Regional Glymphatic Abnormality in Behavioral Variant Frontotemporal Dementia

Jiang, Deming; Liu, Li; Kong, Yu; Chen, Zhongyun; Rosa‐Neto, Pedro; Chen, Kewei; Ren, Liqiang; Chen, Min; Wu, Liyong; Initiative, Frontotemporal Lobar Degeneration Neuroimaging

doi:10.1002/ana.26710

Cited by 23 publications

(10 citation statements)

References 57 publications

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“…1 A–C. As previously noted in a prior study [ 28 ], it was suggested that ROIs in the anterior and posterior regions may exhibit distinct regional glymphatic clearance effects. Therefore, we conducted further adjustments by shifting our manually corrected middle ROIs one and two voxels forward and one and two voxels backward along the y -axis.…”

Section: Methodssupporting

confidence: 57%

“…This method has also been applied to quantify in vivo glymphatic activity in various neurological disorders, including idiopathic normal pressure hydrocephalus (iNPH) [ 25 ], Parkinson’s disease [ 26 ], and multiple sclerosis [ 27 ] (MS), consistently revealing that reduced DTI-ALPS values are associated with disease severity. Choroid plexus volume, suggested as a driving force behind glymphatic function, has demonstrated associations with disease severity in conditions like frontotemporal dementia (FTD) [ 28 ] and AD [ 29 ] and has been used to predict conversion to Parkinson’s disease dementia [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer’s disease continuum participants

Hong,

Luo

et al. 2024

Alz Res Therapy

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Background Glymphatic dysfunction is a crucial pathway for dementia. Alzheimer’s disease (AD) pathologies co-existing with cerebral small vessel disease (CSVD) is the most common pathogenesis for dementia. We hypothesize that AD pathologies and CSVD could be associated with glymphatic dysfunction, contributing to cognitive impairment. Method Participants completed with amyloid PET, diffusion tensor imaging (DTI), and T2 fluid-attenuated inversion-recovery (FLAIR) sequences were included from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). White matter hyperintensities (WMH), the most common CSVD marker, was evaluated from T2FLAIR images and represented the burden of CSVD. Amyloid PET was used to assess Aβ aggregation in the brain. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, the burden of enlarged perivascular spaces (PVS), and choroid plexus volume to reflect glymphatic function. The relationships between WMH burden/Aβ aggregation and these glymphatic markers as well as the correlations between glymphatic markers and cognitive function were investigated. Furthermore, we conducted mediation analyses to explore the potential mediating effects of glymphatic markers in the relationship between WMH burden/Aβ aggregation and cognition. Results One hundred and thirty-three participants along the AD continuum were included, consisting of 40 CN − , 48 CN + , 26 MCI + , and 19 AD + participants. Our findings revealed that there were negative associations between whole-brain Aβ aggregation (r = − 0.249, p = 0.022) and WMH burden (r = − 0.458, p < 0.001) with DTI-ALPS. Additionally, Aβ aggregation (r = 0.223, p = 0.041) and WMH burden (r = 0.294, p = 0.006) were both positively associated with choroid plexus volume. However, we did not observe significant correlations with PVS enlargement severity. DTI-ALPS was positively associated with memory (r = 0.470, FDR-p < 0.001), executive function (r = 0.358, FDR-p = 0.001), visual-spatial (r = 0.223, FDR-p < 0.040), and language (r = 0.419, FDR-p < 0.001). Conversely, choroid plexus volume showed negative correlations with memory (r = − 0.315, FDR-p = 0.007), executive function (r = − 0.321, FDR-p = 0.007), visual-spatial (r = − 0.233, FDR-p = 0.031), and language (r = − 0.261, FDR-p = 0.021). There were no significant correlations between PVS enlargement severity and cognitive performance. In the mediation analysis, we found that DTI-ALPS acted as a mediator in the relationship between WMH burden/Aβ accumulation and memory and language performances. Conclusion Our study provided evidence that both AD pathology (Aβ) and CSVD were associated with glymphatic dysfunction, which is further related to cognitive impairment. These results may provide a theoretical basis for new targets for treating AD.

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Section: Methodssupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer’s disease continuum participants

Hong,

Luo

et al. 2024

Alz Res Therapy

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“…First, the efficacy of the ALPS index in detecting human glymphatic function has not yet been substantially and rigorously validated by pathophysiological studies. While the ALPS index has been confirmed by glymphatic MRI 11 and has been extensively studied in various diseases, 14,15,51 it should be interpreted with caution. Second, the ALPS index was used to assess the global glymphatic activity and cannot reflect regional glymphatic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease

Huang,

Zhang,

Guo

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONAlthough glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood.METHODSWhole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative.RESULTSALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid‐positive transition and clinical progression, and faster rates of amyloid‐ and neurodegeneration‐related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy.DISCUSSIONGlymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.Highlights The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aβ) positron emission tomography (PET) burden and Aβ‐positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aβ42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aβ PET and brain atrophy mediated the link of ALPS index with cognitive decline.

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“…30 Recently, several methods have been developed that may reveal regional glymphatic activity. [54][55][56] Therefore, the relationship between the DTI-ALPS index and glycemic clearance should be interpreted with caution. The sequential effect among glymphatic dysfunction, tau deposition, and clinical symptoms needs to be verified in longitudinal studies.…”

Section: Limitationsmentioning

confidence: 99%

Dominance of Tau Burden in Cortical Over Subcortical Regions Mediates Glymphatic Activity and Clinical Severity in PSP

Hsu,

Wei,

Hsiao

et al. 2024

Clin Nucl Med

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Background Progressive supranuclear palsy (PSP) is a tauopathy that involves subcortical regions but also extends to cortical areas. The clinical impact of different tau protein sites and their influence on glymphatic dysfunction have not been investigated. Patients and Methods Participants (n = 55; 65.6 ± 7.1 years; 29 women) with PSP (n = 32) and age-matched normal controls (NCs; n = 23) underwent 18F-Florzolotau tau PET, MRI, PSP Rating Scale (PSPRS), and Mini-Mental State Examination. Cerebellar gray matter (GM) and parametric estimation of reference signal intensity were used as references for tau burden measured by SUV ratios. Glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS). Results Parametric estimation of reference signal intensity is a better reference than cerebellar GM to distinguish tau burden between PSP and NCs. PSP patients showed higher cortical and subcortical tau SUV ratios than NCs (P < 0.001 and <0.001). Cortical and subcortical tau deposition correlated with PSPRS, UPDRS, and Mini-Mental State Examination scores (all P’s < 0.05). Cortical tau deposition was further associated with the DTI-ALPS index and frontal-temporal-parietal GM atrophy. The DTI-ALPS indexes showed a significantly negative correlation with the PSPRS total scores (P < 0.01). Finally, parietal and occipital lobe tau depositions showed mediating effects between the DTI-ALPS index and PSPRS score. Conclusions Cortical tau deposition is associated with glymphatic dysfunction and plays a role in mediating glymphatic dysfunction and clinical severity. Our results provide a possible explanation for the worsening of clinical severity in patients with PSP.

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Regional Glymphatic Abnormality in Behavioral Variant Frontotemporal Dementia

Cited by 23 publications

References 57 publications

The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer’s disease continuum participants

The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer’s disease continuum participants

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease

Dominance of Tau Burden in Cortical Over Subcortical Regions Mediates Glymphatic Activity and Clinical Severity in PSP

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