder (MD) caused by cerebrovascular diseases have primarily focused on post-stroke MD. However, MD can also result from cerebral artery stenosis (CAS) without clinical manifestations of stroke. In this study, we aimed to investigate the clinical characteristics of MD associated with CAS.Materials and MethodsA nationwide multicenter retrospective analysis was performed based on the data from patients with CAS-associated MDs from 16 MD specialized clinics in South Korea, available between January 1999 and September 2019. CAS was defined as the >50% luminal stenosis of the major cerebral arteries. The association between MD and CAS was determined by MD specialists using pre-defined clinical criteria. The collected clinical information included baseline demographics, features of MD, characteristics of CAS, treatment, and MD outcomes. Statistical analyses were performed to identify factors associated with the MD outcomes.ResultsThe data from a total of 81 patients with CAS-associated MD were analyzed. The mean age of MD onset was 60.5 ± 19.7 years. Chorea was the most common MD (57%), followed by tremor/limb-shaking, myoclonus, and dystonia. Atherosclerosis was the most common etiology of CAS (78%), with the remaining cases attributed to moyamoya disease (MMD). Relative to patients with atherosclerosis, those with MMD developed MD at a younger age (p < 0.001) and had a more chronic mode of onset (p = 0.001) and less acute ischemic lesion (p = 0.021). Eight patients who underwent surgical treatment for CAS showed positive outcomes. Patients with acute MD onset had a better outcome than those with subacute-to-chronic MD onset (p = 0.008).ConclusionsThis study highlights the spectrum of CAS-associated with MD across the country. A progressive, age-dependent functional neuronal modulation in the basal ganglia due to CAS may underlie this condition.

Background Physical activity has been suggested to prevent the conversion of mild cognitive impairment (MCI) to dementia in patients. We investigated the association between the continuance and regularity of physical activity and the risk of developing dementia in patients with MCI. Methods We analyzed 6-year followed up data for 247,149 individuals in the National Health Insurance Service (NHIS) cohort of Korea who were enrolled between January 1, 2009, and December 31, 2015. The patients were divided into four groups: those who did not engage in physical activity consistently (Never-PA group), those who initiated physical activity (Initiation-PA group), those who ceased physical activity (Withdrawal-PA group), and those who performed physical activity consistently (Maintenance-PA group). We also divided the patients into two groups: those who engaged in physical activity irregularly (Irregular-PA) and those who undertook physical activity regularly (Regular-PA). Results When the risk for the Never-PA group was set as the benchmark (ref = 1), the Maintenance-PA group had the lowest incidence of dementia of the Alzheimer type (DAT) compared to the other groups (HR = 0.82, 95% CI 0.79–0.86). The DAT risk of the Initiation-PA group (HR = 0.89, 95% CI 0.85–0.93) was lower than the Never-PA group. In addition, compared to the Irregular-PA group, the Regular-PA group had a 15% reduced risk for developing DAT. Conclusions Although no causal inference could be made, continued regular physical activity in patients with MCI is associated with a protective effect against developing DAT. Moreover, ceasing physical activity could halt this protective effect.

Introduction Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) "typical", (2) "limbic-predominant", (3) "hippocampal-sparing", and (4) "mild atrophy". We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes. Methods The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β–positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. Results Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline. Discussion Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.

Despite recent studies suggesting a declining incidence and prevalence of dementia on a global scale, epidemiologic results with respect to Alzheimer's disease (AD) are lacking due to the methodological limitations inherent to conducting large-scale cohort investigations of this topic. The aim of the current study was to investigate the incidence and prevalence of AD in Korea. We conducted a secondary analysis within the National Health Insurance System (NHIS) database, a unique resource that reports medical information for the entire Korean population. AD diagnoses as well as evaluations of vascular risks were defined based on International Statistical Classification of Diseases (ICD-10) codes along with prescription records. The cut-off age for diagnosing AD was defined as the age of the patient's highest Youden index. In this study, the incidence and prevalence of AD in the Korean population aged 40 years or older showed an overall increase between 2006 and 2015. Although both older and younger age groups showed an increase in the incidence and prevalence of AD, the highest increase was observed in older age groups. Based on the highest Youden's index value (sensitivity + specificity – 1), the cut-off value for the diagnosis of AD was 69 years with an area under the curve (AUC) of 0.92. We found that the incidence of AD was higher in individuals with underlying vascular risks. However, in recent years, the prevalence of AD was conversely found to be lower in individuals with hypertension or dyslipidemia. Despite efforts toward reducing the number of AD cases through educational, policy, and various public health and preventive medicine interventions, the incidence and prevalence of AD continues to grow in Korea. Efforts aimed at early diagnosis and the modification of underlying risks may be critical to reducing the socioeconomic burden of AD.

To estimate dopaminergic dysfunction in patients with Parkinson disease (PD) during the premotor stage and to investigate the effect of genetic factors on the trajectories. Using longitudinal dopamine transporter single-photon emission computed tomography data from 367 sporadic PD (sPD), 72 LRRK2 (G2019S), and 39 GBA (N370S) PD patients in the Parkinson’s Progression Markers Initiative (PPMI) study, we estimated the temporal trajectories of putaminal-specific binding ratios using an integrating function between baseline values and their annual change rates. In order to test reproducibility, we computed another trajectory for sPD using positron emission tomography data of 38 sPD patients at Gangnam Severance Hospital (GSH). Temporal trajectories of sPD were compared between the groups separated by age at onset (AAO) and polygenic load for common PD risk variants, and also compared with genetic PD. sPD patients in both the PPMI and GSH cohorts showed similar onset of dopaminergic degeneration around 10 years before motor onset. Early-onset PD patients exhibited later onset of degeneration and a faster decline in dopaminergic activity during the premotor period than late-onset patients. sPD patients with high polygenic load were associated with earlier onset and slower progression of dopaminergic dysfunction. Compared to the sPD and LRRK2 PD groups, GBA PD patients exhibited faster deterioration of dopaminergic function during the premotor stage. Dopaminergic dysfunction in PD appears to start about 10 years before motor onset. Genetic factors may be contributing to the heterogeneity of dopaminergic deterioration during the premotor stage.

