Temporal trajectories of in vivo tau and amyloid-ß accumulation in Alzheimer's disease.

PURPOSE: To investigate the temporal trajectories of tau and amyloid-ß (Aß) accumulation in Alzheimer's disease (AD) by using the longitudinal positron emission tomography (PET) study. METHODS: A total of 132 participants, who were healthy volunteers or recruited in our memory disorder clinic, completed longitudinal 18F-flortaucipir and 18F-florbetaben PET studies with a mean follow-up time of 2 years. Referencing baseline data from 57 Aß-negative cognitively unimpaired individuals, Z-scores and their annual changes were calculated with the global cortical or regional standardized uptake value ratios measured at baseline and follow-up after correcting for partial volume effect. The temporal trajectories of tau and Aß burden as a function of time were obtained based on the spline models from the annual changes and baseline Z-score data. RESULTS: Tau burden first emerged in the Braak's stage I-II regions, followed by stage III-IV regions, and finally in the stage V-VI regions. Time intervals between two time points at which Z-score curves rose above 2 were 17.3 years for the stages I-II and III-IV and 15.2 years for the stages III-IV and V-VI. Rise in the tau curve for stages I-II preceded that for global cortical Aß, while the rise in global cortical Aß curve preceded that for global cortical tau. Aß accumulation rate was attenuated during the surge in tau burden in the global cortex and reached a plateau. CONCLUSION: Sequential appearance of Aß and tau accumulation supports a hypothetical dynamic biomarker model and Braak's hierarchical tau spreading model in AD.

Distinct patterns of amyloid-dependent tau accumulation in Lewy body diseases.

BACKGROUND: In addition to Lewy body pathology, amyloid-ß 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.

In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum.

OBJECTIVE: To determine the in vivo cortical spreading pattern of tau and amyloid and to establish positron emission tomography (PET) image-based tau staging in the Alzheimer disease (AD) spectrum. METHODS: We included 195 participants (53 AD, 52 amnestic mild cognitive impairment [MCI], 23 nonamnestic MCI, and 67 healthy controls) who underwent 2 PET scans ((18) F-florbetaben for amyloid-ß and (18) F-AV-1451 for tau). We assumed that regions with earlier appearances of pathology may show increased binding in a greater number of participants and acquired spreading order of tau accumulation by sorting the regional frequencies of involvement. We classified each participant into image-based tau stage based on the Z score of the composite region for each stage. RESULTS: Tau accumulation was most frequently observed in the medial temporal regions and spread stepwise to the basal and lateral temporal, inferior parietal, posterior cingulate, and other association cortices, and then ultimately to the primary cortical regions. In contrast, amyloid accumulation was found with similar frequency in the diffuse neocortical areas and then finally spread to the medial temporal regions. The image-based tau stage correlated with the general cognitive status, whereas cortical thinning was found only in the advanced tau stages: medial temporal region in stage V and widespread cortex in stage VI. INTERPRETATION: Our PET study replicated postmortem spreading patterns of tau and amyloid-ß pathologies. Unlike the diffuse accumulation of amyloid throughout the neocortex, tau spreading occurred in a stepwise fashion through the networks. Image-based tau staging may be useful for the objective assessment of AD progression. Ann Neurol 2016;80:247-258.

Subcortical 18 F-AV-1451 binding patterns in progressive supranuclear palsy.

BACKGROUND: Accumulation of cortical and subcortical tau pathology is the primary pathological substrate for progressive supranuclear palsy (PSP). 18 F-AV-1451, a radiotracer that binds to the pathological tau protein, may be helpful for in vivo visualization and quantitation of tau pathology in PSP. OBJECTIVES: The objectives of this study were to investigate cortical and subcortical 18 F-AV-1451 binding patterns in patients with PSP. METHODS: We recruited 14 PSP patients and compared their cortical and subcortical binding patterns in 18 F-AV-1451 positron emission tomography (PET) studies with those of 15 Parkinson's disease (PD) patients and 15 healthy controls. RESULTS: In both the PD and PSP groups, subcortical 18 F-AV-1451 binding did not correlate with the severity of motor dysfunctions, and cortical binding did not differ between the controls and each patient group. However, the PSP patients showed greater 18 F-AV-1451 binding in the putamen, globus pallidus, subthalamic nucleus, and dentate nucleus when compared with the controls, whereas the PD patients showed lower 18 F-AV-1451 binding in the substantia nigra than controls. CONCLUSIONS: The PSP and PD patients showed distinct subcortical 18 F-AV-1451 binding patterns reflecting subcortical tau pathology in PSP and reduced nigral neuromelanin in PD. However, there was no correlation with the severity of motor dysfunction, no cortical regions with increased binding in PSP patients, and variable degrees of subcortical binding even in the controls. Therefore, the 18 F-AV-1451 PET may be less than ideal for assessing tau pathology in PSP. Further studies will be required to validate the clinical correlation and to understand the clinical utility of 18 F-AV-1451 PET for PSP patients. © 2016 International Parkinson and Movement Disorder Society.

