Cerebrovascular disease is common in patients on the Lewy body (LB) continuum (dementia with Lewy bodies (DLB) and prodromal-DLB). White matter signal abnormality (WMSA) volume is higher in patients with LB than controls, both globally and in cholinergic white matter. However, it remains unknown if the higher WMSA in cholinergic white matter reflects selective cholinergic vulnerability or results from higher global WMSA. We modelled cingulate and external capsule cholinergic white matter pathways using MRI and segmented WMSA overlapping cholinergic pathways and per brain lobe. We found that patients on the LB-continuum (n = 33) had higher volume and proportion of WMSA in the cholinergic white matter compared to controls (n = 36), independent of global WMSA. Cholinergic WMSA was associated with neurodegeneration in the basal forebrain, decreased integrity of cingulate and external capsule pathways and attention and memory performance. These findings may suggest a selective vulnerability of cholinergic pathways in patients with LB.

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• Journal Article MeSH

Dementia with Lewy bodies often presents with cholinergic degeneration and varying degrees of cerebrovascular disease. There is a lack of radiological methods for evaluating cholinergic degeneration in dementia with Lewy bodies. We investigated the potential of the Cholinergic Pathway Hyperintensities Scale (CHIPS) in identifying cerebrovascular disease-related disruptions in cholinergic white matter pathways, offering a practical and accessible method for assessing cholinergic integrity in neurodegenerative diseases. We assessed the associations of CHIPS with regional brain atrophy, Alzheimer's disease co-pathology and clinical phenotype. Additionally, we compared its diagnostic performance to that of other manual and automated evaluation methods. We included 82 individuals (41 patients in the Lewy body continuum with either probable dementia with Lewy bodies or mild cognitive impairment with Lewy bodies, and 41 healthy controls) from the Sant Pau Initiative on Neurodegeneration cohort. We used CHIPS to assess cholinergic white matter signal abnormalities (WMSA) on MRI, while tractography mean diffusivity provided a complementary measure of cholinergic WMSA. For global WMSA evaluation, we used the Fazekas scale and FreeSurfer. CHIPS successfully identified cerebrovascular disease-related disruptions in cholinergic white matter pathways, as evidenced by its association with tractography and global WMSA markers (P < 0.005 for all associations). Lewy body patients showed a significantly higher degree of WMSA in the external capsule cholinergic pathway despite no significant differences in global WMSA compared to controls. CHIPS score in the posterior external capsule and the mean diffusivity in the external capsule and cingulum exceeded the threshold for an optimal biomarker (sensitivity and specificity values above 80%) in discriminating Lewy body patients from controls. Furthermore, higher CHIPS scores, Fazekas scale and tractography mean diffusivity were associated with more pronounced frontal atrophy in Lewy body patients but not in controls. No associations were found for the four WMSA and integrity methods with the core clinical features, clinical or cognitive measures, or CSF biomarkers. In conclusion, cholinergic WMSA were more pronounced in Lewy body patients compared to healthy controls, independently of global WMSA. Our findings indicate that cerebrovascular disease-related disruptions in cholinergic white matter may be linked to frontal atrophy in Lewy body patients. Clinically, we demonstrate the potential of CHIPS to assess cholinergic WMSA using widely available MRI sequences. Our data suggest cerebrovascular disease co-pathology could drive the cholinergic degeneration in Lewy body patients, opening opportunities for therapeutic interventions targeting vascular health from mild cognitive impairment with Lewy bodies through manifest dementia with Lewy bodies.

• Keywords
• CHIPS, cholinergic white matter pathways, dementia with Lewy bodies, white matter signal abnormalities,
• Publication type
• Journal Article MeSH

Co-pathologies are common in dementia with Lewy bodies and other dementia disorders. We investigated cerebrovascular and Alzheimer's disease co-pathologies in patients with dementia with Lewy bodies in comparison with patients with mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia or Parkinson's disease with dementia and cognitively unimpaired participants. We assessed the association of biomarkers of cerebrovascular and Alzheimer's disease co-pathologies with medial temporal atrophy and global cognitive performance. Additionally, we evaluated whether the findings were specific to dementia with Lewy bodies. We gathered a multi-cohort dataset of 4549 participants (dementia with Lewy bodies = 331, cognitively unimpaired = 1505, mild cognitive impairment = 1489, Alzheimer's disease = 708, mixed dementia = 268, vascular dementia = 148, Parkinson's disease with dementia = 120) from the MemClin Study, Karolinska Imaging in Dementia Study, Gothenburg H70 Birth Cohort Studies and the European DLB Consortium. Cerebrovascular co-pathology was assessed with visual ratings of white matter hyperintensities using the Fazekas scale through structural imaging. Alzheimer's disease biomarkers of β-amyloid and phosphorylated tau were assessed in the cerebrospinal fluid for a subsample (N = 2191). Medial temporal atrophy was assessed with visual ratings and global cognition with the mini-mental state examination. Differences and associations were assessed through regression models, including interaction terms. In dementia with Lewy bodies, 43% had a high white matter hyperintensity load, which was significantly higher than that in cognitively unimpaired (14%), mild cognitive impairment (26%) and Alzheimer's disease (27%), but lower than that in vascular dementia (62%). In dementia with Lewy bodies, white matter hyperintensities were associated with medial temporal atrophy, and the interaction term showed that this association was stronger than that in cognitively unimpaired and mixed dementia. However, the association between white matter hyperintensities and medial temporal atrophy was non-significant when β-amyloid was included in the model. Instead, β-amyloid predicted medial temporal atrophy in dementia with Lewy bodies, in contrast to the findings in mild cognitive impairment where medial temporal atrophy scores were independent of β-amyloid. Dementia with Lewy bodies had the lowest performance on global cognition, but this was not associated with white matter hyperintensities. In Alzheimer's disease, global cognitive performance was lower in patients with more white matter hyperintensities. We conclude that white matter hyperintensities are common in dementia with Lewy bodies and are associated with more atrophy in medial temporal lobes, but this association depended on β-amyloid-related pathology in our cohort. The associations between biomarkers were overall stronger in dementia with Lewy bodies than in some of the other diagnostic groups.

• Keywords
• atrophy, imaging, multi-cohort, naturalistic cohort,
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• Journal Article MeSH

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

• Keywords
• atrophy, dementia with Lewy bodies, magnetic resonance imaging, sex differences,
• MeSH
• Alzheimer Disease * pathology   MeSH
• Atrophy pathology   MeSH
• Lewy Body Disease * diagnostic imaging   pathology   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Cerebral Cortex pathology   MeSH
• Sex Characteristics MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. We used data-driven analysis of magnetic resonance imaging (MRI) data to investigate DLB subtypes. We included 165 DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as β-amyloid, tau, and cerebrovascular biomarkers at baseline, and cognitive decline over three years. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n = 49, 30%); a subtype with low GM volumes in fronto-occipital regions (n = 76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n = 40, 24%). This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions.

• Publication type
• Journal Article MeSH