2023 年 9 巻 p. 5-8
The relationship between Alzheimer’s disease (AD) and cerebrovascular disease (CVD) is attracting attention. To investigate this complex relationship, it is necessary to focus on biomarkers that can assess AD pathophysiology. Positron emission tomography (PET) to detect amyloid-β (Aβ) can visualize the distribution of Aβ accumulation in the brains of AD patients. Amyloid PET imaging has been evaluated qualitatively, but a quantitative evaluation has also been developed to allow better comparison of data across institutions. Quantitative amyloid PET analysis has been used in the development of many disease-modifying drugs against AD. Cerebrospinal fluid and serum biomarkers have also been developed to investigate Aβ pathology, but the advantage of amyloid PET imaging is its ability to assess Aβ accumulation in a site-specific manner.
Spatial assessment of Aβ accumulation by amyloid PET is useful when investigating its association with CVD. We have revealed that more severe CVD findings are associated with milder Aβ accumulation in patients with AD. Simultaneous presence of Aβ and CVD pathologies, compared to the presence of either pathology alone, has been shown to significantly accelerate the onset of clinical dementia and cognitive decline. To prevent cognitive decline in AD patients, it is important to manage vascular risk factors and prevent CVD.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with increasing prevalence and is characterized by cognitive impairment and behavioral disturbances. Interestingly, pathological indicators of AD and cerebrovascular disease (CVD) are often seen simultaneously in the brains of older adults, and the relationship between AD and CVD is attracting attention. However, the role of CVD in AD pathogenesis has not been clarified. To investigate the relationship between AD and CVD, it is necessary to focus on biomarkers that can reflect the disease status of AD. Neuropathological hallmarks of AD brains include neurofibrillary tangles (NFTs) which contain phosphorylated tau protein and senile plaques which contain extracellularly deposited amyloid-β (Aβ) protein fibrils1,2). Previous studies on biomarkers for AD have been conducted focusing on these pathological features. With the establishment of biomarkers for AD using cerebrospinal fluid (CSF) sampling and positron emission tomography (PET) scans, the recent diagnostic procedure of AD no longer relies solely on classical neuropsychological testing but instead assesses patients based on biomarkers. Aβ42 levels in CSF and amyloid PET findings have been validated as biomarkers of Aβ pathology (A), while phosphorylated tau in CSF and tau PET findings have been established as biomarkers of tau pathology (T). In addition, total tau in CSF, decreased glucose metabolism on 18F-fluorodeoxyglucose PET, and brain atrophy on magnetic resonance imaging (MRI) are established biomarkers of neurodegeneration (N). The National Institute on Aging and Alzheimer’s Association (NIA-AA) proposed diagnostic criteria for AD based on biomarkers of Aβ, tau, and neurodegeneration, called the A/T/N biomarkers3). Of these biomarkers for AD diagnosis, Aβ is the first biomarker to become abnormal in carriers with a pathogenic AD mutation4). This finding suggests that abnormalities in biomarkers of Aβ dysregulation may solely serve as a defining AD signature. Amyloid PET, such as 11C-labeled Pittsburgh Compound B PET (11C-PiB PET), can detect cerebral Aβ deposition in vivo and visualize the distribution of Aβ accumulation in AD brains5). Postmortem studies have revealed that increased 11C-PiB uptake on PET images corresponds to areas of abundant senile plaques6). Herein we describe the characteristics of amyloid PET and discuss the relationship between Aβ accumulation and CVD.
The first radiotracer to visualize brain Aβ deposition in AD patients was 18F-2-(1-{6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile (18F-FDDNP)7). However, 18F-FDDNP is not capable of efficiently binding Aβ, while also binding to NFTs, making it less frequently used at present8). PiB is an uncharged derivative of thioflavin-T that has a high affinity for Aβ fibrils and shows very low binding to NFTs and is therefore widely used in clinical studies9). On the other hand, 11C-PIB use is limited because of the short half-life of 11C, and several radiotracers labeled with 18F have been developed as alternatives. Among them, 18F-flutemetamol is a derivative of thioflavin-T, which has a chemical structure almost identical to 11C-PIB. 18F-flutemetamol has a high affinity for Aβ but exhibits higher white matter uptake10). Moreover, 18F-florbetapir and 18F-florbetaben with trans-stilbene derivatives have been developed, and the synthesis devices have been approved under the Japanese Pharmaceuticals and Medical Devices Act (PMDA). Furthermore, two of the above radiotracers (18F-florbetapir and 18F-flutemetamol) are marketed as diagnostic agents in Japan.
