Andrew P. Merluzzi

Gut microbiome alterations in Alzheimer's disease.

Alzheimer’s disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood. Recent studies in rodents suggest that alterations in the gut microbiome may contribute to amyloid deposition, yet the microbial communities associated with AD have not been characterized in humans. Towards this end, we characterized the bacterial taxonomic composition of fecal samples from participants with and without a diagnosis of dementia due to AD. Our analyses revealed that the gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age- and sex-matched individuals. We identified phylum- through genus-wide differences in bacterial abundance including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of AD participants. Furthermore, we observed correlations between levels of differentially abundant genera and cerebrospinal fluid (CSF) biomarkers of AD. These findings add AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.

Age-dependent differences in brain tissue microstructure assessed with neurite orientation dispersion and density imaging

Human aging is accompanied by progressive changes in executive function and memory, but the biological mechanisms underlying these phenomena are not fully understood. Using neurite orientation dispersion and density imaging, we sought to examine the relationship between age, cellular microstructure, and neuropsychological scores in 116 late middle-aged, cognitively asymptomatic participants. Results revealed widespread increases in the volume fraction of isotropic diffusion and localized decreases in neurite density in frontal white matter regions with increasing age. In addition, several of these microstructural alterations were associated with poorer performance on tests of memory and executive function. These results suggest that neurite orientation dispersion and density imaging is capable of measuring age-related brain changes and the neural correlates of poorer performance on tests of cognitive functioning, largely in accordance with published histological findings and brain-imaging studies of people of this age range. Ultimately, this study sheds light on the processes underlying normal brain development in adulthood, knowledge that is critical for differentiating healthy aging from changes associated with dementia.

Association of longitudinal white matter degeneration and cerebrospinal fluid biomarkers of neurodegeneration, inflammation and Alzheimer’s disease in late-middle-aged adults

Alzheimer’s disease (AD) is characterized by substantial neurodegeneration, including both cortical atrophy and loss of underlying white matter fiber tracts. Understanding longitudinal alterations to white matter may provide new insights into trajectories of brain change in both healthy aging and AD, and fluid biomarkers may be particularly useful in this effort. To examine this, 151 late-middle-aged participants enriched with risk for AD with at least one lumbar puncture and two diffusion tensor imaging (DTI) scans were selected for analysis from two large observational and longitudinally followed cohorts. Cerebrospinal fluid (CSF) was assayed for biomarkers of AD-specific pathology (phosphorylated-tau/Aβ42 ratio), axonal degeneration (neurofilament light chain protein, NFL), dendritic degeneration (neurogranin), and inflammation (chitinase-3-like protein 1, YKL-40). Linear mixed effects models were performed to test the hypothesis that biomarkers for AD, neurodegeneration, and inflammation, or two-year change in those biomarkers, would be associated with worse white matter health overall and/or progressively worsening white matter health over time. At baseline in the cingulum, phosphorylated-tau/Aβ42 was associated with higher mean diffusivity (MD) overall (intercept) and YKL-40 was associated with increases in MD over time. Two-year change in neurogranin was associated with higher mean diffusivity and lower fractional anisotropy overall (intercepts) across white matter in the entire brain and in the cingulum. These findings suggest that biomarkers for AD, neurodegeneration, and inflammation are potentially important indicators of declining white matter health in a cognitively healthy, late-middle-aged cohort.

Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia

Objective To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. Methods In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3–like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD–mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). Results In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. Conclusions These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.

Longitudinal white matter microstructural change in Parkinson's disease

Postmortem studies of Parkinsons disease (PD) suggest that Lewy body pathology accumulates in a predictable topographical sequence, beginning in the olfactory bulb, followed by caudal brainstem, substantia nigra, limbic cortex, and neocortex. Diffusion‐weighted imaging (DWI) is sensitive, if not specific, to early disease‐related white matter (WM) change in a variety of traumatic and degenerative brain diseases. Although numerous cross‐sectional studies have reported DWI differences in cerebral WM in PD, only a few longitudinal studies have investigated whether DWI change exceeds that of normal aging or coincides with regional Lewy body accumulation. This study mapped regional differences in the rate of DWI‐based microstructural change between 29 PD patients and 43 age‐matched controls over 18 months. Iterative within‐ and between‐subject tensor‐based registration was completed on motion‐ and eddy current‐corrected DWI images, then baseline versus follow‐up difference maps of fractional anisotropy, mean, radial, and axial diffusivity were analyzed in the Biological Parametric Mapping toolbox for MATLAB. This analysis showed that PD patients had a greater decline in WM integrity in the rostral brainstem, caudal subcortical WM, and cerebellar peduncles, compared with controls. In addition, patients with unilateral clinical signs at baseline experienced a greater rate of WM change over the 18‐month study than patients with bilateral signs. These findings suggest that rate of WM microstructural change in PD exceeds that of normal aging and is maximal during early stage disease. In addition, the neuroanatomic locations (rostral brainstem and subcortical WM) of accelerated WM change fit with current theories of topographic disease progression.

