Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease: a randomized, controlled clinical trial.

BACKGROUND: Evidence links lifestyle factors with Alzheimer's disease (AD). We report the first randomized, controlled clinical trial to determine if intensive lifestyle changes may beneficially affect the progression of mild cognitive impairment (MCI) or early dementia due to AD. METHODS: A 1:1 multicenter randomized controlled phase 2 trial, ages 45-90 with MCI or early dementia due to AD and a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The primary outcome measures were changes in cognition and function tests: Clinical Global Impression of Change (CGIC), Alzheimer's Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks of an intensive multidomain lifestyle intervention compared to a wait-list usual care control group. ADAS-Cog, CDR-SB, and CDR-Global scales were compared using a Mann-Whitney-Wilcoxon rank-sum test, and CGIC was compared using Fisher's exact test. Secondary outcomes included plasma Aß42/40 ratio, other biomarkers, and correlating lifestyle with the degree of change in these measures. RESULTS: Fifty-one AD patients enrolled, mean age 73.5. No significant differences in any measures at baseline. Only two patients withdrew. All patients had plasma Aß42/40 ratios <0.0672 at baseline, strongly supporting AD diagnosis. After 20 weeks, significant between-group differences in the CGIC (p= 0.001), CDR-SB (p= 0.032), and CDR Global (p= 0.037) tests and borderline significance in the ADAS-Cog test (p= 0.053). CGIC, CDR Global, and ADAS-Cog showed improvement in cognition and function and CDR-SB showed significantly less progression, compared to the control group which worsened in all four measures. Aß42/40 ratio increased in the intervention group and decreased in the control group (p = 0.003). There was a significant correlation between lifestyle and both cognitive function and the plasma Aß42/40 ratio. The microbiome improved only in the intervention group (p <0.0001). CONCLUSIONS: Comprehensive lifestyle changes may significantly improve cognition and function after 20 weeks in many patients with MCI or early dementia due to AD. TRIAL REGISTRATION: Approved by Western Institutional Review Board on 12/31/2017 (#20172897) and by Institutional Review Boards of all sites. This study was registered retrospectively with clinicaltrials.gov on October 8, 2020 (NCT04606420, ID: 20172897).

In the Information Age, do dementia caregivers get the information they need? Semi-structured interviews to determine informal caregivers' education needs, barriers, and preferences.

BACKGROUND: Most patients with dementia or cognitive impairment receive care from family members, often untrained for this challenging role. Caregivers may not access publicly available caregiving information, and caregiver education programs are not widely implemented clinically. Prior large surveys yielded broad quantitative understanding of caregiver information needs, but do not illuminate the in-depth, rich, and nuanced caregiver perspectives that can be gleaned using qualitative methodology. METHODS: We aimed to understand perspectives about information sources, barriers and preferences, through semi-structured interviews with 27 caregivers. Content analysis identified important themes. RESULTS: We interviewed 19 women, 8 men; mean age 58.5 years; most adult children (15) or spouses (8) of the care recipient. Dementia symptoms often developed insidiously, with delayed disease acknowledgement and caregiver self-identification. While memory loss was common, behavioral symptoms were most troublesome, often initially unrecognized as disease indicators. Emerging themes: 1.) Barriers to seeking information often result from knowledge gaps, rather than reluctance to assume the caregiver role; 2.) Most caregivers currently receive insufficient information. Caregivers are open to many information sources, settings, and technologies, including referrals to other healthcare professionals, print material, and community and internet resources, but expect the primary care provider (PCP) to recommend, endorse, and guide them to specific sources. CONCLUSIONS: These findings replicated and expanded on results from previous quantitative surveys and, importantly, revealed a previously unrecognized essential factor: despite receiving insufficient information, caregivers place critical value on their relationship with care recipient PCPs to receive recommendations, guidance and endorsement to sources of caregiving information. Implications include: 1.) Greater public education is needed to help caregivers identify and describe diverse cognitive, functional and behavioral symptoms that lead to dementia, and recognize the benefits of early detection in accessing information regarding multi-modality management and care; 2.) Improved methods are needed for PCPs to detect and manage cognitive and behavioral changes, as well as mechanisms that facilitate the busy PCP, either directly or via referral, to provide caregiver information, education, support, and services. The critical relationship between caregivers and PCPs should not be circumvented but should be facilitated to provide more effective guidance regarding dementia caregiver needs.

MRI markers for mild cognitive impairment: comparisons between white matter integrity and gray matter volume measurements.