Paroxysmal freezing of gait in a patient with mesial frontal transient ischemic attacks.

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.

Parkinsonian Patients with Striatal Cribriform State Present Rapidly Progressive Axial Parkinsonism.

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.

Impact of regional striatal dopaminergic function on kinematic parameters of Parkinson's disease.

Among the cardinal parkinsonian motor deficits, the severity of bradykinesia correlates with striatal dopamine loss. However, the impact of regional striatal dopamine loss on specific components of bradykinesia remains unknown. Using gyroscopes, we measured the amplitude, speed, and frequency of finger tapping in 24 untreated patients with Parkinson's disease (PD) and 28 healthy controls. Using positron emission tomography (PET) studies and [(18)F]-N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) in PD patients, we investigated the relationship between the mean values, variability and decrements of various kinematic parameters of finger tapping on one side (e.g. the mean, variability and decrement) and contralateral striatal FP-CIT binding. Compared with controls, PD patients had reduced amplitudes and speeds of tapping and showed greater decrement in those parameters. PD patients also exhibited greater irregularity in amplitude, speed, and frequency. Putaminal FP-CIT uptake levels correlated with the mean speed and amplitude, and caudate uptake levels correlated with mean amplitude. The variability of amplitude and speed correlated only with the caudate uptake levels. Neither caudate nor putaminal uptake correlated with frequency-related parameters or decrement in amplitude or speed. Reduced amplitude and speed of repetitive movement may be related to striatal dopaminergic deficit. Dopaminergic action in the caudate nucleus is required to maintain consistency of amplitude and speed. Although decrement of amplitude and speed is known to be specific for PD, we found that it did not mirror the degree of striatal dopamine depletion.

Movement disorders associated with moyamoya disease: a report of 4 new cases and a review of literatures.

The aim of this study was to define the clinical characteristics of patients who developed movement disorders in association with moyamoya disease (MMD). Using PubMed and medical records of our hospital from 1985 to 2008, we searched for patients who developed movement disorders in association with MMD. This study included 38 patients described in previous studies and 4 patients found in the medical records. The onset of movement disorders was thought to be sudden. In 13 patients, the movement disorders were precipitated by hyperventilation or emotional stress. Twenty-seven of the 42 patients developed chorea, 4 patients developed dystonia, and 4 developed a mixture of both. The movement disorders of the remaining 7 patients were described as dyskinesia. A third of the 42 patients developed bilateral movement disorders, and their mean age was younger than that of those with unilateral movement disorders. In 37 of the 42 patients, brain imaging studies showed ischemic lesions, but the remaining 5 patients showed no parenchymal lesions. Cerebral perfusion studies showed hypoperfusion in the basal ganglia and in the cerebral cortical areas. Most patients improved whether they were treated or not. MMD must be included in the differential diagnosis of the sudden onset of dyskinesias, particularly chorea and focal dystonia. Even in patients with no parenchymal lesion in brain imaging studies, cerebral angiography and cerebral blood perfusion studies must be performed, if they develop a sudden onset or recurrent movement disorders preceded by emotional stress or hyperventilation.

Topographical distribution of cerebral cortical thinning in patients with mild Parkinson's disease without dementia.

