Dana M. Parker

Women face twice the lifetime risk of Alzheimer's disease (AD) compared with men. Inflammatory burden is widely implicated in AD, but whether sex-differentiated vulnerability is determined by cytokine levels or by the brain’s sensitivity to those signals remains unclear. Here, we examined sex-specific associations between peripheral inflammatory markers, medial temporal lobe (MTL) white matter microstructure using NODDI diffusion MRI, and hippocampal-dependent memory in 121 cognitively unimpaired older adults. Women exhibited widespread alterations in MTL white matter microstructure relative to men. In women, peripheral cytokines (TNFα, IL-10) were associated with microstructural variation in hippocampal-prefrontal tracts, whereas these associations were absent in men. An indirect association between TNFα and memory through hippocampal cingulum neurite density was observed only in women. Despite these microstructural and coupling differences, cytokine levels were comparable between sexes, indicating that risk may be better captured by the coupling between peripheral immune signals and circuit integrity than by cytokine levels alone. These findings identify a sex-specific pattern of immune-brain coupling that reframes inflammatory risk in AD as a property of circuit-level sensitivity rather than overall inflammatory burden.

Background: Tau pathology may contribute to the disruption of white matter (WM) integrity in Alzheimer's disease (AD). While previous work has shown global disruption to WM tracts, the specific spatial locations along the impacted tracts with disrupted integrity have yet to be identified. Tractometry is a method that utilizes diffusion MRI tractography to quantify spatial WM integrity by placing equidistant nodes along the length of WM tracts. We assessed WM integrity along the spatial extent of medial temporal lobe (MTL) WM tracts to determine tau pathology or cognitive impairment is associated with spatially specific patterns of WM integrity in older adults across the AD continuum. Method: A total of 159 older adults from ADNI3 (101 cognitively normal and 58 cognitively impaired [MCI/AD) underwent tau‐PET (18F‐Flortaucipir) and multishell diffusion MRI. Fractional anisotropy (FA), a measure of WM integrity, was calculated for each unilateral MTL tract (inferior longitudinal fasciculus [ILF], uncinate fasciculus [UF]) along 100 equidistant nodes using pyAFQ (Figure 1). Tau‐PET composite SUVRs were extracted from the entorhinal cortex and amygdala. A mixed effects model tested the main effects of tau and diagnosis on WM integrity, as well as their interactions by node to assess spatially specific effects. Result: All MTL tracts showed significant three‐way interactions between tau, diagnosis, and node location (ps<0.001), and both tau by node (ps<0.001) and diagnosis by node location interactions (ps<0.001), indicating that these factors impact WM integrity differentially along the tracts. Notably, no significant main effects of tau or diagnosis were found, highlighting the enhanced sensitivity of these spatial analyses. Post‐hoc analyses identified specific nodes within the UF (Figure 2) and ILF (Figure 3) that were significantly associated with tau levels and cognitive impairment, primarily in regions traversing the MTL. Conclusion: Our results show that assessing WM integrity along different spatial locations of WM tracts can provide more sensitive information about WM integrity in AD. Notably, these vulnerable WM nodes overlapped with areas in the MTL known for tau deposition, providing valuable insights into effects of tau pathology.

Background: Tau pathology may contribute to the disruption of white matter (WM) integrity in Alzheimer’s disease (AD). While previous work has shown global disruption to WM tracts, the specific spatial locations along the impacted tracts with disrupted integrity have yet to be identified. Tractometry is a method that utilizes diffusion MRI tractography to quantify spatial WM integrity by placing equidistant nodes along the length of WM tracts. We assessed WM integrity along the spatial extent of medial temporal lobe (MTL) WM tracts to determine tau pathology or cognitive impairment is associated with spatially specific patterns of WM integrity in older adults across the AD continuum. Method: A total of 159 older adults from ADNI3 (101 cognitively normal and 58 cognitively impaired [MCI/AD) underwent tau‐PET (18F‐Flortaucipir) and multishell diffusion MRI. Fractional anisotropy (FA), a measure of WM integrity, was calculated for each unilateral MTL tract (inferior longitudinal fasciculus [ILF], uncinate fasciculus [UF]) along 100 equidistant nodes using pyAFQ (Figure 1). Tau‐PET composite SUVRs were extracted from the entorhinal cortex and amygdala. A mixed effects model tested the main effects of tau and diagnosis on WM integrity, as well as their interactions by node to assess spatially specific effects. Result: All MTL tracts showed significant three‐way interactions between tau, diagnosis, and node location (ps<0.001), and both tau by node (ps<0.001) and diagnosis by node location interactions (ps<0.001), indicating that these factors impact WM integrity differentially along the tracts. Notably, no significant main effects of tau or diagnosis were found, highlighting the enhanced sensitivity of these spatial analyses. Post‐hoc analyses identified specific nodes within the UF (Figure 2) and ILF (Figure 3) that were significantly associated with tau levels and cognitive impairment, primarily in regions traversing the MTL. Conclusion: Our results show that assessing WM integrity along different spatial locations of WM tracts can provide more sensitive information about WM integrity in AD. Notably, these vulnerable WM nodes overlapped with areas in the MTL known for tau deposition, providing valuable insights into effects of tau pathology.