The aim of the study was to evaluate the value of assessing white matter integrity using diffusion tensor imaging (DTI) for classification of mild cognitive impairment (MCI) and prediction of cognitive impairments in comparison to brain atrophy measurements using structural MRI. Fifty-one patients with MCI and 66 cognitive normal controls (CN) underwent DTI and T1-weighted structural MRI. DTI measures included fractional anisotropy (FA) and radial diffusivity (DR) from 20 predetermined regions-of-interest (ROIs) in the commissural, limbic and association tracts, which are thought to be involved in Alzheimer's disease; measures of regional gray matter (GM) volume included 21 ROIs in medial temporal lobe, parietal cortex, and subcortical regions. Significant group differences between MCI and CN were detected by each MRI modality: In particular, reduced FA was found in splenium, left isthmus cingulum and fornix; increased DR was found in splenium, left isthmus cingulum and bilateral uncinate fasciculi; reduced GM volume was found in bilateral hippocampi, left entorhinal cortex, right amygdala and bilateral thalamus; and thinner cortex was found in the left entorhinal cortex. Group classifications based on FA or DR was significant and better than classifications based on GM volume. Using either DR or FA together with GM volume improved classification accuracy. Furthermore, all three measures, FA, DR and GM volume were similarly accurate in predicting cognitive performance in MCI patients. Taken together, the results imply that DTI measures are as accurate as measures of GM volume in detecting brain alterations that are associated with cognitive impairment. Furthermore, a combination of DTI and structural MRI measurements improves classification accuracy.

Systemic immune system alterations in early stages of Alzheimer's disease.

Immune activation and inflammation play significant roles in the pathogenesis of Alzheimer's disease (AD). To test whether AD patients showed systemic manifestations of inflammation, blood from 41 patients with early stages of AD and 31 aged-match elderly controls were evaluated. Cellular markers for monocyte/macrophage (MO) activation and CD8 T lymphocyte were increased in early AD patients. Expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1 (MCP-1), was decreased; however, plasma MCP-1 levels were significantly increased and were related to the degree of MO activation in AD. These findings suggest that AD pathogenesis may be influenced by systemic immunologic dysfunction and provides potential immunologic targets for therapeutic intervention.

Gene expression profiling in peripheral blood mononuclear cells from patients with sporadic amyotrophic lateral sclerosis (sALS).

The aim of this study was to identify gene expression profiles in peripheral blood mononuclear cells (PBMCs) from sporadic amyotrophic lateral sclerosis (sALS) patients to gain insights into the pathogenesis of ALS. We found that upregulation of LPS/TLR4-signaling associated genes was observed in the PMBCs from sALS patients after short-term cultivation, and that elevated levels of gene expression correlated with degree of peripheral blood monocyte activation and plasma LPS levels in sALS. Similar patterns of gene expression were reproduced in LPS stimulated PBMCs from healthy controls. These data suggest that chronic monocyte/macrophage activation may be through LPS/TLR4-signaling pathways in ALS.

Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimer's disease (AD), and other diseases. High-resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups. METHODS: Ninety-one subjects (53 controls (mean age: 69.3 ± 7.3), 20 MCI (mean age: 73.6 ± 7.1), and 18 AD (mean age: 69.1 ± 9.5) were studied with a high-resolution T2 weighted imaging sequence aimed at the hippocampus. Entorhinal cortex (ERC), subiculum, CA1, CA1-CA2 transition zone (CA1-2), CA3 & dentate gyrus (CA3&DG) were manually marked in the anterior third of the hippocampal body. Hippocampal volume was obtained from the Freesurfer and manually edited. RESULTS: Compared to controls, AD had smaller volumes of ERC, subiculum, CA1, CA1-2, and total hippocampal volumes. MCI had smaller CA1-2 volumes. Discriminant analysis and power analysis showed that CA1-2 was superior to total hippocampal volume for distinction between controls and MCI. CONCLUSION: The patterns of subfield atrophy in AD and MCI were consistent with patterns of neuronal cell loss/reduced synaptic density described by histopathology. These preliminary findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD and for detection of other disease effects than measurement of total hippocampus.

ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia.

We compared the predictive value of cerebral perfusion as measured by arterial-spin labeling magnetic resonance imaging (ASL-MRI) with MRI-derived hippocampal volume for determining future cognitive and functional decline and subsequent conversion from mild cognitive impairment to dementia. Forty-eight mild cognitive impairment subjects received structural and ASL-MRI scans at baseline and clinical and neuropsychologic assessments annually. Thirteen subjects became demented during the period of longitudinal observation (2.7+/-1.0 y). Cox regression analyses suggest that baseline hippocampal volume [relative risk (RR)=0.99, P=0.004], baseline right inferior parietal (RR=0.64, P=0.01) and right middle frontal (RR=0.73, P=0.01) perfusion were associated with conversion to dementia. Results from linear mixed effects modeling suggest that baseline perfusion from the right precuneus predicted subsequent declines in Clinical Dementia Rating Sum of Boxes (P=0.002), Functional Activates Questionnaire (P=0.01), and selective attention (ie, Stroop switching, P=0.009) whereas baseline perfusion from the right middle frontal cortex predicted subsequent episodic memory decline (ie, total recognition discriminability score from the California Verbal Learning Test, P=0.03). These results suggest that hypoperfusion as detected by ASL-MRI can predict subsequent clinical, functional, and cognitive decline and may be useful for identifying candidates for future Alzheimer disease treatment trials.