The pathology of Parkinson's disease (PD) is not confined to the brainstem regions, but spreads to involve the neocortical areas. Using surface-based cortical thickness analysis, we studied the topographical distribution of cortical thinning in nondemented patients with mild PD. The high-resolution magnetic resonance imaging (MRI) studies were performed in 48 patients with PD without dementia and 56 age-matched healthy controls. Using the Freesurfer software, surface-based analysis was done to find changes in cerebral cortical thickness in patients with PD. Compared to the controls, patients with PD showed significant cortical thinning in the temporal, inferior parietal, rostral frontal, and orbitofrontal cortical areas. Thinning of the cerebral cortex occurs even in nondemented patients with mild PD, and its topographical distribution was similar to that of the neocortical Lewy bodies. Further studies are needed to find pathological and clinical correlates of thinned cerebral cortex found in nondemented patients with mild PD.

Impaired finger dexterity in patients with parkinson's disease correlates with discriminative cutaneous sensory dysfunction.

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.

Cerebral glucose metabolism of Parkinson's disease patients with mild cognitive impairment.

BACKGROUND: Half of Parkinson's disease (PD) patients with mild cognitive impairment (MCI) develop dementia. We studied topographic distribution of cerebral hypometabolism in PD with different types of MCI. METHODS: This study included 61 nondemented PD patients and 14 age-matched controls. PD patients were grouped into normal cognition (PD-NC, n = 20), single amnestic (PD-SA, n = 12), single nonamnestic (PD-SN, n = 11), and multidomain MCI (PD-MD, n = 18). Using [(18)F]-fluorodeoxy-glucose PET, cerebral glucose metabolism of MCI groups was compared with that of controls and the PD-NC group. RESULTS: In comparison with controls, PD-NC and PD-SA groups showed no hypometabolic brain areas. However, the PD-SN group showed hypometabolism in parieto-temporo-occipital cortices. The PD-MD group showed widespread hypometabolism that predominantly involved parieto-occipital cortices. In comparison with the PD-NC group, only the PD-MD group showed hypometabolism in lateral frontal, cingulate, and parieto-temporo-occipital cortices. CONCLUSIONS: The distribution of hypometabolic brain areas of the PD-MD group suggests that PD-MD seems to be caused by a common pathology with PD dementia. PD-SA and PD-SN seem to be caused by very mild or topographically heterogeneous cerebral dysfunction. Longitudinal clinical and neuroimaging studies are needed to define whether PD patients with single domain MCI progress to PD-MD and finally to dementia.

Gene expression profile in the anterior regeneration of the earthworm using expressed sequence tags.

In order to gain insight into the gene expression profiles associated with anterior regeneration of the earthworm, Perionyx excavatus, we analyzed 1,159 expressed sequence tags (ESTs) derived from cDNA library early anterior regenerated tissue. Among the 1,159 ESTs analyzed, 622 (53.7%) ESTs showed significant similarity to known genes and represented 338 genes, of which 233 ESTs were singletons and 105 ESTs manifested as two or more ESTs. While 663 ESTs (57.2%) were sequenced only once, 308 ESTs (26.6%) appeared 2 to 5 times, and 188 ESTs (16.2%) were sequenced more than 5 times. A total of 803 genes were categorized into 15 groups according to their biological functions. Among 1,159 ESTs sequenced, we found several gene encoding signaling molecules, such as Notch and Distal-less. The ESTs used in this study should provide a resource for future research in earthworm regeneration.

Brain Iron Accumulation in Atypical Parkinsonian Syndromes: in vivo MRI Evidences for Distinctive Patterns.

Recent data suggest mechanistic links among perturbed iron homeostasis, oxidative stress, and misfolded protein aggregation in neurodegenerative diseases. Iron overload and toxicity toward dopaminergic neurons have been established as playing a role in the pathogenesis of Parkinson's disease (PD). Brain iron accumulation has also been documented in atypical parkinsonian syndromes (APS), mainly comprising multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Iron-sensitive magnetic resonance imaging (MRI) has been applied to identify iron-related signal changes for the diagnosis and differentiation of these disorders. Topographic patterns of widespread iron deposition in deep brain nuclei have been described as differing between patients with MSA and PSP and those with PD. A disease-specific increase of iron occurs in the brain regions mainly affected by underlying disease pathologies. However, whether iron changes are a primary pathogenic factor or an epiphenomenon of neuronal degeneration has not been fully elucidated. Moreover, the clinical implications of iron-related pathology in APS remain unclear. In this review study, we collected data from qualitative and quantitative MRI studies on brain iron accumulation in APS to identify disease-related patterns and the potential role of iron-sensitive MRI.

Progressive Tau Accumulation in Alzheimer Disease: 2-Year Follow-up Study.

