Neuropathologic Correlates of Human Cortical Proteins in Alzheimer Disease and Related Dementias

Background and Objectives:Alzheimer’s dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that are implicated in Alzheimer’s dementia. To understand the pathologic correlates of these proteins for underlying disease mechanisms, we investigated cortical protein associations with common age-related neuropathologies.Methods:Participants were community-dwelling older adults from two cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We refer Alzheimer’s disease (AD) to pathologically defined disease, and refer Alzheimer’s dementia to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis, macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriolosclerosis were quantified during uniform structured neuropathologic evaluations. High-throughput protein abundances from frozen dorsolateral prefrontal cortex were quantified using mass spectrometry based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer’s dementia, including ACE, CHSP1, CATH, DOC2A, ICA1L, LACTB, PKHA1, RTF2, SNX32, STX4, and STX6, were previously identified using an integrative approach. Logistic regression analysis examined the association of protein expression with each of the neuropathologic indices.Results:A total of 391 older adults were included. We did not observe associations of these protein targets with pathologic diagnosis of AD. By contrast, multiple proteins were associated with non-AD neurodegenerative and cerebrovascular conditions. In particular, higher CHSP1 expression was associated with cortical Lewy bodies and macroscopic infarcts, and higher CATH expression was associated with LATE-NC and arteriolosclerosis. Further, while higher STX6 expression increased the risk of Alzheimer’s dementia, the protein was not associated with any of the neuropathologic indices investigated.Discussion:Cortical proteins implicated in Alzheimer’s dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases, as well as other pathways are at play. Further, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.

Dementia with Lewy bodies

Lewy bodies are spherical neuronal inclusions, first described by the German neuropathologist Friederich Lewy while working in Alzheimer's laboratory in Munich in 1912. In 1961, Okazaki published case reports about two elderly men who presented with dementia and died shortly after with severe extrapyramidal rigidity. Autopsy showed Lewy bodies in their cerebral cortex. Over the next 20 years, 34 similar cases were reported, all by Japanese workers. Lewy body disease was thus considered to be a rare cause of dementia, until a series of studies in Europe and North America, in the late 1980s, identified Lewy bodies in the brains of between 15 and 20 per cent of elderly demented cases reaching autopsy. Dementia with Lewy bodies (DLB) is unlikely to be a newly occurring disorder, since re-examination of autopsy material collected from elderly demented patients in Newcastle during the 1960s, reveals cortical Lewy bodies in 17 per cent of cases. The recent recognition of DLB as the second most common form of degenerative dementia in old age is largely due to the widespread use of improved neuropathological techniques, initially antiubiquitin immunocytochemistry, and more recently specific staining for alpha-synuclein which is a core constituent of Lewy bodies and related lesions.

Dementia in Parkinson's Disease Correlates withα-Synuclein Pathology but Not with Cortical Astrogliosis

Dementia is a common feature in Parkinson’s disease (PD) and is considered to be the result of limbic and cortical Lewy bodies and/or Alzheimer changes. Astrogliosis may also affect the development of dementia, since it correlates well with declining cognition in Alzheimer patients. Thus, we determined whether cortical astrogliosis occurs in PD, whether it is related to dementia, and whether this is reflected by the presence of glial fibrillary acidic protein (GFAP) and vimentin in cerebrospinal fluid (CSF). We have examined these proteins by immunohistochemistry in the frontal cortex and by Western blot in CSF of cases with PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and nondemented controls. We were neither able to detect an increase in cortical astrogliosis in PD, PDD, or DLB nor could we observe a correlation between the extent of astrogliosis and the degree of dementia. The levels of GFAP and vimentin in CSF did not correlate to the extent of astrogliosis or dementia. We did confirm the previously identified positive correlation between the presence of cortical Lewy bodies and dementia in PD. In conclusion, we have shown that cortical astrogliosis is not associated with the cognitive decline in Lewy body-related dementia.