Despite extensive research, open questions about the biological underpinnings of Alzheimer’s disease (AD) remain. Neuroimaging biomarkers based on positron emission tomography (PET) and magnetic resonance imaging (MRI) offer in vivo insights into these complex biological changes and interactions. However, most evidence to date comes from cross-sectional studies, limiting our understanding of disease progression. Longitudinal studies enable the investigation of biological changes within individuals, revealing how pathology evolves over time. With this review, we provide an overview of how longitudinal imaging biomarker studies have advanced the field and how they can contribute to future research. We highlight longitudinal biomarker studies that have provided critical insights into disease trajectories, staging, and individual variability. We further assess longitudinal multimodal studies which have elucidated interactions between AD-specific pathology, amyloid-β and tau, and broader biological changes like neurodegeneration, neuronal dysfunction, vascular disease, and inflammation. Further, we discuss associations of brain changes with symptomatology and clinical outcomes and conclude with challenges and future directions.

Diffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer’s disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting-edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD-related changes in medial temporal lobe (MTL) WM than traditional tensor metrics. In total, 199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75 years; 60% female; cognitively unimpaired, n = 121; cognitively impaired MCI/dementia, n = 77) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate). A subset of participants received 18F-florbetapir or 18F-florbetaben to measure Aβ (n = 146; converted to Centiloids), 18F-flortaucipir to measure tau (n = 135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR-SB) and memory composite score (ADNI-MEM). NODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures. For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus and the uncinate, and with ODI in the fornix ST. Both ODI and NDI across the majority of tracts were associated with CDR-SB and ADNI-MEM. In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid-beta, while MD in MTL tracts showed limited correlations with pathology or cognition. NDI partially mediated the relationship between AD pathology (entorhinal tau, meta temporal tau, or Aβ) and the memory composite score. Random forest modeling showed that a combination of NODDI metrics and DTI had the strongest estimates of memory performance and clinical impairment. NODDI metrics offer more sensitive insights about MTL WM integrity in AD that could have been previously missed due to the limitations of DTI analyses. Additionally, combining NODDI with DTI yielded the strongest predictive performance for memory and clinical impairment, suggesting that the two approaches are complementary. The use of advanced diffusion acquisitions such as multishell which allows for analyses such as NODDI is crucial for the future development of disease identification and structural understanding.

Background: Diffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer’s disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting‐edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD‐related changes in medial temporal lobe (MTL) WM than traditional tensor metrics.Method: 199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75; 60% female; cognitively unimpaired, n=121; cognitively impaired MCI/dementia, n=78) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate; Figure 1). A subset of participants received 18F‐florbetapir or 18F‐florbetaben to measure Aß (n = 146; converted to Centiloids), 18F‐flortaucipir to measure tau (n=135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR‐SB) and memory composite score (ADNI‐MEM).Result: NODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures (Figure 2). For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus (r=‐0.375; p<0.001) and the uncinate (r=‐0.373; p<0.001), and with ODI in the fornix ST (r =‐0.288; p=0.004). Both ODI and NDI across the majority of tracts were associated with CDR‐SB and ADNI‐MEM (see Figure 2). In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid‐beta, while MD in MTL tracts showed limited correlations with pathology or cognition.Conclusion: NODDI metrics offer additional insights about MTL WM integrity in AD that were previously missed due to the limitations of DTI analyses. These results highlight the sensitivity of NODDI applied to multishell diffusion MRI acquisitions to further investigate how WM degeneration contributes to cognitive decline.

Background: Diffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer’s disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting‐edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD‐related changes in medial temporal lobe (MTL) WM than traditional tensor metrics.Method: 199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75; 60% female; cognitively unimpaired, n=121; cognitively impaired MCI/dementia, n=78) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate; Figure 1). A subset of participants received 18F‐florbetapir or 18F‐florbetaben to measure Aβ (n = 146; converted to Centiloids), 18F‐flortaucipir to measure tau (n=135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR‐SB) and memory composite score (ADNI‐MEM).Result: NODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures (Figure 2). For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus (r=‐0.375; p<0.001) and the uncinate (r=‐0.373; p<0.001), and with ODI in the fornix ST (r =‐0.288; p=0.004). Both ODI and NDI across the majority of tracts were associated with CDR‐SB and ADNI‐MEM (see Figure 2). In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid‐beta, while MD in MTL tracts showed limited correlations with pathology or cognition.Conclusion: NODDI metrics offer additional insights about MTL WM integrity in AD that were previously missed due to the limitations of DTI analyses. These results highlight the sensitivity of NODDI applied to multishell diffusion MRI acquisitions to further investigate how WM degeneration contributes to cognitive decline.

