Gomperts SN, Locascio JJ, Makaretz SJ, Schultz A, Caso C, Vasdev N, Sperling R, Growdon JH, Dickerson BC, Johnson K.
Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases.
JAMA Neurol. 2016 Nov 1;73(11):1334-1341.
PubMed.
The primary pathologic feature of DLB and PD dementia involves the accumulation of α-synuclein, but a subset of patients also have varying degrees of amyloid and tau deposition. It is important to be able to detect and track these pathologies during life in order to understand how they contribute to the clinical features of the disease, but also to be able to monitor the effectiveness of emerging treatments that target these specific pathologies. This study by Gomperts et al. provides evidence that tau deposition can be measured in living patients with DLB and PD dementia, and that those with greater tau deposition tend to have greater cognitive impairment and greater dementia severity. Even though the overall tau aggregation is lower than what is typically seen in Alzheimer’s disease, this relationship suggests that tau deposition contributes meaningfully to the dementia associated with Lewy body disease. Replication is certainly needed, but this is an important first step to establishing the usefulness of this tau imaging biomarker in patients with Lewy body disease.
The paper by Gomperts et al. is an important investigation of AV-1451 binding in Lewy body dementias. Accumulation of tau pathology in patients with DLB has been recognized through autopsy studies. The study demonstrates that tau deposition is present in patients with Lewy body disease who have cognitive impairment. This is particularly true in cases of dementia with Lewy bodies (DLB) and underscores the importance of tau accumulation in Lewy body diseases.
The limited sample size (n <10) in each clinical group calls for confirmation of findings in a larger sample. Furthermore, the absence of a relationship between amyloid deposition and tau deposition in DLB is unexpected and may be impacted by the small number of cases in the study. Understanding the accumulation of amyloid and tau in Lewy body diseases is critical for multitarget treatment strategies in these disorders.
The findings of this in vivo imaging study are consistent with data from neuropathologic postmortem studies and once again highlight the fact that the aging human brain is frequently characterized by the presence of multiple pathologies. It is very important for all researchers in the field to be aware of this cerebral multimorbidity as it implies that seemingly homogenous patient cohorts (e.g., AD) may in fact show heterogenous neuropathologies (e.g., AD with and without concomitant TDP-43 pathology).
The authors found considerable cortical tau pathology in the absence of elevated Aβ in the DLB group, suggesting a synergistic interaction between α-synuclein and tau pathology, which has been suggested by transgenic animal studies and human postmortem studies. However, the absence of a statistically significant correlation between cortical amyloid and tau burden does not per se preclude an influence of Aβ on tau in these cases, as it has been demonstrated that specific amyloid subspecies (e.g., pyroglutamylated Aβ, phospho Aβ), rather that general Aβ burden, have an aggravating effect of tau pathology.
Four out of 17 Lewy body disease cases with low amyloid burden showed higher tau burden than normal controls in the inferior temporal gyrus; this finding is consistent with neuropathological data clearly demonstrating that Aβ is not necessary for the development of tau pathology. Indeed, a diagnostic category termed primary age-related tauopathy (PART) has recently been described. PART is characterized by the presence of tau pathology up to Braak stage IV and either complete lack of (definite PART) or very low (possible PART) Aβ pathology, respectively. Of note, PART cases (without other pathology) are usually not cognitively impaired and high Braak stages V/VI (which are cognitively impaired) have not been observed without Aβ, suggesting that Aβ is necessary for the development of end-stage high-tau pathology. Therefore, the most likely neuropathological correlate for dementia in the group with low amyloid burden and higher than normal tau burden in the inferior temporal gyrus in this study is α-synuclein pathology.
In conclusion, this is an exciting study that should stimulate future research in which the age-associated neurodegenerative condition is not simply categorized according to disease groups, but rather described according to the neuropathological changes present in the individual human brain. While such an approach is already pursued in neuropathological postmortem studies, further diagnostic tools are needed to follow this path in clinical in vivo studies.
