Amyloid-Tau-Neurodegeneration Profiles and Longitudinal Cognition in Sporadic Young-Onset Dementia.

We examined amyloid-tau-neurodegeneration biomarker effects on cognition in a Southeast-Asian cohort of 84 sporadic young-onset dementia (YOD; age-at-onset <65 years) patients. They were stratified into A+N+, A- N+, and A- N- profiles via cerebrospinal fluid amyloid-ß1-42 (A), phosphorylated-tau (T), MRI medial temporal atrophy (neurodegeneration- N), and confluent white matter hyperintensities cerebrovascular disease (CVD). A, T, and CVD effects on longitudinal Mini-Mental State Examination (MMSE) were evaluated. A+N+ patients demonstrated steeper MMSE decline than A- N+ (ß = 1.53; p = 0.036; CI 0.15:2.92) and A- N- (ß = 4.68; p = 0.001; CI 1.98:7.38) over a mean follow-up of 1.24 years. Within A- N+, T- CVD+ patients showed greater MMSE decline compared to T+CVD- patients (ß = - 2.37; p = 0.030; CI - 4.41:- 0.39). A+ results in significant cognitive decline, while CVD influences longitudinal cognition in the A- sub-group.

Safety and Usefulness of Lumbar Puncture for the Diagnosis and Management of Young-Onset Cognitive Disorders.

BACKGROUND: Young-onset cognitive disorders (YOCD) often manifests with complex and atypical presentations due to underlying heterogenous pathologies. Therefore, a biomarker-based evaluation will allow for timely diagnosis and definitive management. OBJECTIVE: Here, we evaluated the safety and usefulness of cerebrospinal fluid (CSF) sampling through lumbar puncture (LP) in YOCD patients in a tertiary clinical setting. METHODS: Patients with mild cognitive impairment (MCI) and mild dementia with age of onset between 45-64 years were evaluated. Patients underwent magnetic resonance imaging and their medial temporal lobe atrophy (MTA) was rated. LP side-effects and the impact of the CSF findings on diagnosis and management were analyzed. RESULTS: 142 patients (53 (37.32%) MCI, 51 (35.92%) dementia of the Alzheimer's disease [DAT] type, and 38 (26.76%) non-AD type dementia) who underwent LP between 2015 to 2021 were analyzed. Using post-LP results and MTA ratings, 74 (52.11%) patients met the AT(N) criteria for AD. 56 (39.44%) patients (28 out of 53 (50.0%) MCI, 12 out of 51 (21.43%) DAT, and 16 out of 38 (28.57%) non-AD dementia) had a change in diagnosis following LP. 13 (9.15%) patients developed side-effects post-LP (11 (84.62%) patients had headache, 1 (7.69%) patient had backache, and 1 (7.69%) patient had headache and backache). 32 (22.54%) patients had a change in management post-LP, 24 (75.0%) had medication changes, 10 (31.30%) had referrals to other specialists, and 3 (9.40%) was referred for clinical trial with disease modifying interventions. CONCLUSION: LP is well-tolerated in YOCD and can bring about relevant clinical decisions with regards to the diagnosis and management of this complex clinical condition.

Association between white matter hyperintensity load and grey matter atrophy in mild cognitive impairment is not unidirectional.

Neuroimaging measures of Alzheimer's disease (AD) include grey matter volume (GMV) alterations in the Default Mode Network (DMN) and Executive Control Network (ECN). Small-vessel cerebrovascular disease, often visualised as white matter hyperintensities (WMH) on MRI, is often seen in AD. However, the relationship between WMH load and GMV needs further examination. We examined the load-dependent influence of WMH on GMV and cognition in 183 subjects. T1-MRI data from 93 Mild Cognitive Impairment (MCI) and 90 cognitively normal subjects were studied and WMH load was categorized into low, medium and high terciles. We examined how differing loads of WMH related to whole-brain voxel-wise and regional DMN and ECN GMV. We further investigated how regional GMV moderated the relationship between WMH and cognition. We found differential load-dependent effects of WMH burden on voxel-wise and regional atrophy in only MCI. At high load, as expected WMH negatively related to both ECN and DMN GMV, however at low load, WMH positively related to ECN GMV. Additionally, negative associations between WMH and memory and executive function were moderated by regional GMV. Our results demonstrate non-unidirectional relationships between WMH load, GMV and cognition in MCI.

Cerebral Small Vessel Disease Influences Hippocampal Subfield Atrophy in Mild Cognitive Impairment.