Full dynamics of biofluid biomarkers have been unknown in patients with Parkinson’s disease (PD). Using data from 396 PD patients and 182 controls in the Parkinson's Progression Markers Initiative (PPMI) database, we estimated long-term temporal trajectories of CSF α-synuclein (α-syn), amyloid-β (Aβ), total tau (t-tau), phosphorylated tau (p-tau) and serum neurofilament light chain (NfL) by integrating function between the baseline levels and annual changes. At baseline, PD patients showed lower CSF α-syn, Aβ, t-tau and p-tau levels than those of the controls. In all PD patients, CSF α-syn and Aβ decreased in a negative exponential pattern before the onset of motor symptoms, whereas CSF t-tau and p-tau, and serum NfL increased. Patients with cognitive impairment exhibited faster decline of Aβ and α-syn and faster rise of t-tau, p-tau and NfL, when compared to those without. Similarly, low Aβ group showed earlier decline of α-syn, faster rise of t-tau, p-tau and NfL, and faster decline of cognitive performances, when compared to high Aβ group. Our results suggest that longitudinal changes in biomarkers can be influenced by cognitive impairment and Aβ burden at baseline. PD patients with Aβ pathology may be associated with early appearance of α-synuclein pathology, rapid progression of axonal degeneration and neurodegeneration, and consequently greater cognitive decline.

Background and purpose High uric acid (UA) levels have been shown to exert a neuroprotective effect in Parkinson's disease (PD) by inhibiting oxidative stress in the nigrostriatal pathway. However, the association between striatal dopamine activity and UA level has not been clarified. Methods A total of 213 patients with early PD were enrolled. All patients underwent positron emission tomography using 18 F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and a venous blood test for quantification of serum UA. All patients were stratified into either the lower UA group or the higher UA group using the median UA level. After normalizing the positron emission tomography images, differences in the regional standardized uptake value ratios (SUVRs) were analyzed with a volume-of-interest template. All tested SUVRs were also compared after categorizing patients by gender. Results The UA affected dopamine transporter SUVRs in different ways by gender. In female patients, the higher UA level group showed a smaller reduction in dopamine transporter uptake in the posterior putamen, whereas there was no such association observed in male patients. Conclusions Higher UA levels were correlated with higher dopamine transporter uptake in the putamen in female patients with early PD. This finding suggests that UA has a neuroprotective effect, as demonstrated by the relatively preserved striatal dopamine activity in women.

Introduction Dopamine transporter imaging and myocardial 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy have been widely used to diagnose and discriminate degenerative parkinsonism. Many studies have reported that both imaging findings are associated with a variety of motor and non-motor phenomena in Parkinson's disease (PD). However, the association between striatal dopamine activity and myocardial 123I-MIBG uptake has not been well investigated. The objective of this study is to identify the dopamine transporter activity of the corpus striatum and thalamus according to myocardial 123I-MIBG uptake in PD. Methods Ninety-six newly diagnosed, non-medicated PD patients were enrolled. All patients underwent 123I-MIBG myocardial scintigraphy, positron emission tomography (PET) using 18F N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and T1-weighted magnetic resonance imaging (MRI). Patients were stratified into normal and decreased 123I-MIBG groups according to their delayed heart-to-mediastinum ratio (cutoff value = 1.78). After normalizing the PET images with spatially normalized MRI, the regional standardized uptake value ratios (SUVRs) were analyzed with a volume-of-interest template between the two groups. Results Thirty-one patients showed normal myocardial 123I-MIBG uptake, and 65 patients showed reduced uptake. The SUVR of the globus pallidus in the group with reduced 123I-MIBG uptake was significantly lower than the SUVR in the normal 123I-MIBG uptake group. The heart-to-mediastinum ratio was correlated well with the SUVR of the globus pallidus, independent of age, disease duration, and the severity of motor symptoms. Conclusion Early PD patients with normal 123I-MIBG uptake showed a relatively preserved dopamine reserve in the globus pallidus than patients with reduced 123I-MIBG uptake.

Tau PET enables in vivo visualization and quantitation of tau accumulation in Alzheimer disease (AD). In cross-sectional tau PET studies, tau burden reflects disease severity and phenotypic variation. We investigated longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients with AD. Methods: We enrolled 107 participants (45 amyloid-β–negative cognitively unimpaired [CU−], 7 amyloid-β–positive cognitively unimpaired [CU+], 31 with prodromal AD [mild cognitive impairment; MCI+], and 24 with AD dementia [DEM+]) who completed 2 baseline PET scans ((18)F-flortaucipir and (18)F-florbetaben), MRI, and neuropsychologic tests. All participants underwent the same assessments after 2 y. After correcting for partial-volume effect, we created SUV ratio (SUVR) images. By using a linear mixed-effect model, we investigated the changes in SUVR across time within each group. We also investigated a correlation between the progression of tau accumulation and cognitive decline. Results: In contrast to no change in global cortical SUVR in the CU− and CU+ groups during the 2-y period, global cortical SUVR increased by 0.06 (2.9%) in the MCI+ group and 0.19 (8.0%) in the DEM+ group at follow-up. The MCI+ group was associated with additional tau accumulation predominantly in the medial and inferior temporal cortices, whereas the DEM+ group showed increases in the lateral temporal cortex. Progressive tau accumulation occurred in the diffuse cortical areas in the MCI+ patients who developed dementia and the DEM+ patients who showed deterioration of global cognition, whereas there was only a small increase of additional tau accumulation in the lateral temporal cortex in those who did not show worsening of cognition. Deterioration of global cognition and language functions was associated with progression of diffuse tau accumulation in the association neocortex. Conclusion: Progressive tau accumulation occurs in prodromal AD and DEM patients in the cortical areas at different levels of tau accumulation. Progression of cognitive dysfunction may be related to the additional tau accumulation in regions of higher Braak stage. (18)F-flortaucipir PET is an imaging biomarker for monitoring the progression of AD.

