Crossed Hemispheric Accumulation of β-Amyloid and Tau Protein in a Patient With Typical Alzheimer Disease : Alzheimer Disease & Associated Disorders

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Crossed Hemispheric Accumulation of β-Amyloid and Tau Protein in a Patient With Typical Alzheimer Disease

Kim, Hyung-Ji MD*; Jo, Sungyang MD*; Lee, Sunju MD*; Oh, Minyoung MD, PhD; Lee, Jae-Hong MD, PhD*

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Alzheimer Disease & Associated Disorders: July–September 2022 - Volume 36 - Issue 3 - p 263-265
doi: 10.1097/WAD.0000000000000460
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Accumulation and spread of amyloid β42 (Aβ) and tau proteins are pathologic hallmarks of Alzheimer disease (AD). Molecular neuroimaging uses positron emission tomography (PET) that enables assessment of the extent of these protein accumulations to evaluate the pathologic state of patients with AD.1 According to the amyloid hypothesis, tau accumulation comes secondary to Aβ deposition in AD. However, research has revealed that the relationship between tau and Aβ is more complex. Genetic variations, environmental factors, and amyloid proteins have been implicated in the patterns of tau accumulation and spread,2,3 and the mediation of this process has yet to be determined in AD.

Herein, we report the case of a 74-year-old woman with a clinical course consistent with typical AD, which showed Aβ deposition restricted to the left hemisphere on an amyloid PET scan ([18F]-florbetaben) and tau deposition confined in the right hemisphere on the tau PET scan ([18F]PI-2620, second-generation tau tracer). This complete disparity has not been reported previously. The observations of this case suggest that tau protein deposition and spread may occur independently of Aβ deposition.


A 74-year-old woman visited the memory clinic of Asan Medical Center, Seoul, with a 1-year history of progressive memory impairment, time disorientation, and executive dysfunction. She is of Asian descent with 13 years of education. She is a housewife and had recently been taking care of her grandchildren. Medical notes indicated hyperlipidemia and no history of alcohol, smoking, or drug misuse. She had no family history of neurodegenerative diseases. Her caregivers reported progressive cognitive decline over the 12 months before her initial assessment, and her daughter noted that episodic memory loss had deteriorated in the preceding 8 months.

Her general neurological examination including apraxia test and evaluation of movement disorders was unremarkable except for mild disorientation in time. She scored 26 on the Korean version of the Mini-Mental State Examination (K-MMSE) and 2 on the Global Deterioration Scale (GDS). Neuropsychological assessment revealed encoding deficits in verbal and visual memory tasks, visuospatial dysfunction, deficits in semantic and phonemic word fluency, and decreased psychomotor speed. She was reported to have anxiety, depressive mood, mood deflection, mild apathy, and change of appetite reflected in the Neuropsychiatry Inventory (NPI) scale. There was no significant dysfunction in activities of daily living. Her ApoE genotype was E3/E3.

The patient was enrolled in a clinical trial (Clinical evaluation of [18F]PI-2620 PET for imaging tau protein in patients with tauopathies and healthy volunteers. Identifier: NCT03510572) and underwent baseline amyloid and tau PET and repeat tau PET according to the study protocol.

Structural brain magnetic resonance imaging (MRI) revealed regional atrophy in both temporal lobes with moderate leukoaraiosis in bilateral periventricular white matter (Fig. 1A). PET imaging with [18F]-florbetaben documented left-sided tracer uptake involving the posterior cingulate/precuneus, frontal, temporal, and parietal lobe, and the anterior striatum. On the right hemisphere, no significant tracer uptake was observed (Fig. 2A). Tau imaging with [18F]PI-2620 revealed rightward tracer uptake involving the parieto-temporal lobe and posterior cingulate gyri consistent with Braak stage IV-V. However, no significant tracer uptake was observed in the left hemisphere (Fig. 2B). On the basis of the clinical and radiologic findings, a diagnosis of amnestic mild cognitive impairment due to AD was made. The time interval between amyloid and tau PET scans was 6 days with amyloid PET taken first.

