Cerebrospinal Fluid Total Tau Protein Correlates With Longitudinal, Progressing Cognitive Dysfunction in Anti-Neural Autoantibody-Associated Dementia and Alzheimer’s Dementia: A Case–Control Study

Abstract

BackgroundNeural autoantibody-associated dementia (NABD) is an increasing phenomenon in memory clinics with a high impact on later therapy. Biomarkers are lacking that differentiate this type of dementia from neurodegenerative dementia such as Alzheimer’s dementia (AD). Our aim is to analyze neurodegeneration markers and their relationship to progressing cognitive dysfunction in NABD and AD to test for tools differentiating these two forms of dementia prior to neural autoantibody testing.MethodsIn our retrospective, observational study, we investigated 14 patients with dementia and serum and/or cerebrospinal fluid (CSF) neural autoantibodies as well as 14 patients with AD by relying on recent CSF and clinical criteria for AD. Patient files were checked for psychopathology, neuropsychological test performance, autoimmune indicators, CSF, and MRI results.ResultsOur patient groups did not differ in their psychopathology, autoimmune indicators, or MRI profile. The progression of cognitive dysfunction [as measured by the difference in Mini-Mental State Examination (MMSE) scores since disease onset, and the yearly progression rate (MMSE loss/per year)] did not vary significantly between groups. Total tau protein was significantly higher in AD patients than NABD patients revealing no signs of Alzheimer’s disease pathology in their CSF (p < 0.05). Total tau protein levels in CSF correlated with cognitive decline since disease onset (r = 0.38, p < 0.05) and yearly progression rates (r = 0.56, p < 0.005) in all patients.DiscussionOur results suggest that the progression of cognitive dysfunction as defined by MMSE does not seem to be an appropriate biomarker for distinguishing NABD from AD. However, the total tau protein level in CSF might be a relevant molecular biomarker that can indicate disease pathology and/or progression in both known AD and NABD, which is often accompanied by axonal degeneration. Total tau protein may be an additional diagnostic tool with which to differentiate anti-neural-associated dementia from AD if further research confirms these proof-of-concept findings in larger patient cohorts.

Prevalence of Anti-neural Autoantibodies in a Psychiatric Patient Cohort-Paradigmatic Application of Criteria for Autoimmune-Based Psychiatric Syndromes

“…Thus, in our delirium patients, it is unclear if the autoantibodies present are associated with the dementia condition or the delirium, and more research is necessary to clarify this question. Neural autoantibody- associated dementia ( 1 , 3 – 5 ) is a growing field in immunopsychiatry that deserves further attention. In an earlier study we showed that a substantial proportion of patients with cognitive impairment reveal an association with neural autoantibodies ( 4 ).…”

“…Furthermore, cell membrane-surface ( 11 – 16 ) and intracellular antibodies ( 17 , 18 ) have been reported in delirium states. Neural autoantibodies occur in cognitive impairment ( 1 , 3 – 5 ), which is known to be a risk factor for triggering delirium ( 19 ). It thus makes sense to look for autoantibodies especially in patients with delirium and preexisting cognitive dysfunction.…”

Biomarkers of neurodegeneration in neural autoantibody-associated psychiatric syndromes: A retrospective cohort study

“…This finding confirms studies that reported AD associated with significantly decreased Aβ42 and a lower ratio Aβ42/40 compared to patients suffering from autoantibody-associated cognitive dysfunction [ 26 ]. Tau enables us to distinguish between AD and autoantibody-associated dementia, since this biomarker is significantly elevated in AD patients [ 27 ]. Another of our studies' findings is that the Ab-p group's neurodegeneration biomarkers did not differ significantly between syndromes.…”

“…However, note that as the ptau 181 neurodegeneration biomarker failed to differ significantly between our antibody-positive cohort and AD cohort, this evidence can be interpreted as an indication of axonal neurodegeneration in the antibody-positive group. Elevated ptau 181 in autoantibody-associated psychiatric disorders has been demonstrated [ 27 , [34] , [35] , [36] , [37] ], and should be further validated in large-scale studies, as this is where diagnostic and therapeutic opportunities lie for psychiatric patients. Our finding that psycho-organic syndrome showed the most severe neurodegeneration among syndromes was expected because of its organic component and its overlap with symptoms of neurodegenerative dementia pathologies.…”

Autoantibodies targeting neuronal proteins as biomarkers for neurodegenerative diseases

“…This process may lead to the emergence of immune cells producing Ab reacting to surface proteins of intact neurons and other brain cells, as well as peptides and proteins released after their pathological breakdown 38 - 40 . Such autoimmune reaction has been implicated in autoimmune response-related psychosis and schizophrenia 41 , 42 as well as neural autoantibody-associated dementias (NABD) with signs of axonal degeneration 43 , 44 . Quantitative analysis and profiling of Aabs targeting neuronal proteins, may, therefore, provide specific and instructive information on the onset, mechanisms, and severity of brain pathology.…”