This study aimed to evaluate the effect of levodopa on the phase coordination index (PCI) and gait asymmetry (GA) of patients with Parkinson’s disease (PD) and to investigate correlations between the severity of motor symptoms and gait parameters measured using an inertial sensor. Twenty-six patients with mild-to-moderate-stage PD who were taking levodopa participated in this study. The Unified Parkinson’s Disease Rating Scale part III (UPDRS III) was used to assess the severity of motor impairment. The Postural Instability and Gait Difficulty (PIGD) subscore was calculated from UPDRS III. Patients were assessed while walking a 20-m corridor in both “OFF” and “ON” levodopa medication states, and gait analysis was performed using inertial sensors. We investigated the changes in gait parameters after taking levodopa and the correlations between UPDRS III, PIGD, and gait parameters. There was a significant improvement in PCI after taking levodopa. No significant effect of levodopa on GA was found. In “OFF” state, PCI and GA were not correlated with UPDRS III and PIGD. However, in “ON” state, PCI was the only gait parameter correlating with UPDRS III, and it was also highly correlated with PIGD compared to other gait parameters. Significant improvement in bilateral-phase coordination was identified in patients with PD after taking levodopa, without significant change in gait symmetricity. Considering the high correlation with UDPRS III and PIGD in “ON” states, PCI may be a useful and quantitative parameter to measure the severity of motor symptoms in PD patients who are on medication.

This study aimed to investigate the risk and prognosis of Alzheimer's disease (AD) and vascular dementia (VaD) in patients with insomnia using the National Health Insurance Service database covering the entire population of the Republic of Korea from 2007 to 2014. In total, 2,796,871 patients aged 40 years or older with insomnia were enrolled, and 5,593,742 controls were matched using a Greedy digit match algorithm. Mortality and the rate of admission to a long-term care facility were estimated using multivariable Cox analysis. Of all patients with insomnia, 138,270 (4.94%) and 26,706 (0.96%) were newly diagnosed with AD and VaD, respectively. The incidence rate ratios for AD and VaD were 1.73 and 2.10, respectively, in patients with insomnia compared with those without. Higher mortality rates and long-term care facility admission rates were also observed in patients with dementia in the insomnia group. Known cardiovascular risk factors showed interactions with the effects of insomnia on the risk of AD and VaD. However, the effects of insomnia on the incidence of AD and VaD were consistent between the groups with and without cardiovascular risk factors. Insomnia is a medically modifiable and policy-accessible risk factor and prognostic marker of AD and VaD.

Background We aimed to investigate the clinical correlates of principal components (PCs) of tau positron emission tomography (PET) and their predictability for longitudinal changes in tau accumulation in Alzheimer’s disease (AD). Methods We enrolled 272 participants who underwent two PET scans [18F-flortaucipir for tau and 18F-florbetaben for amyloid-β (Aβ)], brain magnetic resonance imaging, and neuropsychological tests as baseline assessments. Among them, 187 participants underwent the same follow-up assessments after an average of 2 years. Using Aβ-positive AD dementia-specific PCs obtained from the baseline scans of 56 Aβ-positive patients with AD dementia, we determined the expression of the first two PCs (PC1 and PC2) in all participants. We assessed the correlation of PC expression with baseline clinical characteristics and tau accumulation rates. Moreover, we investigated the predictability of PCs for the longitudinal tau accumulation in training and test sets. Results PC1 corresponded to the tau distribution pattern in AD, while the two PC2 extremes reflected the parietal or temporal predominance of tau distribution. PC1 expression increased with tau burden and decreased with cognitive impairment, while PC2 expression decreased with advanced age and visuospatial and attention function deterioration. The tau accumulation rate was positively correlated with PC1 expression (greater tau burden) and negatively correlated with PC2 expression (temporal predominance). A regression model using both PCs could predict longitudinal changes in the tau burden (intraclass correlation coefficient = 0.775, R2 = 0.456 in test set). Conclusions PC analysis of tau PET could be useful for evaluating disease progression, characterizing the tau distribution pattern, and predicting longitudinal tau accumulation.

Background To assess the effects of apolipoprotein E (ApoE) ε4 genotype on amyloid-β (Aβ) and tau burden and their longitudinal changes in Alzheimer’s disease (AD) spectrum. Methods Among 272 individuals who underwent PET scans (18F-florbetaben for Aβ and 18F-flortaucipir for tau) and ApoE genotyping, 187 individuals completed 2-year follow-up PET scans. After correcting for the partial volume effect, we compared the standardized uptake value ratio (SUVR) for Aβ and tau burden between the ε4+ and ε4− groups. By using a linear mixed-effect model, we measured changes in SUVR in the ApoE ε4+ and ε4− groups. Results The ε4+ group showed greater baseline Aβ burden in the diffuse cortical regions and greater tau burden in the lateral, and medial temporal, cingulate, and insula cortices. Tau accumulation rate was higher in the parietal, occipital, lateral, and medial temporal cortices in the ε4+ group. In Aβ+ individuals, baseline tau burden was greater in the medial temporal cortex, while Aβ burden was conversely greater in the ε4− group. Tau accumulation rate was higher in the ε4+ group in a small region in the lateral temporal cortex. The effect of ApoE ε4 on enhanced tau accumulation persisted even after adjusting for the global cortical Aβ burden. Conclusions Progressive tau accumulation may be more prominent in ε4 carriers, particularly in the medial and lateral temporal cortices. ApoE ε4 allele has differential effects on the Aβ burden depending on the existing amyloidosis and may enhance vulnerability to progressive tau accumulation in the AD spectrum independent of Aβ.

Odor identification ability may serve as an important diagnostic biomarker in Alzheimer’s disease (AD). The aim of the study is to investigate the contribution of A/T/N neuroimaging biomarkers to impaired odor identification ability in the Alzheimer’s disease spectrum. In 127 participants, we compared A/T/N neuroimaging biomarkers between normosmia and hyposmia groups, and performed correlation analysis between the biomarkers and Cross-Cultural Smell Identification Test (CCSIT) scores. Additionally, path analysis for odor identification ability was performed using cognitive function as a mediator. In between-group comparison, individuals with hyposmia showed higher frequency of amyloid-β (Aβ) positivity, and lower neuropsychological test performance than those with normosmia. After correction for covariates including total cognition scores, there was no difference in the Aβ or tau burden between the normosmia and hyposmia groups, and no correlation between CCSIT scores and Aβ or tau burden. Meanwhile, cortical volumes in the lateral and medial temporal cortices were smaller in the hyposmia group and decreased with the worsening of CCSIT scores. Path analysis showed that only neurodegeneration had a direct effect on odor identification, while Aβ and tau burden contributed to odor identification with the mediation of cognition. In the Alzheimer’s disease spectrum, impaired odor identification ability may be attributable to neurodegeneration rather than the direct effect of Aβ or tau burden.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis. ispartof: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM vol:40 issue:8 pages:1576-1585 ispartof: location:United States status: published