To investigate patterns of hippocampal subfield atrophy among patients with amnestic mild cognitive impairment, stratified by severity of small vessel disease (SVD) and corresponding associations with cognitive domains. One hundred seventy-six MCI subjects (mean age = 65.56 years, SD = 8.77) underwent neuropsychological assessments and magnetic resonance imaging. SVD was rated 0 (no SVD), 1 (mild SVD) and 2 (moderate to severe SVD) based on load of white matter hyperintensities (WMH) and lacunes. Demographics, cerebrovascular risk factors, grey and white matter volumes and hippocampal subfield atrophies were compared across SVD severity through ANCOVA analyses. Subjects were categorized into positive or negative SVD-hippocampal subfield atrophy (HSA) and influence of positive SVD-HSA on episodic memory and frontal executive function was evaluated through ANCOVA analyses. All analyses corrected for covariates and bias-corrected bootstrap estimation with 1000 resamples was applied with Bonferroni correction. Hippocampal subfield atrophy worsened with increasing SVD severity. Positive SVD-HSA was characterised by significant atrophy in the subiculum, CA1, CA4, molecular layer and dentate gyrus. Greater atrophy was seen with moderate to severe SVD compared to mild SVD in these subfields. Atrophy in the five subfields of SVD-HSA was significantly associated with poor episodic memory and frontal executive function. Presence and burden of SVD influences the pattern and severity of hippocampal subfield atrophy. SVD-related hippocampal subfield atrophy is associated with poorer episodic memory and frontal executive function in mild cognitive impairment.

Age Moderates Associations of Hypertension, White Matter Hyperintensities, and Cognition.

BACKGROUND: Hypertension and white matter hyperintensities (WMH) are mutually associated risk factors for cognitive impairment. However, age may modify the associations between hypertension and WMH, and their links to cognitive impairment. OBJECTIVE: We evaluated the interaction between age and hypertension on WMH, and the age-stratified associations of hypertension and WMH with cognition. METHODS: Key measures include systolic blood pressure (SBP), WMH (modified Fazekas visual ratings of cranial MRI), and the Montreal Cognitive Assessment (MoCA). Participants (N = 488) with prodromal and mild dementia were age-stratified (≤49, 50-59, 60-69,≥70), and considered hypertensive if their SBP≥140 mmHg. The interaction between age strata and hypertension on WMH, and age-stratified associations of hypertension and WMH with cognition, were evaluated using multiple linear regression analyses. Analyses controlled for other risk factors for WMH and cognitive impairment. RESULTS: Age moderated the association between SBP and WMH. Hypertension was associated with higher WMH only in those aged 60-69, and WMH trends across age bands differed between those with and without hypertension. Finally, WMH and SBP≥140 were independently associated with lower MoCA scores within the 50-59 age band, while WMH alone was associated with poorer MoCA scores in the≥70 age band. CONCLUSION: In adults with prodromal or mild dementia, hypertension was associated with WMH specifically in the 60-69 age strata. Associations between hypertension and WMH with poorer cognition also differed across age bands. Future studies will be needed to investigate whether blood pressure management to slow cognitive decline by targeting WMH may be age dependent.

Medial Temporal Atrophy in Amyloid-Negative Amnestic Type Dementia Is Associated with High Cerebral White Matter Hyperintensity.

BACKGROUND: Non-amyloid mechanisms behind neurodegeneration and cognition impairment are unclear. Cerebrovascular disease (CVD) may play an important role in suspected non-Alzheimer's pathophysiology (SNAP), especially in Asia. OBJECTIVE: To examine the association between CVD and medial temporal lobe atrophy (MTA) in amyloid-ß negative patients with mild amnestic type dementia. METHODS: Thirty-six mild dementia patients with complete neuropsychological, cerebrospinal fluid (CSF) biomarker, and neuroimaging information were included. Only patients with clinically significant MTA were recruited. Patients were categorized based on their CSF Aß levels. Neuroimaging and neuropsychological variables were analyzed. RESULTS: Despite comparable MTA between Aß positive and negative patients, Aß-negative patients had significantly greater white matter hyperintensities (WMH; Total Fazekas Rating) than their Aß-positive counterparts (6.42 versus 4.19, p = 0.03). A larger proportion of Aß-negative patients also had severe and confluent WMH. Regression analyses controlling for baseline characteristics yielded consistent results. CONCLUSION: Our findings demonstrate that MTA is associated with greater CVD burden among Aß-negative patients with amnestic type dementia. CVD may be an important mechanism behind hippocampal atrophy. This has implications on clinical management strategies, where measures to reduce CVD may slow neurodegeneration and disease progression.