Devanand, Davangere P.

AbstractBackgroundInexpensive, non‐invasive tests may improve the identification of persons at increased risk for cognitive decline and dementia. We compared impairment in odor identification and global cognition with neuro‐imaging biomarkers to predict cognitive decline and dementia in the population‐based Mayo Clinic Study of Aging (MCSA).MethodAt the 2008 assessment, 647 participants who were ≥ 55 years old with at least one follow‐up had the following procedures: modified Blessed Information‐Memory‐Concentration Test (BIMCT), 12‐item Brief Smell Identification Test (BSIT), brain magnetic resonance imaging (MRI), and Positron Emission Tomography (PET) amyloid imaging with 11C‐Pittsburgh compound B (11C‐PiB). A subsample (n=556) also had 18F‐fluorodeoxyglucose (18F‐FDG) PET scans. The utility of these baseline measures to predict cognitive decline (cognitively unimpaired to mild cognitive impairment [MCI] or dementia, or MCI to dementia) was examined during follow‐up (mean 8.1 SD 3.4 years). Transition to dementia was a secondary outcome.ResultAmong 647 participants without dementia (mean age 74.0 SD 8.1 years; 54.4% male) at baseline, 102 participants manifested cognitive decline and 34 participants transitioned to dementia. In Cox regression survival analyses for cognitive decline, PiB PET showed the strongest predictive utility (hazard ratio HR 5.05, 95% CI = 3.32‐7.69, p<.001). Impaired BSIT (HR 3.46, 95% CI = 2.34‐5.11, p<.001), impaired BIMCT (HR 3.63, 95% CI 2.46‐5.36, p<.001), MRI and FDG measures were also significant predictors. After adjusting for age, sex and education, these predictors remained significant with attenuated effects (PiB HR 3.89, 95% CI 2.54‐5.95, p<.001; BSIT HR 2.77, 95% CI 1.85‐4.14, p<.001; BIMCT HR 3.3, 95% CI 2.21‐4.95, p<.001). After adding these demographic variables in the model, the combination of BSIT and BIMCT showed strong predictive utility (C‐index=0.85), similar to PiB PET (C‐index=0.84). Combining all predictors showed a C‐index of 0.89. These measures showed similar but stronger results for dementia transition.ConclusionTests of global cognition and odor identification provide a brief, non‐invasive, inexpensive method comparable to PET amyloid imaging for identifying community‐dwelling persons likely to decline cognitively or transition to dementia. Other potential uses for this combination include identification of persons likely to benefit from disease‐modifying medications and determination of eligibility for prevention trials.

AbstractBackgroundPrevious studies have linked impaired odor identification and global cognition with increased risk of cognitive decline and transition to dementia. However, the reverse question remains: if individuals have intact performance on these measures, are they at reduced risk for transition? We aimed to examine the accuracy of intact odor identification and global cognition for identifying lack of transition to dementia/cognitive decline using the population‐based Mayo Clinic Study of Aging and compare their accuracy against and in combination with amyloid PET (Positron Emission Tomography).Methodn = 647 participants age≥55 without dementia completed at baseline the Brief Smell Identification Test (BSIT; ‘Intact’ = 9‐12), Blessed Information‐Memory‐Concentration Test (BIMCT; ‘Intact’ = 18‐20,), and amyloid PET (‘Normal/Intact’ SUVR<1.48). We calculated sensitivity, specificity, positive predictive value, and negative predictive value for these measures, with “lack of transition to dementia” as the gold standard/target. “Lack of cognitive decline” (cognitively unimpaired to mild cognitive impairment [MCI]; cognitively unimpaired to dementia; or MCI to dementia) was a secondary target.Result94.7% of participants (613/647) did not transition to dementia and 84.2% (545/647) did not cognitively decline over 11.25‐year‐follow‐up. The combination of intact BSIT+BIMCT had high rates of lack of transition to dementia (98.3%, 355/361) and lack of cognitive decline (93.1%, 336/361). This combination yielded mixed sensitivity (0.579) and specificity (0.824) though had high positive predictive value (0.983) for identifying lack of transition to dementia. Intact amyloid PET alone exhibited comparable rates of lack of transition to dementia (99.0%, 418/423) and lack of cognitive decline (92.4%, 391/423). When evaluated conjointly, the combination of all three intact measures also had mixed sensitivity (0.421) and specificity (0.962) though higher positive predictive value (PPV = 0.996) for lack of transition to dementia. 99.6% (258/259) of participants with intact/normal status on all three did not transition to dementia and 96.5% (250/259) did not cognitively decline.ConclusionThis replicates prior reports that intact olfaction/global cognition have strong utility for identifying individuals unlikely to develop MCI/dementia. Intact/normal amyloid PET further enhances the positive predictive value. Clinically, identifying individuals at low risk of transition can shorten diagnostic workups, reduce need for early follow‐up visits, and screen patients in‐or‐out of clinical trials.

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune‐related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. Highlights The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

AbstractINTRODUCTIONWe evaluated impaired odor identification and global cognition as simple, cost‐effective alternatives to neuroimaging biomarkers to predict cognitive decline and dementia in the Mayo Clinic Study of Aging.METHODSSix hundred forty‐seven participants (mean 8.1, standard deviation 3.4 years’ follow‐up) had the following baseline procedures: modified Blessed Information Memory Concentration Test (BIMCT), 12‐item Brief Smell Identification Test (BSIT), structural brain magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging with 11C‐Pittsburgh compound B (11C‐PiB) and fluorodeoxyglucose (FDG; subset).RESULTSCognitive decline developed in 102 participants and dementia in 34 participants. In survival analyses, PiB PET showed robust prediction for cognitive decline. Impaired BSIT, impaired BIMCT, MRI, and FDG measures were also significant predictors. The combination of demographics + BSIT + BIMCT showed strong predictive utility (C‐index 0.81), similar to demographics + PiB PET (C‐index 0.80). Similar but stronger results were obtained for prediction of dementia.DISCUSSIONImpairment in both odor identification test and global cognition was comparable to PiB PET for predicting cognitive decline and dementia.Highlights In 647 participants in the population‐based Mayo Clinic Study of Aging, several clinical markers and biomarkers each predicted cognitive decline or dementia during an average 8 years of follow‐up. The combination of the demographic variables of age, sex, and education with a brief odor identification test (BSIT) and a global cognitive test (Blessed Information Memory Concentration Test) showed strong predictive utility (C‐index 0.81) for cognitive decline that was similar to the demographic variables combined with Pittsburgh Compound B amyloid imaging (C‐index 0.80). Combining a brief odor identification test with a brief cognitive test needs consideration as a simple, cost‐effective option in the clinical assessment of individuals at risk of cognitive decline and dementia, as well as a potential tool to identify individuals who may benefit from disease‐modifying treatments and to screen participants for prevention trials.

Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Abstract Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age‐related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled “Sensory and Motor Dysfunctions in Aging and AD.” The scientific sessions of the workshop focused on age‐related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory‐motor deficits in AD may enhance patient function as AD progresses.