Introduction Olfactory dysfunction is a sensitive biomarker of neurodegeneration and a cardinal premotor symptom of Parkinson's disease (PD). Although several non-motor symptoms of PD have been correlated with decreased dopamine transporter uptake, olfactory dysfunction and reduced dopamine transporter uptake have not been widely investigated in PD. In this study, we aimed to identify the dopamine transporter status of the corpus striatum and thalamus using a magnetic resonance imaging (MRI)-guided spatial normalization method in patients with PD according to olfactory function. Methods Among 87 PD patients, 50 had hyposmia and 37 had normosmia. All patients underwent positron emission tomography (PET) using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (18F-FP-CIT) and T1-weighted MRI. PET images were normalized with simultaneously performed spatially normalized MRI and the regional standardized uptake value ratios (SUVR) with a volume of interest template were compared according to olfactory function. Results The bilateral caudates and the left anterior and posterior putamen of the hyposmic group showed significantly reduced dopamine transporter uptake compared to the normosmic group. In partial correlation coefficient analysis, olfactory identification impairment was correlated with the SUVR values of the caudate nuclei. Conclusion More dopaminergic impairment of the bilateral caudate nuclei was found in hyposmic PD. This finding suggests that decreased dopamine uptake in the caudate nucleus may be an imaging trace of olfactory dysfunction in patients with PD.

In recent years, several radiotracers that selectively bind to pathological tau proteins have been developed. Evidence is emerging that binding patterns of in vivo tau positron emission tomography (PET) studies in Alzheimer’s disease (AD) patients closely resemble the distribution patterns of known neurofibrillary tangle pathology, with the extent of tracer binding reflecting the clinical and pathological progression of AD. In Lewy body diseases (LBD), tau PET imaging has clearly revealed cortical tau burden with a distribution pattern distinct from AD and increased cortical binding within the LBD spectrum. In progressive supranuclear palsy, the globus pallidus and midbrain have shown increased binding most prominently. Tau PET patterns in patients with corticobasal syndrome are characterized by asymmetrical uptake in the motor cortex and underlying white matter, as well as in the basal ganglia. Even in the patients with multiple system atrophy, which is basically a synucleinopathy, 18F-flortaucipir, a widely used tau PET tracer, also binds to the atrophic posterior putamen, possibly due to off-target binding. These distinct patterns of tau-selective radiotracer binding in the various degenerative parkinsonisms suggest its utility as a potential imaging biomarker for the differential diagnosis of parkinsonisms.

Background In addition to Lewy body pathology, amyloid-β plaques and neurofibrillary tangles that are characteristic for Alzheimer's disease are also frequently found in Lewy body diseases. Objectives The objective of this study was to investigate tau accumulation patterns in dementia with Lewy bodies and other Lewy body diseases using in vivo 18 F-AV-1451 PET. Methods The study included 12 Parkinson's disease (PD) patients with normal cognition, 22 PD patients with cognitive impairment, and 18 dementia with Lewy bodies patients. In addition, 25 Alzheimer's disease patients and 25 healthy controls were included for comparison. All participants underwent 18 F-AV-1451 and 18 F-florbetaben PET scans, and cortical binding values were compared between the controls and each disease group. Results When compared with the controls, dementia with Lewy bodies patients showed slightly increased 18 F-AV-1451 binding in the primary sensorimotor and visual cortices and the parieto-temporal cortices, which failed to survive multiple comparisons. Amyloid-positive dementia with Lewy bodies patients showed significantly increased binding in the same regions when compared with controls, and even greater binding in the primary sensorimotor and visual cortices than Alzheimer's disease. Meanwhile, binding in the lateral and medial temporal cortices was less prominent than in Alzheimer's disease. In dementia with Lewy bodies, 18 F-AV-1451 binding in the occipital cortex correlated with 18 F-florbetaben binding. Amyloid-negative patients with normal cognition, patients with cognitive impairment, and dementia with Lewy bodies patients did not show increased 18 F-AV-1451 binding. Conclusions Dementia with Lewy bodies patients may harbor 18 F-AV-1451 binding patterns distinct from Alzheimer's disease, with greater involvement of the primary cortices and less involvement of the temporal cortex. Tau burden increases in the Lewy body disease spectrum, and amyloid may play an important role in the accumulation of neocortical tau in Lewy body diseases. © 2017 International Parkinson and Movement Disorder Society.

Background Rare patients have been reported who developed a mixture of gait disturbances following a focal lesion in the frontal lobe. Thus, the exact location of frontal lesion responsible for a specific gait disturbance is not well defined. Case presentation We describe a 47-year-old man who experienced two episodes of paroxysmal freezing of gait of the right leg. During the attacks, he had no motor weakness, sensory change, or disequilibrium. He had past history of panic attacks. Recently, he had been under severe emotional stress. T2 and diffusion brain magnetic resonance imaging scans were normal. So far, the most likely clinical diagnosis might be functional freezing of gait. However, magnetic resonance angiography showed atherosclerosis in the proximal left anterior cerebral artery. Perfusion scans showed a delayed mean transit time in the left mesial frontal lobe. He developed two more attacks during the four months of follow up. Conclusions The presented case illustrates that the mesial frontal lobe may be important in the pathophysiology of freezing of gait. We speculate that the supplementary motor area may generate a neuronal command for the initiation of locomotion that in our case may have been inhibited by a transient ischemia.

