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.

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.

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.

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.

Predicted sequence of cortical tau and amyloid-ß deposition in Alzheimer disease spectrum.

We investigated sequential order between tau and amyloid-ß (Aß) deposition in Alzheimer disease spectrum using a conditional probability method. Two hundred twenty participants underwent 18F-flortaucipir and 18F-florbetaben positron emission tomography scans and neuropsychological tests. The presence of tau and Aß in each region and impairment in each cognitive domain were determined by Z-score cutoffs. By comparing pairs of conditional probabilities, the sequential order of tau and Aß deposition were determined. Probability for the presence of tau in the entorhinal cortex was higher than that of Aß in all cortical regions, and in the medial temporal cortices, probability for the presence of tau was higher than that of Aß. Conversely, in the remaining neocortex above the inferior temporal cortex, probability for the presence of Aß was always higher than that of tau. Tau pathology in the entorhinal cortex may appear earlier than neocortical Aß and may spread in the absence of Aß within the neighboring medial temporal regions. However, Aß may be required for massive tau deposition in the distant cortical areas.

Predominant subcortical accumulation of 18F-flortaucipir binding in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is the most common form of frontotemporal dementia, and tau pathology can be found in 40%-50% of bvFTD patients. In this study, we sought to investigate 18F-flortaucipir-binding patterns and their correlates in clinically diagnosed bvFTD patients by comparing with results for Alzheimer's disease (AD) patients. We enrolled 20 bvFTD, 20 AD, and 20 age-matched healthy subjects who underwent neuropsychological tests, magnetic resonance imaging, and tau positron emission tomography scans with 18F-flortaucipir. Regional standardized uptake value ratios for the cerebral cortex and underlying white matter were compared between the 2 groups. The bvFTD patients showed increased 18F-flortaucipir binding in the putamen and globus pallidus when compared to the healthy controls. In addition, bvFTD was associated with increased binding in the white matter regions underlying the frontal, anterior cingulate, and insula cortices. The bvFTD patients may exhibit predominantly subcortical 18F-flortaucipir-binding pattern that is distinct from the patterns seen in AD patients. We hypothesize that the clinical characteristics of bvFTD patients may be attributable to the dysfunctional frontal-subcortical networks. However, concerns remain regarding unknown "off-target" binding in the white matter and the basal ganglia.

Tau Positron Emission Tomography Imaging in Degenerative Parkinsonisms.

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.

Abnormal somatosensory temporal discrimination in Parkinson's disease: Pathophysiological correlates and role in motor control deficits.

OBJECTIVE: The somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval required for two tactile stimuli to be perceived as separate, is longer in patients with Parkinson's disease (PD). In this review, we discuss STDT findings in healthy subjects and in PD patients and the relationship between altered STDT and motor disturbances. METHODS: A search was conducted on PubMed for papers dealing with PD and temporal discrimination published from January 1990 to July 2017. RESULTS: Abnormal STDT in PD correlates with disease duration, disease severity and degree of nigrostriatal dopamine loss, and responds to dopaminergic medication. In PD, a prolonged STDT does not correlate, or only marginally correlates, with clinically assessed bradykinesia of finger tapping. By contrast, a prolonged STDT correlates with the variability in amplitude and speed of finger tapping as assessed by means of neurophysiological techniques and may contribute to impaired finger dexterity in PD. CONCLUSIONS: We suggest that abnormal temporal processing of sensory information in PD generates incorrect signals for the execution and control of voluntary movements. SIGNIFICANCE: This review sheds light on unsolved questions regarding the relationship between STDT alterations and motor disturbances in PD and proposes directions for future research on this topic.

Off-Target 18F-AV-1451 Binding in the Basal Ganglia Correlates with Age-Related Iron Accumulation.

