Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe (MTL) in in vivo 3 Tesla MRI. The method performs segmentation on a T2-weighted MRI scan with 0.4 × 0.4 × 2.0 mm3 resolution, partial brain coverage, and oblique orientation. Hippocampal subfields, entorhinal cortex, and perirhinal cortex are labeled using a pipeline that combines multi-atlas label fusion and learning-based error correction. In contrast to earlier work on automatic subfield segmentation in T2-weighted MRI (Yushkevich et al., 2010), our approach requires no manual initialization, labels hippocampal subfields over a greater anterior-posterior extent, and labels the perirhinal cortex, which is further subdivided into Brodmann areas 35 and 36. The accuracy of the automatic segmentation relative to manual segmentation is measured using cross-validation in 29 subjects from a study of amnestic Mild Cognitive Impairment (aMCI), and is highest for the dentate gyrus (Dice coefficient is 0.823), CA1 (0.803), perirhinal cortex (0.797) and entorhinal cortex (0.786) labels. A larger cohort of 83 subjects is used to examine the effects of aMCI in the hippocampal region using both subfield volume and regional subfield thickness maps. Most significant differences between aMCI and healthy aging are observed bilaterally in the CA1 subfield and in the left Brodmann area 35. Thickness analysis results are consistent with volumetry, but provide additional regional specificity and suggest non-uniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

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Objective To compare the utility and diagnostic accuracy of the MoCA and MMSE in the diagnosis of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) in a clinical cohort. Method 321 AD, 126 MCI and 140 older adults with healthy cognition (HC) were evaluated using the the MMSE, MoCA, a standardized neuropsychological battery according to the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD-NB) and an informant based measure of functional impairment, the Dementia Severity Rating Scale (DSRS). Diagnostic accuracy and optimal cut-off scores were calculated for each measure, and a method for converting MoCA to MMSE scores is presented also. Results The MMSE and MoCA offer reasonably good diagnostic and classification accuracy as compared to the more detailed CERAD-NB; however, as a brief cognitive screening measure the MoCA was more sensitive and had higher classification accuracy for differentiating MCI from HC. Complementing the MMSE or the MoCA with the DSRS significantly improved diagnostic accuracy. Conclusion The current results support recent data indicating that the MoCA is superior to the MMSE as a global assessment tool, particularly in discerning earlier stages of cognitive decline. In addition, we found that overall diagnostic accuracy improves when the MMSE or MoCA is combined with an informant-based functional measure. Finally, we provide a reliable and easy conversion of MoCA to MMSE scores. However, the need for MCI-specific measures is still needed to increase the diagnostic specificity between AD and MCI.

Objective We utilized the amyloid imaging ligand Pittsburgh Compound-B (PiB) to determine the presence of AD pathology in different MCI subtypes and to relate elevated PiB binding to other markers of early AD and longitudinal outcome. Methods Twenty-six patients with MCI – 13 single domain amnestic-MCI (sd a-MCI), 6 multiple domain amnestic-MCI (md a-MCI), and 7 non-amnestic MCI (na-MCI) – underwent PiB imaging. Twenty-three had clinical follow-up [21.2 ± 16.0 (SD) months] subsequent to their PiB scan. Results Using cutoffs established from a control cohort, 14 (54%) had elevated levels of PiB retention and were considered “amyloid-positive.” All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 sd a-MCI, 5/6 md a-MCI, 3/7 na-MCI). There were no obvious differences in the distribution of PiB retention in the na-MCI group despite their atypical early AD phenotype. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, increased age, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up revealed 5/13 amyloid-positive patients, but 0/10 amyloid-negative patients, converted to clinical AD. Further, 3/10 amyloid-negative patients “reverted to normal” on follow-up. Interpretation These data support the notion that amyloid-positive patients are likely to have early AD and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data is consistent with longitudinal studies suggesting that a significant percentage of all MCI subtypes will develop clinical AD.

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD).Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism.Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

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