Background THK5351 and flortaucipir tau ligands have high affinity for paired helical filament tau, yet diverse off-target bindings have been reported. Recent data support the hypothesis that THK5351 binds to monoamine oxidase B (MAO-B) expressed from reactive astrocytes and that flortaucipir has an affinity toward MAO-A and B; however, pathological evidence is lacking. We performed a head-to-head comparison of the two tau ligands in a sporadic Creutzfeldt-Jakob disease (CJD) patient and performed an imaging-pathological correlation study. Case presentation A 67-year-old man visited our clinic a history of 6 months of rapidly progressive dementia, visual disturbance, and akinetic mutism. Diffusion-weighted imaging showed cortical diffusion restrictions in the left temporo-parieto-occipital regions. 18F-THK5351 PET, but not 18F-flortaucipir PET showed high uptake in the left temporo-parieto-occipital regions, largely overlapping with the diffusion restricted areas. Cerebrospinal fluid analysis was weakly positive for 14–3-3 protein and pathogenic prion protein was found. The patient showed rapid cognitive decline along with myoclonic seizures and died 13 months after his first visit. A post-mortem study revealed immunoreactivity for PrPsc, no evidence of neurofibrillary tangles, and abundant astrocytosis which was reactive for MAO-B antibody. Conclusions Our findings add pathological evidence that increased THK5351 uptake in sporadic CJD patients might be caused by an off-target binding driven by its high affinity for MAO-B. Electronic supplementary material The online version of this article (10.1186/s12883-019-1434-z) contains supplementary material, which is available to authorized users.

Brain inflammation is associated with various types of neurodegenerative diseases, including Alzheimer disease (AD). Quantifying inflammation with PET is a challenging and invasive procedure, especially in frail patients, because it requires blood sampling from an arterial catheter. A widely used alternative to arterial sampling is a supervised clustering algorithm (SVCA), which identifies the voxels with minimal specific binding in the PET images, thus extracting a reference region for noninvasive kinetic modeling. Methods: We tested this algorithm on a large population of subjects injected with the translocator protein radioligand (11)C-PBR28 and compared the kinetic modeling results obtained with the gold standard of arterial input function (V(T)/f(p)) with those obtained by SVCA (distribution volume ratio [DVR] with Logan plot). The study comprised 57 participants (21 healthy controls, 11 mild cognitive impairment patients, and 25 AD patients). Results: We found that V(T)/f(p) was greater in AD patients than in controls in the inferior parietal, combined middle and inferior temporal, and entorhinal cortices. SVCA-DVR identified increased binding in the same regions and in an additional one, the parahippocampal region. We noticed however that the average amplitude of the reference curve obtained from subjects with genetic high-affinity binding for (11)C-PBR28 was significantly larger than that from subjects with moderate affinity. This suggests that the reference curve extracted by SVCA was contaminated by specific binding. Conclusion: SVCA allows the noninvasive quantification of inflammatory biomarker translocator protein measured with (11)C-PBR28 but without the need of arterial sampling. Although the reference curves were contaminated with specific binding, the decreased variance of the outcome measure, SVCA DVR, allowed for an apparent greater sensitivity to detect regional abnormalities in brains of patients with AD.

Depression can occur before the onset of motor symptoms in Parkinson's disease (PD) patients. The pathophysiology of depression in PD involves various brain regions and relevant functional circuits. This study investigated whether there exist distinctive patterns of presynaptic monoamine transporter densities in the basal ganglia depending on the degree of depression in patients with PD. A total of 123 early and drug-naïve PD patients were enrolled. Their affective status was evaluated by the Montgomery–Asberg Depression Rating Scale (MADRS), and subjects were subgrouped into one of the following three groups according to their MADRS scores: no depression, mild depression, and moderate-to-severe depression. All patients underwent positron emission tomography (PET) using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane. The PET images were normalized, and differences in the regional standardized uptake value ratios (SUVRs) for each side of the caudate, putamen, globus pallidus, thalamus, and ventral striatum were analyzed and compared between the three groups. A trend analysis was performed across the groups to discern any associations between SUVR values of the basal ganglia and depression severity. The SUVR values of the caudate, anterior caudate nuclei, and ventral striatum declined as MADRS increased. The SUVR values of the striatum showed an inverse dose-dependent trend of antero- and ventroposterior gradient across the groups. This result indirectly revealed the involvement of the associative and limbic circuitry of the brain that are modulated by monoamines in early PD with depression. This might suggest an in vivo causal relationship between the ventral striatum, caudate and depression.

Of the two 18F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [18F]FPEB is reportedly superior because [18F]SP203 undergoes glutathionlyation, generating [18F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [11C]FPEB and [11C]SP203 from [11C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake ( BPND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [11C]SP203, like [18F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume ( VT) over the scan period. Absolute VT values were ∼30% lower for 11C-labeled compared with 18F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the 11C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for 11C-ligands. Thus, the evidence suggests that [11C]FPEB is superior to [11C]SP203. If prepared in higher specific activity, [11C]FPEB would presumably be as effective as [18F]FPEB for quantifying mGluR5 in human brain.

Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited disorders characterized by iron deposition in the brain, and NBIA exhibits the clinical features of movement disorders [1]. Over the last decade, several causative genes, directly involved in iron homeostasis, mitochondrial function, lipid metabolism, and autophagic activity, have been identified including FTL, CP, PANK2, PLA2G6, C19orf12, COASY, FA2H, WDR45, and ATP13A2 [2]. Of the known causes of NBIA, the most common cause of NBIA is pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in the PANK2 gene, followed by PLA2G6-related neurodegeneration (PLAN) due to mutations in the PLA2G6 gene [1,3]. The diagnosis of NBIA is made by combining clinical features and magnetic resonance imaging evidence of iron accumulation in the brain [3]. NBIA patients commonly exhibit mixed extrapyramidal and pyramidal features [1,4]. However, the clinical spectrum ranges from global neurodevelopmental delay in infancy to dystonia-parkinsonism in adulthood, with wide phenotypic variability within the specific NBIA subtypes [1,3,5]. In PKAN, the classic form is characterized by early childhood onset with rapid progression [1,6]. The atypical variant presents in the second or third decade of life with less severe and slow-progressive extrapyramidal and pyramidal signs [1,6]. Cognitive impairment and neuropsychiatric symptoms may be prominent [1,6]. Similar age-dependent presentations have also been recognized in PLAN [1,3,4]. Adult-onset NBIA may also mimic the clinical presentations of other neurodegenerative diseases, making the diagnosis challenging [4]. To date, reports on the clinical and genetic profile of Korean patients with NBIA have been restricted to single cases or case series that were lacking in detailed data [7-18]. To investigate the current status of NBIA in Korea, we collected NBIA data from twelve nationwide referral hospitals and from a review of the literature. We also conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical PKAN.