Off-target binding in the basal ganglia is commonly observed in the 18F-AV-1451 PET studies of the elderly. We sought to investigate the relationship between this phenomenon in the basal ganglia and iron accumulation using iron-sensitive R2* MRI. Methods: Fifty-nine healthy controls and 61 patients with Alzheimer disease and mild cognitive impairment underwent 18F-AV-1451 PET and R2* MRI studies. A correlation analysis was performed for age, 18F-AV-1451 binding, and R2* values. Results: There was an age-related increase in both 18F-AV-1451 binding in the basal ganglia and R2* values in the putamen in both the controls and the Alzheimer disease/mild cognitive impairment patients. 18F-AV-1451 binding in the basal ganglia increased with R2* values. Conclusion: Off-target 18F-AV-1451 binding in the basal ganglia is associated with the age-related increases in iron accumulation. Postmortem studies are required to further investigate the nature of this association.

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.

Brain regional iron contents in progressive supranuclear palsy.

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.

18F-AV-1451 binds to motor-related subcortical gray and white matter in corticobasal syndrome.

OBJECTIVE: To investigate tau distribution in patients with corticobasal syndrome (CBS) using 18F-AV-1451 PET. METHODS: Six consecutively recruited patients with CBS and 20 age-matched healthy controls underwent 2 PET scans with 18F-AV-1451 (for tau) and 18F-florbetaben (for ß-amyloid). We compared standardized uptake value ratio maps of the 18F-AV-1451 PET images between the patients with CBS and controls. RESULTS: Compared to controls, patients with CBS exhibited asymmetrically increased 18F-AV-1451 binding in the putamen, globus pallidus, and thalamus contralateral to the clinically more affected side and in the ipsilateral globus pallidus and dentate nucleus. Voxel-based comparison additionally showed asymmetrically increased 18F-AV-1451 binding in the focal regions of the precentral gray and white matter and in the midbrain, predominantly in the contralateral side. 18F-AV-1451 binding in the precentral white matter correlated with motor severity. CONCLUSIONS: 18F-AV-1451 asymmetrically binds to motor-related subcortical gray and white matter structures in patients with CBS. This pattern corresponds to tau pathology distribution in postmortem studies, and motor deficit in patients with CBS may be associated with tau accumulation predominantly in the subcortical white matter underlying the motor cortex, leading to disruptions in motor-related networks.

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.

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.

Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism.

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.

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.

Tau PET in Alzheimer disease and mild cognitive impairment.

OBJECTIVE: To investigate the topographical distribution of tau pathology and its effect on functional and structural changes in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) by using (18)F-AV-1451 PET. METHODS: We included 20 patients with AD, 15 patients with MCI, and 20 healthy controls, and performed neuropsychological function tests, MRI, as well as (18)F-florbetaben (for amyloid) and (18)F-AV-1451 (for tau) PET scans. By using the regional volume-of-interest masks extracted from MRIs, regional binding values of standardized uptake value ratios and volumes were measured. We compared regional binding values among 3 diagnostic groups and identified correlations among the regional binding values, performance in each cognitive function test, and regional atrophy. RESULTS: (18)F-AV-1451 binding was increased only in the entorhinal cortex in patients with MCI, while patients with AD exhibited greater binding in most cortical regions. In the 35 patients with MCI and AD, (18)F-AV-1451 binding in most of the neocortex increased with a worsening of global cognitive function. The visual and verbal memory functions were associated with the extent of (18)F-AV-1451 binding, especially in the medial temporal regions. The (18)F-AV-1451 binding also correlated with the severity of regional atrophy of the cerebral cortex. CONCLUSIONS: Tau PET imaging with (18)F-AV-1451 could serve as an in vivo biomarker for the evaluation of AD-related tau pathology and monitoring disease progression. The accumulation of pathologic tau is more closely related to functional and structural deterioration in the AD spectrum than ß-amyloid.

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.

Tau Accumulation in Primary Motor Cortex of Variant Alzheimer's Disease with Spastic Paraparesis.

We studied topographic distribution of tau and amyloid-ß in a patient with variant Alzheimer's disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-ß in the primary motor cortex.