Background: Damage to white matter (WM) within the medial temporal lobe (MTL) may underlie memory decline in aging and Alzheimer’s disease (AD). We measured MTL WM tract integrity through diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging (NODDI). We tested WM integrity associations with memory performance and amyloid‐β pathology in cognitively normal older adults.Method: 105 cognitively normal older adults (70.8 years old, 65% female) with diffusion MRI were processed with MRtrix3. Standard diffusion metrics of fractional anisotropy (FA) and mean diffusivity (MD) were calculated. NODDI MDT was used to generate the neurite density index (NDI), representing number of voxels with unhindered diffusion, and the orientation dispersion index (ODI), representing the variability of neurite orientation. We calculated these measures for MTL tracts from the JHU WM Atlas: cingulum‐hippocampus, fornix column/body, and fornix/stria terminalis. Participants received 18F‐florbetapir (FBP) to measure Aβ pathology (n = 94), and global FBP SUVR was calculated. Memory was measured with the Rey Auditory Verbal Learning Test delayed recall score (RAVLT, n = 81). Analyses covaried for age and/or education.Result: Better memory was associated with lower ODI in the fornix column/body (r = ‐0.27, p = 0.018), with trends for higher FA (r = 0.021, p = 0.06) and lower NDI (r = ‐0.19, p = 0.09). Better memory was also associated with higher MD in the cingulum‐hippocampus (right: r = 0.23, p = 0.04; left: r = 0.25, p = 0.03), with trends for lower ODI (right: r = ‐.20, p = 0.08; left: r = ‐0.20, p = 0.09). Higher FBP SUVR was associated with increased FA in the fornix column/body (r = 0.31, p = 0.003) and a trend in the left cingulum hippocampus (r = 0.20, p = 0.054). Memory or FBP SUVR was not significantly related to integrity of the fornix/stria terminalis.Conclusion: Integrity of fornix column/body and cingulum‐hippocampus were related to both memory performance and Aβ pathology. Our results suggest that using a combination of NODDI as well as diffusion tensor metrics provided a more robust understanding of memory impacts in aging.

Background: Damage to white matter (WM) within the medial temporal lobe (MTL) may underlie memory decline in aging and Alzheimer’s disease (AD). We measured MTL WM tract integrity through diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging (NODDI). We tested WM integrity associations with memory performance and amyloid‐ß pathology in cognitively normal older adults.Method: 105 cognitively normal older adults (70.8 years old, 65% female) with diffusion MRI were processed with MRtrix3. Standard diffusion metrics of fractional anisotropy (FA) and mean diffusivity (MD) were calculated. NODDI MDT was used to generate the neurite density index (NDI), representing number of voxels with unhindered diffusion, and the orientation dispersion index (ODI), representing the variability of neurite orientation. We calculated these measures for MTL tracts from the JHU WM Atlas: cingulum‐hippocampus, fornix column/body, and fornix/stria terminalis. Participants received 18F‐florbetapir (FBP) to measure Aß pathology (n = 94), and global FBP SUVR was calculated. Memory was measured with the Rey Auditory Verbal Learning Test delayed recall score (RAVLT, n = 81). Analyses covaried for age and/or education.Result: Better memory was associated with lower ODI in the fornix column/body (r = ‐0.27, p = 0.018), with trends for higher FA (r = 0.021, p = 0.06) and lower NDI (r = ‐0.19, p = 0.09). Better memory was also associated with higher MD in the cingulum‐hippocampus (right: r = 0.23, p = 0.04; left: r = 0.25, p = 0.03), with trends for lower ODI (right: r = ‐.20, p = 0.08; left: r = ‐0.20, p = 0.09). Higher FBP SUVR was associated with increased FA in the fornix column/body (r = 0.31, p = 0.003) and a trend in the left cingulum hippocampus (r = 0.20, p = 0.054). Memory or FBP SUVR was not significantly related to integrity of the fornix/stria terminalis.Conclusion: Integrity of fornix column/body and cingulum‐hippocampus were related to both memory performance and Aß pathology. Our results suggest that using a combination of NODDI as well as diffusion tensor metrics provided a more robust understanding of memory impacts in aging.

Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.3; SD = 14.1). The clinical measures used were A6MCT, Revised Upper Limb Module (RULM), Adapted Test of Neuromuscular Disorders (ATEND), and Egen Klassifikation Scale 2 (EK2). Perceived fatigue was assessed using the Fatigue Severity Scale (FSS), and effort was assessed using the Rate of Perceived Exertion (RPE). Data were analyzed for: (1) Feasibility, (2) Clinical discrimination, and (3) Associations between A6MCT with clinical characteristics and outcomes. Results showed the A6MCT was feasible for 95% of the tested subjects, discriminated between functional groups (p = 0.0086), and was significantly associated with results obtained from RULM, ATEND, EK2, and Brooke (p < 0.0001; p = 0.029; p < 0.001; p = 0.005). These findings indicate the A6MCT’s potential to evaluate muscular endurance in non-ambulatory SMA individuals, complementing clinician-rated assessments. Nevertheless, further validation with a larger dataset is needed for broader application.