Impaired finger dexterity occurs in Parkinson's disease (PD) and has been considered a limb-kinetic apraxia associated with primary sensory cortical dysfunction. To study the role of nigrostriatal dopamine loss and elementary parkinsonian motor deficits in impaired finger dexterity of PD. Thirty-two right-handed untreated PD patients and 30 right-handed healthy controls were included. All patients underwent [18F] FP-CIT positron emission tomography studies. We examined the associations among unilateral coin rotation (CR) score, Unified Parkinson's Disease Rating Scale (UPDRS) subscores for bradykinesia and rigidity of the corresponding arm, and contralateral regional striatal dopamine transporter (DAT) uptake. We also measured the effect of oral levodopa dose on CR scores and UPDRS subscores. PD patients performed worse than controls on the CR task. Unilateral arm UPDRS bradykinesia scores were associated with DAT uptake in the contralateral putamen. The left CR score was associated with left arm bradykinesia and rigidity scores and DAT uptake in the right posterior putamen, whereas no such associations were found for the right CR score. There was a significant effect of handedness on the association of putamen DAT uptake with CR scores, but not with UPDRS subscores. An oral levodopa challenge improved CR scores and UPDRS subscores on both sides. Impaired finger dexterity in PD is related to elementary parkinsonian motor deficits and nigrostriatal dopamine loss. Impaired dominant hand dexterity associated with nigrostriatal dopamine loss seems to be compensated to some extent by the dominant cerebral cortex specialized for controlling precise finger movements.

Introduction Weight loss in Parkinson's disease (PD) is associated with poorer clinical outcomes and rapid disease progression. However, it is unclear whether a longitudinal association between weight loss and striatal dopaminergic degeneration exists. Methods Using data from 171 PD patients in the Parkinson's Progression Markers Initiative (PPMI) cohort, we investigated longitudinal associations of change in body mass index (BMI) with striatal dopaminergic activity on 123I-N-3-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane (123I-FP-CIT) single positron emission computed tomography (SPECT). We defined BMI loss as a reduction in BMI value > 5% of baseline, and categorized the PD patients into 2 subgroups (patients with and without BMI loss). Linear mixed model (LMM) analysis was employed to compare the progression of striatal dopaminergic degeneration. Results In LMM analyses, BMI values in PD patients were not correlated with clinical severities of parkinsonian motor deficits, cognitive impairment and depressive mood. However, BMI values were positively associated with changes in striatal 123I-FP-CIT binding over 24 months (caudate nucleus, estimate = 9.37 × 10−3, p = 0.009; putamen, estimate = 7.04 × 10−3, p = 0.031). Patients with BMI loss exhibited greater deterioration of striatal dopaminergic activity than those without (caudate nucleus, estimate = 3.35 × 10−3, p = 0.008; putamen, estimate = 2.34 × 10−3, p = 0.025). Conclusion Our findings suggest a potential association between striatal dopaminergic activity with body weight or impairment in energy homeostasis. Body weight and its change may be a clinical biomarker reflecting striatal dopaminergic dysfunction in PD.

IMPORTANCE: The positron emission tomography (PET) tracer [(18)F]flortaucipir allows in vivo quantification of paired helical filament tau, a core neuropathological feature of Alzheimer disease (AD), but its diagnostic utility is unclear. OBJECTIVE: To examine the discriminative accuracy of [(18)F]flortaucipir for AD vs non-AD neurodegenerative disorders. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, 719 participants were recruited from 3 dementia centers in South Korea, Sweden, and the United States between June 2014 and November 2017 (160 cognitively normal controls, 126 patients with mild cognitive impairment [MCI], of whom 65.9% were amyloid-β [Aβ] positive [ie, MCI due to AD], 179 patients with AD dementia, and 254 patients with various non-AD neurodegenerative disorders). EXPOSURES: The index test was the [(18)F]flortaucipir PET standardized uptake value ratio (SUVR) in 5 predefined regions of interest (ROIs). Cut points for tau positivity were determined using the mean +2 SDs observed in controls and Youden Index for the contrast AD dementia vs controls. MAIN OUTCOMES AND MEASURES: The reference standard was the clinical diagnosis determined at the specialized memory centers. In the primary analysis, the discriminative accuracy (ie, sensitivity and specificity) of [(18)F]flortaucipir was examined for AD dementia vs all non-AD neurodegenerative disorders. In secondary analyses, the area under the curve (AUC) of [(18)F]flortaucipir SUVR was compared with 3 established magnetic resonance imaging measures (hippocampal volumes and AD signature and whole-brain cortical thickness), and sensitivity and specificity of [(18)F]flortaucipir in MCI due to AD vs non-AD neurodegenerative disorders were determined. RESULTS: Among 719 participants, the overall mean (SD) age was 68.8 (9.2) years and 48.4% were male. The proportions of patients who were amyloid-β positive were 26.3%, 65.9%, 100%, and 23.8% among cognitively normal controls, patients with MCI, patients with AD dementia, and patients with non-AD neurodegenerative disorders, respectively. [(18)F]flortaucipir uptake in the medial-basal and lateral temporal cortex showed 89.9% (95% CI, 84.6%-93.9%) sensitivity and 90.6% (95% CI, 86.3%-93.9%) specificity using the threshold based on controls (SUVR, 1.34), and 96.8% (95% CI, 92.0%-99.1%) sensitivity and 87.9% (95% CI, 81.9%-92.4%) specificity using the Youden Index–derived cutoff (SUVR, 1.27) for distinguishing AD dementia from all non-AD neurodegenerative disorders. The AUCs for all 5 [(18)F]flortaucipir ROIs were higher (AUC range, 0.92-0.95) compared with the 3 volumetric MRI measures (AUC range, 0.63-0.75; all ROIs P