Comments
Mayo Clinic
The primary pathologic feature of DLB and PD dementia involves the accumulation of α-synuclein, but a subset of patients also have varying degrees of amyloid and tau deposition. It is important to be able to detect and track these pathologies during life in order to understand how they contribute to the clinical features of the disease, but also to be able to monitor the effectiveness of emerging treatments that target these specific pathologies. This study by Gomperts et al. provides evidence that tau deposition can be measured in living patients with DLB and PD dementia, and that those with greater tau deposition tend to have greater cognitive impairment and greater dementia severity. Even though the overall tau aggregation is lower than what is typically seen in Alzheimer’s disease, this relationship suggests that tau deposition contributes meaningfully to the dementia associated with Lewy body disease. Replication is certainly needed, but this is an important first step to establishing the usefulness of this tau imaging biomarker in patients with Lewy body disease.
View all comments by Tanis FermanMayo Clinic
The paper by Gomperts et al. is an important investigation of AV-1451 binding in Lewy body dementias. Accumulation of tau pathology in patients with DLB has been recognized through autopsy studies. The study demonstrates that tau deposition is present in patients with Lewy body disease who have cognitive impairment. This is particularly true in cases of dementia with Lewy bodies (DLB) and underscores the importance of tau accumulation in Lewy body diseases.
The limited sample size (n <10) in each clinical group calls for confirmation of findings in a larger sample. Furthermore, the absence of a relationship between amyloid deposition and tau deposition in DLB is unexpected and may be impacted by the small number of cases in the study. Understanding the accumulation of amyloid and tau in Lewy body diseases is critical for multitarget treatment strategies in these disorders.
View all comments by Kejal KantarciNewcastle University
The findings of this in vivo imaging study are consistent with data from neuropathologic postmortem studies and once again highlight the fact that the aging human brain is frequently characterized by the presence of multiple pathologies. It is very important for all researchers in the field to be aware of this cerebral multimorbidity as it implies that seemingly homogenous patient cohorts (e.g., AD) may in fact show heterogenous neuropathologies (e.g., AD with and without concomitant TDP-43 pathology).
The authors found considerable cortical tau pathology in the absence of elevated Aβ in the DLB group, suggesting a synergistic interaction between α-synuclein and tau pathology, which has been suggested by transgenic animal studies and human postmortem studies. However, the absence of a statistically significant correlation between cortical amyloid and tau burden does not per se preclude an influence of Aβ on tau in these cases, as it has been demonstrated that specific amyloid subspecies (e.g., pyroglutamylated Aβ, phospho Aβ), rather that general Aβ burden, have an aggravating effect of tau pathology.
Four out of 17 Lewy body disease cases with low amyloid burden showed higher tau burden than normal controls in the inferior temporal gyrus; this finding is consistent with neuropathological data clearly demonstrating that Aβ is not necessary for the development of tau pathology. Indeed, a diagnostic category termed primary age-related tauopathy (PART) has recently been described. PART is characterized by the presence of tau pathology up to Braak stage IV and either complete lack of (definite PART) or very low (possible PART) Aβ pathology, respectively. Of note, PART cases (without other pathology) are usually not cognitively impaired and high Braak stages V/VI (which are cognitively impaired) have not been observed without Aβ, suggesting that Aβ is necessary for the development of end-stage high-tau pathology. Therefore, the most likely neuropathological correlate for dementia in the group with low amyloid burden and higher than normal tau burden in the inferior temporal gyrus in this study is α-synuclein pathology.
In conclusion, this is an exciting study that should stimulate future research in which the age-associated neurodegenerative condition is not simply categorized according to disease groups, but rather described according to the neuropathological changes present in the individual human brain. While such an approach is already pursued in neuropathological postmortem studies, further diagnostic tools are needed to follow this path in clinical in vivo studies.
View all comments by Johannes AttemsMake a Comment
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