Michelle M. Mielke

The Association of Neuropsychiatric Symptoms in MCI with Incident Dementia and Alzheimer Disease

OBJECTIVESnIndividuals with mild cognitive impairment (MCI) are at high risk of developing dementia and/or Alzheimer disease (AD). Among persons with MCI, depression and anxiety have been associated with an increased risk of incident dementia. We examined whether neuropsychiatric symptoms in MCI increased the risk of incident dementia (all-cause) and incident AD.nnnDESIGNnLongitudinal cohort study followed annually (median: 1.58 years).nnnSETTINGnNational Alzheimers Coordinating Center database combining clinical data from 29 Alzheimers Disease Centers.nnnPARTICIPANTSnA total of 1,821 participants with MCI.nnnMEASUREMENTSn1) Progression to dementia (all-cause) or AD, 2) Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Geriatric Depression Scale (GDS), 4) Clinical Dementia Rating Global Score and Sum of Boxes, and 5) Mini-Mental State Examination (MMSE). The association of covariates with risk of incident dementia or AD was evaluated with hazard ratios (HR) determined by Cox proportional-hazards models adjusted for age, ethnicity, Clinical Dementia Rating Global Score and Sum of Boxes, and MMSE.nnnRESULTSnA total of 527 participants (28.9%) progressed to dementia and 454 (24.9%) to AD. Baseline GDS > 0 was associated with an increased risk of incident dementia (HR: 1.47, 95% CI: 1.17-1.84) and AD (HR: 1.45, 95% CI: 1.14-1.83). Baseline NPI > 0 was associated with an increased risk of incident dementia (HR: 1.37, 95% CI: 1.12-1.66) and AD (HR: 1.35, 95% CI: 1.09-1.66).nnnCONCLUSIONSnNeuropsychiatric symptoms in MCI are associated with significantly an increased risk of incident dementia and AD. Neuropsychiatric symptoms may be among the earliest symptoms of preclinical stages of AD and targeting them therapeutically might delay transition to dementia.

Effects of Cardiovascular Medications on Rate of Functional Decline in Alzheimer Disease

BACKGROUNDnEvidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD.nnnMETHODSnIn the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors.nnnRESULTSnCDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline.nnnCONCLUSIONSnIn this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.

Fornix integrity and hippocampal volume predict memory decline and progression to Alzheimer's disease

The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimers disease (AD). The aims of the present study were to: (1) examine the cross‐sectional relationship between fornix diffusion tensor imaging (DTI) measurements (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity, and radial diffusivity), hippocampal volume, and memory performance, and (2) compare fornix DTI measures with hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment to AD dementia.

Alterations of the Sphingolipid Pathway in Alzheimer’s Disease: New Biomarkers and Treatment Targets?

The public health burden of Alzheimer disease (AD), the most common neurodegenerative disease, threatens to explode in the middle of this century. Current FDA-approved AD treatments (e.g. cholinesterase inhibitors, NMDA-receptor agonists) do not provide a “cure”, but rather a transient alleviation of symptoms for some individuals. Other available therapies are few and of limited effectiveness so additional avenues are needed. Sphingolipid metabolism is a dynamic process that modulates the formation of a number of bioactive metabolites, or second messengers critical in cellular signaling and apoptosis. In brain, the proper balance of sphingolipids is essential for normal neuronal function, as evidenced by a number of severe brain disorders that are the result of deficiencies in enzymes that control sphingolipid metabolism. Laboratory and animals studies suggest both direct and indirect mechanisms by which sphingolipids contribute to amyloid-beta production and Alzheimer pathogenesis but few studies have translated these findings to humans. Building on the laboratory and animal evidence demonstrating the importance of sphingolipid metabolism in AD, this review highlights relevant translational research incorporating and expanding basic findings to humans. A brief biological overview of sphingolipids (sphingomyelins, ceramides, and sulfatides) in AD is first described, followed by a review of human studies including post-mortem studies, clinical and epidemiological studies. Lastly, the potential role of peripheral ceramides in AD pathogenesis is discussed, as well as the possible use of sphingolipids as biomarkers for AD.