Background PLA2G6 -associated neurodegeneration (PLAN) encompasses infantile- or atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism. Examination of the intrafamilial phenotypic variability of PLAN by neuroimaging data and background genetic differences has not been reported. Methods We report clinical, genetic (whole exome sequencing data), and neuroimaging findings from a Korean PLAN family showing intrafamilial phenotypic variability. Non-synonymous single nucleotide variants (SNVs) in Mendelian disorder genes related to parkinsonism, dystonia, ataxia, dementia or neurodegeneration with brain iron accumulation were compared between affected siblings. Results The proband presented with adult-onset dystonia-parkinsonism, whereas the affected brother presented with childhood-onset atypical neuroaxonal dystrophy. In the proband, an [ 18 F]FP-CIT PET study showed markedly reduced uptake in the whole putamen, but fluid attenuated inversion recovery and gradient echo MRI studies revealed mild hypointensities in the substantia nigra and the putamen and severe hypointensities in the pallidum. On the other hand, in the affected brother, MRI scans showed severe hypointensities in the substantia nigra and the pallidum, and a [ 18 F]-FP-CIT PET scan was normal. Analysis of the non-synonymous SNVs that were not shared between the two family members revealed non-synonymous SNVs related to parkinsonism including a novel heterozygous mutation (p.T44N) in FBX07 (PARK15) only in the proband, and non-synonymous SNVs related to neurodegeneration with brain iron accumulation in the affected brother. Conclusion Our data suggests that dopaminergic neuronal degeneration may not secondary to iron accumulation in PLAN. The burden of pathogenic SNVs may influence the intrafamilial phenotypic variability of PLAN.

Huntington’s disease (HD) is a well-known neurological disorder of inherited genetic cause, the incurable nature of which has made patients and doctors helpless. Even after the discovery of the CAG repeat expansion of the IT-15 gene in 1993, no satisfactory treatment has emerged [1]. In Korea, studies involving genetically confirmed HD patients were first published from 1996, and the first clinical analysis was presented in 1997 [2–5]. These studies showed that there were a number of genetically confirmed HD patients without a family history of the disease, and also revealed that caudate atrophy might be ambiguous even after several years of disease duration. Recently, decreased cortical glucose metabolism was suggested as a predictor of disease progression in Korean patients with HD [6]. However, the current status of HD in Korea requires additional investigation. Huntington’s disease is an example of a rare disease, which are also referred to as rare and intractable diseases or orphan diseases, and are defined as affecting fewer than 20,000 people in Korea (Korean Centers for Disease Control and Prevention, 2006) [7]. The Korean National Health Insurance (NHI) is a quasi-governmental organization supplying medical services for the entire Korean population, and its database contains a comprehensive dataset of its users. In July 2009, a nationwide registry for rare and intractable diseases (Rare Diseases Registry, RDR), was established by the Korean NHI in cooperation with the Ministry of Health and Welfare, and patients with HD have been registered in the RDR. The RDR database differs from the NHI database in that it gathers identifying information on each patient with a physician-certified diagnosis, making it possible to know the cumulative number of patients regardless of the usage of the NHI during a given period. Moreover, the annual incidence of diagnosis could be estimated by the number of newly registered patients with a given disease. To investigate the current status of HD in Korea, we collected data from 10 nationwide referral hospitals and used open data from the databases of the RDR and NHI.

The prognosis of focal hand dystonia (FHD) remains unclear. We retrospectively studied six patients with typist's cramp in our hospitals, and five cases in the PubMed database. All of them were right-handed. We compared clinical features between simple (dystonia in only one specific task), and dystonic/progressive groups (dystonia in several and/or new tasks). The initially affected right hand ratio was significantly higher in dystonic/progressive groups than in simple group (p=0.015). Initially affected hand may be a predictor for the progression, implying that the progression may be associated with the amount of daily routine hand movements.

Introduction To determine motor-related brain regions in which iron contents correlate with the degree of motor deficits of progressive supranuclear palsy (PSP). Methods Twenty-four patients with probable PSP and 20 controls were included. Using a 3.0T magnetic resonance imaging scanner, R2* values were measured in the putamen, globus pallidus (GP), substantia nigra (SN), subthalamic nucleus, and dentate nucleus. After adjustment for disease duration and age at examination, correlations between regional brain R2* values and Unified Parkinson Disease Rating Scale (UPDRS) total motor scores or subscores for bradykinesia, rigidity, tremor, or axial motor deficits were investigated. Results Compared to controls, patients with PSP had significantly higher R2* values in all of the five brain regions. UPDRS total motor scores and subscores for bradykinesia and axial motor deficits did not correlate with R2* values of the five brain regions. However, UPDRS subscores for unilateral rigidity were correlated with R2* values of the contralateral putamen and GP. In addition, unilateral UPDRS subscores for tremor were associated with R2* values of the ipsilateral dentate nucleus, contralateral putamen, GP, and SN. Conclusion In PSP, excessive iron accumulation occurs in motor-related subcortical regions. Iron-related PSP pathologies in the lenticular nucleus are associated with rigidity severity, while those in the nigro-striato-pallidal unit and dentate nucleus are associated with tremor severity. Bradykinesia and axial motor deficits of PSP seem to be associated with widespread pathologies in the cerebrum, brainstem, cerebellum, as well as the basal ganglia.

Objective: To define the significance of striatal cribriform state (SCS) observed in patients with primary progressive parkinsonism. Methods: We reviewed medical records and brain magnetic resonance imaging studies of 1,260 patients with primary progressive parkinsonism. We identified 23 patients with SCS and analyzed their clinical features. Results: All 23 patients had rapidly progressive parkinsonism predominated by postural instability and gait disturbance. Clinical features of 18 of the 23 patients were compatible with progressive supranuclear palsy (PSP); 2 patients were compatible with parkinsonian type multiple system atrophy; 2 patients were compatible with mixed clinical features of both; and 1 patient had PSP-like clinical features. Conclusions: Most parkinsonian patients with SCS present rapidly progressive parkinsonism predominated by postural instability and gait disturbance. SCS observed in patients with parkinsonism does not seem to be a coincidental finding associated with the generalized cerebrovascular process.

Objective Patients with drug-induced parkinsonism (DIP) may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP. Methods Forty-one DIP patients were classified into normal and abnormal [18F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied. Results Twenty-eight patients had normal (Group I) and 13 patients had abnormal (Group II) scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040). Three patients of Group I and six of Group II had hyposmia (p = 0.018). After drug withdrawal, Group I showed greater improvement in Unified Parkinson’s Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity. Conclusion None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP.