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-ß-negative cognitively unimpaired [CU-], 7 amyloid-ß-positive cognitively unimpaired [CU+], 31 with prodromal AD [mild cognitive impairment; MCI+], and 24 with AD dementia [DEM+]) who completed 2 baseline PET scans (18F-flortaucipir and 18F-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. 18F-flortaucipir PET is an imaging biomarker for monitoring the progression of AD.

18F-flortaucipir uptake patterns in clinical subtypes of primary progressive aphasia.

We analyzed 18F-flortaucipir uptake patterns and structural changes in patients with subtypes of primary progressive aphasia (PPA) using 18F-flortaucipir positron emission tomography and volumetric magnetic resonance imaging. We enrolled 34 consecutive patients with PPA (10 nonfluent/agrammatic PPA [nfvPPA], 18 semantic variant PPA [svPPA], and 6 logopenic variant PPA [lvPPA], as well as 20 healthy controls, and 20 patients with Alzheimer's disease. 18F-flortaucipir uptake was increased in the frontal cortex and underlying white matter, and subcortical nuclei in the 10 nfvPPA and 8 nfvPPA-amyloid-ß (Aß)- subgroup patients. In the svPPA patients (both the 13 svPPA-Aß- and 5 svPPA-Aß+), uptake generally increased in the widespread neocortex with left anterior temporal predominance. 18F-flortaucipir uptake patterns in the 6 lvPPA and the 5 lvPPA-Aß+ subgroup patients were similar to those seen in the patients with Alzheimer's disease with mild predominance in the left lateral temporal cortex. Cortical thinning in each PPA subtype corresponded with increased 18F-flortaucipir uptake. 18F-flortaucipir uptake patterns and cortical atrophy were distinct and corresponded to areas related to the specific language functions that are impaired in each subtype of PPA.

Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease.

Mutations in five PARK genes (SNCA, PARKIN, DJ-1, PINK1, and LRRK2) are well-established genetic causes of Parkinson disease (PD). Recently, G2385R substitution in LRRK2 has been determined as a susceptibility allele in Asian PD. The objective of this study is to determine the frequency of mutations in these PARK genes in a Korean early-onset Parkinson disease (EOPD) cohort. The authors sequenced 35 exons in SNCA, PARKIN, DJ-1, PINK1, and LRRK2 in 72 unrelated EOPD (age-at-onset

Drug-induced and psychogenic resting suprahyoid neck and tongue tremors.

We describe three patients who presented with 4 to 5 Hz tremors of the suprahyoid region of the neck. Two developed their tremors in association with levosulpiride treatment. When they opened their mouths, the neck tremors disappeared; no tongue tremors were observed. However, a videofluoroscopic examination showed the presence of tongue tremors at rest. The remaining patient had a psychogenic tremor.

Anticholinergic-responsive gait freezing in a patient with pantothenate kinase-associated neurodegeneration.

A 43-year-old male patient suddenly developed freezing of gait (FOG) when making a first step, turning, or passing through a narrow path. Dystonic plantar flexion of his left foot always accompanied with FOG. He could walk without FOG when stepping on visual cues. Brain magnetic resonance imaging study showed typical "eye of the tiger" sign in the globus pallidus. He had heterozygous mutations in the exons 3 and 4 in the PANK2 gene. His FOG dramatically responded to the anticholinergic treatment. We report the first instance of a patient with genetically confirmed pantothenate kinase associated neurodegeneration showing typical FOG that responded to anticholinergic treatment.

Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson's disease is related to disability of the patients.

We investigated neuronal number and size in the pars compacta of the pedunculopontine nucleus (PPN) in Parkinson's disease (PD). In PD, the number of Luxol fast blue (LFB) neurons was reduced by 27% from the mean control value (p=0.04) and the cholinergic (choline acetyltransferase, ChAT-positive) neuron number was reduced by 36% (p=0.03). In addition to neuronal loss, the remaining neurons in the PPN in PD were smaller than in controls. The profile area of LFB neurons was reduced by 14% (p=0.009) and that of ChAT-positive neurons by 26% (p=0.001). There was more severe loss of ChAT-positive neurons with a more severe stage of the disease, evaluated by the modified Hoehn and Yahr scale (r=-0.66, p=0.03). The neuron number decreased much more than could be expected on the basis of decrease in cell size alone.