Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer’s disease

Visser, Pieter Jelle; Lm, Reus; Gobom, Johan; Jansen, Iris E.; Dicks, Ellen; Tsolaki, Magda; Fr, Verhey; Popp, Julius; Martínez-Lage, Pablo; Vandenberghe, Rik; Lleó, Alberto; Jl, Molinuevo; Engelborghs, Sebastiaan; Freund‐Levi, Yvonne; Froelich, Lutz; Sleegers, Kristel; Dobricic,; Hong, Shengjun; Lovestone, Simon; Streffer, Johannes; Sj, Vos; Bos, Inge; Ab, Smit; Blennow, Kaj; Scheltens, Philip; Ce, Teunissen; Bertram, Lars; Zetterberg, Henrik; Bm, Tijms

doi:10.1101/2020.10.29.20211920

Cited by 6 publications

(6 citation statements)

References 74 publications

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“…Unlike PET measures of fibrillar amyloid deposits in brain, low concentrations of CSF Aβ 42 in AD were strongly associated with synaptic proteins that increased in CSF and decreased in brain (16). These changes begin early in the asymptomatic phases of disease (10,16,17) and, together with the metabolic changes noted above, may reflect synaptic plasticity, microglial pruning, and extrusion of synaptic material, as we and others have discussed previously (16,27). We speculate that reductions in CSF Aβ 42 thus reflect changes in synaptic biology rather than deposition into plaques in brain.…”

Section: Discussionmentioning

confidence: 65%

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer’s disease

Haque,

Watson,

Liu

et al. 2023

Sci. Transl. Med.

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Alzheimer’s disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry–selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer’s Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aβ 42 , tTau, and pTau 181 ) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.

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Section: Discussionmentioning

confidence: 65%

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer’s disease

Haque,

Watson,

Liu

et al. 2023

Sci. Transl. Med.

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“…There was also a significant interaction between delusional severity and tau burden, consistent with prior literature suggesting a putative role for tau in mediating psychosis in dementia [12] and providing further evidence that tau's role may be even more prominent in patients with more severe psychopathology. CSF tau is a microtubule-associated protein located in neuronal axons [31], and increased CSF tau levels are related to axonal loss [32] and neuronal degeneration [31]. As was shown, the NABM volume and integrity biomarkers in particular had significant interactions between the highest delusional severity and CSF tau, suggesting tau may play a role in disrupting the structural integrity of the NABM of delusional subjects.…”

Section: Discussionmentioning

confidence: 84%

Delusional Severity Is Associated with Abnormal Texture in FLAIR MRI

Khoury¹,

Bahsoun²,

Fadhel³

et al. 2022

Preprint

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<p>Background: This study examines the relationship between delusional severity in cognitively impaired adults with automatically computed volume and texture biomarkers from the Normal Appearing Brain Matter (NABM) in FLAIR MRI. Methods: Patients with mild cognitive impairment (MCI, n = 24) and Alzheimer's Disease (AD, n = 18) with delusions of varying severities based on Neuropsychiatric Inventory-Questionnaire (NPI-Q) (1-mild, 2-moderate, 3-severe) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed for this task. The NABM region, which is gray matter (GM) and white matter (WM) combined, was automatically segmented in FLAIR MRI volumes with intensity standardization and thresholding. Three imaging biomarkers were computed from this region, including NABM volume and two texture markers called "Integrity" and "Damage". Together, these imaging biomarkers quantify structural changes in brain volume, microstructural integrity and tissue damage. Multivariable regression was used to investigate relationships between imaging biomarkers and delusional severities (1, 2 and 3). Sex, age, education, APOE4 and baseline cerebrospinal fluid (CSF) tau were included as co-variates. Results: Biomarkers were extracted from a total of 42 participants with longitudinal time points representing 164 imaging volumes. Significant associations were found for all three NABM biomarkers between delusion level 3 and level 1. Integrity was also sensitive enough to show differences between delusion level 1 and delusion level 2. A significant specified interaction was noted with severe delusions (level 3) and CSF tau for all imaging biomarkers (p < 0.01). APOE4 homozygotes were also significantly related to the biomarkers. Conclusion: Cognitively impaired older adults with more severe delusions have greater global brain disease burden in the WM and GM combined (NABM) as measured using FLAIR MRI. Relative to patients with mild delusions, tissue degeneration in the NABM was more pronounced in subjects with higher delusional symptoms, with a significant association with CSF tau. Future studies are required to establish potential tau-associated mechanisms of increased delusional severity. </p>

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“…Diagnosis of the disorder is complex and patients often face underdiagnosis because of the difficulty identifying initial symptoms, with diagnosis typically being late, when cognitive impairment has become severe. Currently, AD is recognized by a group of clinical symptoms perceived by the patient and/or family members, together with neuropsychological screening tests such as the Mini-Mental state Exam (MMSE), and complementary imaging scans such as MRI 3,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Physiopathologically, AD is characterized by the aggregation of beta-amyloid (Aβ) proteins associated with the pathological alteration in the tau protein, where elevated levels in cerebrospinal fluid (CSF) are explained by axonal loss. In addition, the acetylcholine neurotransmitter (ACh) undergoes changes in its function and is low in the brain of AD patients, an event associated with cognitive damage 5,7,8 .…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease: a case study involving the most prevalent neurocognitive disorder in older people

Zanotto

Pivatto

Pinculini

et al. 2023

Rev. bras. geriatr. gerontol.

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Objective To analyze the clinical evolution of a patient affected by Alzheimer's disease and discuss the repercussions of an early diagnosis. Method Instrumental case study of qualitative and descriptive type that was developed in three stages: 1) selection and delimitation of the case; 2) collection of data in the field; and 3) organization and writing of the report. This study is based on the analysis of the clinical evolution described in the medical records of a patient diagnosed with Alzheimer's disease, treated and followed-up by the Center for Psychosocial Care (CAPS), for a period of 10 years, in the Alto Vale do Rio do Peixe region. Results This study was conducted with the patient M.R., female, 71 years old, married, housewife, with incomplete elementary education, carrier of AD and hypothyroidism, who started her follow-up at CAPS II on September 10, 2012. Patient submitted to the Mini Mental State Examination (MMSE), with a result of 14 points in the first test, below the cut-off point for the patient's level of education. Later, in 2018, she scored 10 points on the MMSE, and in 2020 she scored 11, already under medication treatment for AD: memantine 10mg 2x/day and donepezilla 5mg 1x/day. Conclusion Early diagnosis of AD is extremely important for appropriate treatment to slow the progression of the disease. However, mental disorders such as depression are barriers in the initial clinical analysis of patients and in some cases presents itself as a prodrome for AD.

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Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer’s disease

Cited by 6 publications

References 74 publications

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer’s disease

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer’s disease

Delusional Severity Is Associated with Abnormal Texture in FLAIR MRI

Alzheimer’s disease: a case study involving the most prevalent neurocognitive disorder in older people

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