QUANTITATIVE T1 IN ALZHEIMER’S DISEASE

dichotomous classification into hypo-/normo-cholinergic status based on control values. Cognitive test scores were z-transformed based on control values and used to derive global cognitive and domain-specific composite scores. Relations between cBF volume, cortical AChE-activity, and cognitive performance were studied using linear models. Specificity of the effects for cholinergic degeneration was assessed by comparison to hippocampal volume. Results:When stratifying PD patients according to cortical AChEstatus, hypo-cholinergic patients showed significantly reduced cBF volumes compared to both normo-cholinergic patients (p1⁄40.006) and controls (p1⁄40.04), independent of age, gender and education (see Figure). Across all PD patients, reduced cBF volume was significantly associated with lower cortical AChE-activity (p1⁄40.003), being most pronounced in anterior cingulate, temporal and posterior cortical areas. Hippocampal volume was not associated with continuous or dichotomous cortical AChE-activity. Both reduced cBF volume and cortical AChE-activity correlated with impaired global cognition (p’s<0.001), mostly affecting the memory domain. In a combined regression model, AChE-activity and cBF volume, but not hippocampal volume, independently predicted cognitive performance. Conclusions: In-vivo neuroimaging markers of cholinergic system degeneration are promising tools for characterizing the distinct contributions of cholinergic system deficits to cognitive decline in neurodegenerative disease.

RELATIONSHIP BETWEEN ALZHEIMER’S DISEASE BIOMARKERS AND CHANGE IN MYELIN AMONG COGNITIVELY UNIMPAIRED ADULTS

Figure 1. Relationship between NGRN and myelin change over approximately two years, with 95% confidence intervals (R1⁄40.216). Linear regression revealed a positive correlation in three regions, two corresponding to white matter underlying the superior frontal gyrus, and one corresponding to the corpus callosum. Shown is the region corresponding to the corpus callosum. Rok Po zar, Bruno Giordani, Voyko Kavcic, University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technologies, Koper, Slovenia; University of Primorska, Andrej Maru si c Institute, Koper, Slovenia; Michigan Alzheimer’s Disease Center, Ann Arbor, MI, USA; Wayne State University, Detroit, MI, USA; International Institute of Applied Gerontology, Ljubljana, Slovenia. Contact e-mail: giordani@med.umich.edu

GUT MICROBIOME ALTERATIONS IN ALZHEIMER'S DISEASE AND THE RELATIONSHIP WITH CSF BIOMARKERS

more cortical atrophy compared to APOE e4-positive prodromal AD (p<0.05). There was a tendency to increased cortical tau retention in APOEe4-negative AD (but not in the entorhinal cortex). Conclusions: Although AD patients have similar degree of Ab-pathology independent of APOE e4 status, AD is heterogenic and APOE e4-negative patients have more executive dysfunction, white matter lesions, cortical atrophy, neurochemical signs of differences in Ab-metabolism and axonal injury, and possibly also tau pathology, compared to APOE e4-positive AD. These differences may reflect APOE e4-independent risk factors and mechanisms for AD. Since most effects were identified at the prodromal stage of the disease they open for the possibility that early stage disease-modifying interventions may be tailored per APOE e4-status.

BEYOND AMYLOID AND TAU: A ROLE FOR INFLAMMATION AND NEURAL BIOMARKERS IN DEMENTIA DUE TO ALZHEIMER’S DISEASE

have been demonstrated in the progression and subsequent conversion to dementia in mild cognitive impairment (MCI) (Papaliagkas, 2011), and have also been detected in presymptomatic individuals (Quiroz et al., 2011). Although ERPs have the potential to be sensitive biomarkers with low cost and low invasiveness, the promise of this technique in clinical practice has not yet been fully realized. Methods:Thirty-eight subjects who presented with memory loss underwent standard clinical workup including history and physical, neuroimaging, laboratory studies, and a neuropsychological battery, leading to a clinical diagnosis. All subjects consented to an ERP session using a three-tone auditory oddball paradigm with a seven-electrode device. ERP results were reviewed by two behavioral neurologists blinded to the clinical details of each subject. Amplitude and latency of ERP peaks were rated in the AD or healthy older adult range (Cecchi et al 2015). The total sum of the number of peaks in the diseased rangewas computed and a diagnostic rating was made for each ERP study as consistent with MCI due to AD, mild AD, moderate AD, or inconsistent with AD. Results: Spearman’s correlation showed that the total number of ERP peaks that fell into the mild AD range correlated inversely with Montreal Cognitive Assessment (MOCA); correlation coefficient of -.535 and p-value of .001. (Figure 1). Conclusions:These results validate the clinical utility of ERPs in general and the specific ERP review method used, showing that it correlates well with screening measures of cognitive decline. Future analyses can evaluate whether ERPs can reliably distinguish between AD and other neurodegenerative conditions, and also how ERPs compare to other AD biomarkers including amyloid PET scans and quantitative MRI cortical volume measurements.

LIFETIME PHYSICAL ACTIVITY IS ASSOCIATED WITH CSF AMYLOID IN COGNITIVELY ASYMPTOMATIC APOE ɛ4+ ADULTS

Elisa R. Torres, Andrew P. Merluzzi, Henrik Zetterberg, Kaj Blennow, Cynthia M. Carlsson, Sanjay Asthana, Sterling C. Johnson, Barbara B. Bendlin, University of Wisconsin-Madison School of Nursing, Madison, WI, USA; Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, M€olndal, Sweden; Geriatric Research Education and Clinical Center, W.S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. Contact e-mail: elisa.torres@wisc.edu