The baseline evaluation of structural brain magnetic resonance imaging (MRI) showed mild leukoaraiosis in the fluid attenuated inversion recovery (FLAIR) image and mild diffuse brain atrophy in the 3-dimensional T1 image (A). A repeat MRI a year after (B) showed no definite interval change.
A, The baseline [18F]-florbetaben scan showed left-sided tracer uptake involving posterior cingulate/precuneus, frontal, temporal, parietal lobe, and the anterior striatum. B, In contrast, [18F]PI-2620 scan showed rightward tracer uptake on the parieto-temporal lobe and posterior cingulate gyri. C, A year later, repeat [18F]PI-2620 scan showed the same patterns of tracer uptake. White dashed lines and white thin arrows represent of [18F]-florbetaben tracer uptake, the white thick arrows represent the site of [18F]PI-2620 tracer uptake.

Follow-up Evaluation

Follow-up neuropsychological evaluation, structural brain MRI, and tau PET imaging was conducted 12 months after initial assessment. The K-MMSE score decreased from 26/30 to 25/30. Neuropsychological evaluation suggested a decline in overall cognition with intact left parietal lobe function. Prominent declines were noted in the visuospatial function test (the z scores of Rey Figure copy test, −2.02 to −2.45), visual memory recognition test (the z scores of Rey Figure recognition test, −1.22 to −4.19), and frontal/executive function test (the z scores of Stroop color reading test, −0.34 to −2.47). No significant change in NPI score was observed. MRI showed no definite interval change (Fig. 1B). Follow-up tau PET imaging highlighted the same topographic pattern as the initial analysis. Regional tracer uptake had increased in the right temporal, parietal, and cingulate gyri (Fig. 2C).


Tau and Aβ proteins interact reciprocally in the process of development and progression of AD.4 Abnormal hyperphosphorylation of the tau protein increases as Aβ accumulates and phosphorylated tau dissociates from microtubules and aggregates into neurofibrillary tangles, causing neurodegeneration and, ultimately, neuronal death. As such, phosphorylated tau is thought to be a mediator of Aβ-induced neuronal degeneration and synaptic dysfunction. In a clinical context, Aβ proteins do not show a significant clinical correlation with cognitive dysfunction, whereas localized cognitive impairment is strongly correlated with tau proteins.5

[18F]PI-2620 is a novel second-generation tau tracer. The off-target bindings of [18F]PI-2620 are much less than the first-generation tracers such as [18F]-flortaucipir and [18F]-THK5351. It is known to be useful in detecting not only 4R tauopathies such as corticobasal degeneration and progressive supranuclear palsy,6 but also AD.7 In this case, even though there was a strong asymmetry of tau tracer uptake, the brunt of the lesion was not in the supplementary motor area or the basal ganglia and midbrain, which is compatible with corticobasal degeneration and progressive supranuclear palsy, respectively. The regions of elevated [18F]PI-2620 binding in this case seem to correspond with Braak stage III-IV of AD. However, we cannot completely rule out the possibility of mixed degenerative pathologies.

Several models have been proposed to explain the spatial pattern of these proteins. According to Thal and Braak staging, Aβ and tau have distinct accumulation and spreading patterns, but also overlap in some brain regions.8 The case we have described here is a good example of the spatial disparity of Aβ and tau accumulation. The asymmetry of topographical dissociation is so severe that there was no overlap in these 2 protein accumulations.

To our knowledge, there has been no report of entirely segregated Aβ and tau protein accumulation in the separate hemispheres. As in this case, supported by the development of novel tau tracers such as PI-2620, studies are actively investigating the relationship between Aβ and tau in AD pathogenesis. Previous research has described Aβ and tau accumulation concerning the brain functional network in patients with AD, represented by the transneuronal model and white matter integrity. Amyloid accumulation has been associated with brain functional connectivity and tau accumulation with cerebral white matter integrity in these models.2,9 Interestingly, asymmetric brain functional connectivity and white matter integrity has been reported even in individuals without neurodegenerative processes.10 The asymmetric Aβ and tau accumulation shown in this case could be ascribed to the asymmetry of the functional connectivity and white matter integrity, in line with previous studies.

In summary, this case suggests that the deposition and spreading of tau proteins may occur independently of Aβ deposition. Further analysis using functional MRI and diffusion tensor imaging is warranted to elucidate this mechanism.


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Alzheimer disease; amyloid; tau proteins

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