In general, the amyloid PET images are rated as positive or negative by inspection; they are rated as “positive” if the uptake level in the cerebral cortex is higher than that in the white matter. The standardized uptake value ratio (SUVR) represents a quantitative measure of tracer uptake, which is normalized to the average uptake in a reference region. As it is known that radiotracer uptake in the cerebellar cortex does not differ between AD patients and healthy controls6), it is commonly used as the reference region in amyloid PET analysis. Generally, qualitative evaluation of amyloid PET imaging by inspection shows consistent results across institutions. While SUVR values are useful for quantitative assessment, there is considerable variation in the reported SUVR measurement methods used among institutions. A common quantitative output value, regardless of the tracer or method, would allow better comparison of amyloid PET data across institutions. For this reason, the main objective of the Centiloid Project is to standardize amyloid PET results and reconstruct objective quantitative data11). The tracer results were standardized by a quantitative index of amyloid imaging, by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls ( ≤ 45 years old) and typical AD patients; the unit of measurement used in this scale was named “Centiloid”12). Quantitative amyloid PET analysis, as described above, has been introduced in the development of many disease-modifying drugs targeting AD pathology. Ongoing Phase 2 and 3 clinical trials for AD are dominated by disease-modifying drugs that target Aβ, and a significant number of these studies are evaluating changes in Aβ accumulation using amyloid PET evaluation before and after treatment.
Although amyloid PET is used frequently in both clinical practice and research, Poul et al. indicated the following problems with amyloid PET13). Firstly, amyloid PET imaging biomarkers for assessing Aβ deposition have insufficient in vivo specificity. It has been shown that uncharged derivatives of thioflavin-T (11C-PiB and 18F-flutemetamol) can be nonspecifically retained by tissue targets other than Aβ, including estrogen sulfotransferase, an enzyme that is elevated during brain inflammation14,15). Additionally, quantification of the signal in gray matter is particularly problematic when there is cortical atrophy, as observed in AD brains.
In addition to amyloid PET, immunological measurements, such as Aβ42 levels in CSF, have also recently been used as markers of Aβ pathology. Reduction of Aβ42 levels in CSF is significantly correlated with Aβ deposition in amyloid PET16). Recently, serum Aβ biomarkers have been developed and are shown to correlate with CSF biomarkers17).
Since immunoserological biomarkers are being developed at a lower cost than amyloid PET, amyloid PET imaging would need to confer advantages over immunoserological biomarkers. Indeed, the biggest advantage of amyloid PET seems to be its ability to assess Aβ accumulation in a site-specific manner. For example, Hwang et al. reported that AD with Aβ accumulation in the occipital region showed a younger onset than AD without occipital Aβ accumulation18), an example of the advantage of using amyloid PET to identify Aβ distribution to inform clinical characteristics. Another example is the use of amyloid PET for investigating differences in cerebral Aβ deposition at normally appearing white matter and white matter with high intensity lesions in T2-weighted MRI. Use of 18F-florbetapir PET revealed that retention of the tracer in white matter is associated with demyelination in AD19). Taken together, these data suggest that amyloid PET will play an important role in studies requiring to evaluate Aβ accumulation at specific brain regions.
The pathologies of AD and CVD often overlap in the brains of older individuals, and epidemiological studies indicate that comorbid AD and CVD is common20). Several studies have reported that vascular risk factors (VRFs), such as hypertension, hypercholesterolemia, and diabetes mellitus, are associated with an increased risk of developing AD21,22,23). Furthermore, it has been reported that VRFs are correlated with CVD24). The most common comorbidity in AD is stroke, and more specifically, ischemic infarction25). A recent cohort study has provided evidence that a history of stroke conferred a more than 2-fold increase in the risk of late-onset AD26). Cerebral MRI is useful to visually assess the extent of CVD and cerebral white matter lesions (WML), thus constituting imaging biomarkers of CVD27,28).
Using amyloid PET to assess Aβ accumulation in different brain regions is useful when investigating the association between cerebral ischemic changes and Aβ accumulation. We used 11C-PiB PET and MRI to investigate the association between cerebral Aβ accumulation and CVD in AD patients29) and revealed that higher WML scores significantly correlated with lower mean cortical SUVRs, especially in the frontal region, suggesting that more severe ischemic MRI findings are associated with milder Aβ accumulation in AD patients. We concluded that CVD may hasten the onset of cognitive decline and promote early detection of dementia. Supporting our findings, others have reported that the simultaneous presence of Aβ and CVD pathologies, compared to either pathology alone, significantly accelerates the rate of cognitive decline30). The results of various clinical studies on amyloid PET indicate that CVD and Aβ accumulation are thought to be independent processes in the clinical course of AD but additively affect cognitive decline30,31). On the contrary, Bannai et al . indicated that the reduced blood flow observed in the cerebral arteries attenuated the dynamics of the interstitial fluid leading to congestion and subsequently facilitated Aβ aggregation in the AD mouse model32). These findings suggest an interaction between CVD and Aβ accumulation in AD patients; further investigations and clinical studies are required to clarify this complex relationship.
In conclusion, amyloid PET can be used to evaluate Aβ accumulation in different brain regions and is useful when investigating the association between Aβ accumulation and CVD. Various studies describe the association between Aβ accumulation and CVD and have shown that CVD in AD patients may accelerate the occurrence of cognitive decline. To prevent cognitive decline in AD patients, it is important to manage VRFs and prevent any degradation with the progression of CVD.
This study was supported, in part, by an “Grants-in-Aid for Scientific Research (C) (21K15675 to H.K)” award from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Disclosures: The authors have no potential conflicts of interest to declare.
