Citations

Abstract Introduction Neuroimaging biomarkers are important for early diagnosis of Alzheimer's disease, and comparing multimodality neuroimaging to autopsy data is essential. Methods We compared the pathologic findings from a prospective autopsy cohort (n = 100) to Pittsburgh compound B PET (PiB‐PET), 18 F‐fluorodeoxyglucose PET (FDG‐PET), and MRI. Correlations between neuroimaging biomarkers and neuropathologic schemes were assessed. Results PiB‐PET showed strong correlations with Thal amyloid phase and Consortium to Establish a Registry for Alzheimer's Disease score and categorized 44% of Thal phase 1 participants as positive. FDG‐PET and MRI correlated modestly with Braak tangle stage in Alzheimer's type pathology. A subset of participants with “none” or “sparse” neuritic plaque scores had elevated PiB‐PET signal due to diffuse amyloid plaque. Participants with findings characterized as “suspected non‐Alzheimer's pathophysiology” represented 15% of the group. Discussion PiB‐PET is associated with Alzheimer's disease, neuritic plaques, and diffuse plaques. FDG‐PET and MRI have modest correlation with neuropathologic schemes. Participants with findings characterized as suspected non‐Alzheimer's pathophysiology most commonly had primary age‐related tauopathy.

AbstractIntroductionPrimary age‐related tauopathy (PART) is characterized by the presence of neurofibrillary tangles and absent‐minimal β‐amyloid deposition. Transactive response DNA‐binding protein of 43 kDa (TDP‐43), a third protein, has recently garnished a lot of attention in Alzheimer's disease where it is associated with memory loss and amygdala and hippocampal atrophy. We aimed to determine whether TDP‐43 is associated with brain atrophy in PART.MethodsWe assessed the frequency of TDP‐43 in PART and performed voxel‐level analysis in SPM12, as well as region‐of‐interest analysis using linear regression modeling, controlling for variables of interest, to assess for associations between TDP‐43 and brain atrophy.ResultsOf 116 PART cases, 31 (26.7%) had TDP‐43. The presence of TDP‐43 was associated with significantly greater amygdala, hippocampal, and anterior temporal atrophy in both the region‐of‐interest and the voxel level analyses.DiscussionTDP‐43 is associated with greater brain atrophy in PART.

AbstractIntroductionOur primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy‐confirmed cohort of Alzheimer's disease cases.MethodsA retrospective study was conducted in the Florida Autopsied Multi‐Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self‐reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539).ResultsHispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups.DiscussionDespite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.

Abstract While the accumulation and aggregation of amyloid-β and tau are central events in the pathogenesis of Alzheimer’s disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer’s disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood–brain barrier. Because the blood–brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer’s disease pathogenesis. However, the pathological relationship between blood–brain barrier properties and Alzheimer’s disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer’s disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer’s disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer’s disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer’s disease-related proteins, in particular amyloid-β40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer’s disease is associated with insoluble amyloid-β40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-β40, amyloid-β42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer’s disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer’s disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer’s disease pathogenesis in both synergistic and additive manners to typical amyloid-β and tau pathologies.

Abstract Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART ) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross‐PIA white paper that provides both a concise “state‐of‐the‐science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.