Aside from the glucocerebrosidase gene, the genetic risk factors for cognitive decline in Parkinson's disease (PD) are controversial. We investigated whether the G2385R polymorphism in leucine-rich repeat kinase 2 gene (LRRK2), a risk variant for the development of PD in East Asians, is associated with cognitive dysfunction in PD. We recruited 299 PD patients, consisting of 23 carriers and 276 non-carriers of LRRK2 G2385R, from 14 centers. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). PD with cognitive dysfunction was defined as an MMSE Z score that, adjusting for age at study entry and years of education, was below -1.0 standard deviations. In multivariate analysis, PD duration, age at study entry and depression were significant risk factors for cognitive dysfunction as assessed by MMSE performance or the MoCA. In linear regression analysis of the association between MMSE Z scores and PD duration, there was no significant difference associated with the LRRK2 G2385R genotype. The interaction terms between PD duration and the LRRK2 G2385R genotype were not significant for the MMSE Z score but were significant for the MoCA. In conclusion, the LRRK2 G2385R genotype may not be associated with cognitive dysfunction in PD.

Introduction Sensory information is essential for the precise control of movement. Patients with Parkinson’s disease (PD) have higher-order sensory dysfunctions including prolonged temporal discrimination threshold (TDT). However, the impact of prolonged TDT on parkinsonian motor deficits is uncertain. Methods This study includes 33 PD patients and 24 healthy controls. TDT values were measured in the index finger. Using coin rotation task (CRT), dexterous finger movement was assessed. Using an inertial sensor, the speed, amplitude, and frequency of finger tapping were measured. The impact of prolonged index finger TDT on two different finger movements was analyzed using the general estimating equation. Results Compared to healthy controls, TDT was prolonged in the PD patients. There was no impact of TDT on mean values or decrement for amplitude and speed, as well as mean values, decrement and variability of tapping frequency. However, prolonged TDT had a significant impact on the variability in amplitude (B = 436.905 × 10−4, Wald χ2 = 9.140, p = 0.014) and speed (B = 425.655 × 10−4, Wald χ2 = 9.876, p = 0.014) of finger tapping. There was a marginal correlation between TDT and CRT. In addition, CRT correlated with variability in amplitude and speed of finger tapping. Conclusion In PD, cutaneous temporal discriminative sensory dysfunction appears to be related to increased variabilities in the speed and amplitude of fast repetitive finger movements and disturbed finger dexterity.

Objectives Patients with Parkinson's disease (PD) have higher-order discriminative sensory dysfunction including prolonged somesthetic temporal discrimination threshold (sTDT). We studied the effect of striatal dopamine loss on the prolongation of sTDT and also studied the impact of prolonged sTDT values on the various parkinsonian motor deficits. Materials and Methods In 30 patients with PD, the severity of parkinsonian motor deficits was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores during levodopa off and on periods. The UPDRS motor subscores were calculated, representing bradykinesia, rigidity, tremor, and axial motor deficits. During levodopa off and on periods, the sTDT value of each index finger was studied. Using [18F]-N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane (FPCIT) positron emission tomography studies, caudate and putaminal dopamine transporter uptake levels were measured. Multiple regression analysis covariated with age was used for statistical analysis. Results During the off period, the striatal FPCIT uptake levels had an impact on the sTDT values (P

Lee MS, Lyoo CH, Ryu YH, Lim HS, Nam CM, Kim HS, Rinne JO. The effect of age on motor deficits and cerebral glucose metabolism of Parkinson’s disease. Acta Neurol Scand: 2011: 124: 196–201. © 2010 John Wiley & Sons A/S. Background – No systematic study has been made to separate age-related clinical deterioration and dysfunctional brain areas from those associated with Parkinson’s disease (PD). Methods – This study included 73 de novo patients with PD and 43 age-matched controls. All subjects underwent [18F]-fluorodeoxy glucose (FDG) positron emission tomography studies. The severity of parkinsonian motor deficit was measured using unified PD rating scale (UPDRS) motor scores. Multiple linear regression analysis was used to identify those parkinsonian motor deficits for which severity was correlated with the age of the patients and to locate brain areas in which normalized FDG uptake values were inversely correlated with the age of the subjects. Results – Patient age was positively correlated with total UPDRS motor scores and with subscores for bradykinesia and axial motor deficits, but not with subscores for tremor and rigidity. In the control group, an age-related decline in glucose uptake was found only in the cingulate cortex. However, in the patient group, an inverse correlation between age and glucose uptake was observed in the prefrontal, cingulate, orbitofrontal, perisylvian areas, caudate, and thalamus. Conclusions – In PD, widespread age-related decline in cerebral function may exaggerate the deterioration associated with bradykinesia and the axial motor deficits associated with nigral neuronal loss.

To study the influence of discriminative cutaneous sensory dysfunction on impaired finger dexterity in Parkinson's disease (PD), we evaluated 48 right-handed PD patients during a practically defined off-medication period and 24 healthy age-matched controls. With visual deprivation, a finger tapping task (FTT) was performed to assess the speed of simple repetitive finger movements and a coin rotation task (CRT) was used to assess finger dexterity. The tasks were performed with the right hand. We measured the somesthetic temporal discrimination threshold (sTDT) in the right index finger. The mean ± SD FTT score of the patient group was lower than that of the control group (24.0 ± 8.0 vs. 29.8 ± 7.8; P < 0.01). The patient group performed worse on the CRT than the control group (8.5 ± 3.5 vs. 12.6 ± 1.7; P < 0.001). The mean sTDT value of the patient group was longer than that of the control group (124.0 ± 44.8 vs. 78.1 ± 26.2 ms; P < 0.001). The CRT scores correlated with the sTDT values (Pearson's correlation coefficient = -0.43; P < 0.01), but not with the Unified Parkinson's Disease Rating Scale (UPDRS) finger bradykinesia scores or FTT scores. Multiple regression analysis showed that the sTDT values (parameter estimate = -0.03, SE = 0.01; P < 0.01), but not patient age, UPDRS finger bradykinesia score, or FTT score, affected the CRT score. Slowness of simple repetitive finger movements did not have a strong impact on the impaired manual dexterity of PD. Discriminative sensory dysfunction and consequent abnormal sensorimotor integration seem to be involved in the impaired finger dexterity of PD.