Blood-based biomarkers of microvascular pathology in Alzheimer’s disease

Sporadic Alzheimers disease (AD) is a genetically complex and chronically progressive neurodegenerative disorder with molecular mechanisms and neuropathologies centering around the amyloidogenic pathway, hyperphosphorylation and aggregation of tau protein, and neurofibrillary degeneration. While cerebrovascular changes have not been traditionally considered to be a central part of AD pathology, a growing body of evidence demonstrates that they may, in fact, be a characteristic feature of the AD brain as well. In particular, microvascular abnormalities within the brain have been associated with pathological AD hallmarks and may precede neurodegeneration. In vivo assessment of microvascular pathology provides a promising approach to develop useful biological markers for early detection and pathological characterization of AD. This review focuses on established blood-based biological marker candidates of microvascular pathology in AD. These candidates include plasma concentration of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) that are increased in AD. Measures of endothelial vasodilatory function including endothelin (ET-1), adrenomedullin (ADM), and atrial natriuretic peptide (ANP), as well as sphingolipids are significantly altered in mild AD or during the predementia stage of mild cognitive impairment (MCI), suggesting sensitivity of these biomarkers for early detection and diagnosis. In conclusion, the emerging clinical diagnostic evidence for the value of blood-based microvascular biomarkers in AD is promising, however, still requires validation in phase II and III diagnostic trials. Moreover, it is still unclear whether the described protein dysbalances are early or downstream pathological events and how the detected systemic microvascular alterations relate to cerebrovascular and neuronal pathologies in the AD brain.

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

A blood‐based biomarker of Alzheimers disease (AD) would be superior to cerebrospinal fluid (CSF) and neuroimaging measures in terms of cost, invasiveness, and feasibility for repeated measures. We previously reported that blood ceramides varied in relation to timing of memory impairment in a population‐based study. The present objective was to examine whether plasma ceramides varied by AD severity in a well‐characterized clinic sample and were associated with cognitive decline and hippocampal volume loss over 1 year.

Depressive symptoms predict incident cognitive impairment in cognitive healthy older women

OBJECTIVEnThere is an increasing evidence that depressive symptoms are associated with the development of cognitive impairment and dementia in late life. The authors sought to examine whether depression increased the risk of incident cognitive impairment in a longitudinal study of older women.nnnMETHODSnObservational study, up to six examinations spanning up to 9 years.nnnSETTINGnUniversity-based Division of Geriatric Medicine.nnnPARTICIPANTSnCommunity-based sample of 436 older, nondemented women.nnnMEASUREMENTSnParticipants were followed up with regular medical and neuropsychiatric evaluations. Cognitive assessment included episodic immediate and delayed memory, psychomotor speed, and executive functioning. Participants were characterized as having incident impairment on a cognitive test when scores fell below the 10th percentile on age-adjusted norms. Baseline depressive symptoms were measured using the Geriatric Depression Scale (GDS) (30-item). Discrete-time Cox proportional hazards regression with generalized linear models were used to determine whether baseline risk factors predicted incident impairment on each cognitive test, defined as performance below the tenth percentile on age-adjusted norms.nnnRESULTSnBaseline GDS was highly associated with incident impairment on all cognitive tests (p <0.03). These associations were unaffected by vascular conditions except diabetes, which was associated with incident impairment in delayed recall and psychomotor speed.nnnCONCLUSIONnThese data suggest that depression may be the risk factors for cognitive decline, and thus a potential target for diagnostic and therapeutic interventions.

Lipids and the pathogenesis of Alzheimer's disease: Is there a link?

Summary Alzheimers disease (AD) is a heterogeneous neurodegenerative disorder characterized pathologically by amyloid-beta plaques, neurofibrillary tangles and neuronal loss. Its fundamental cause(s) and the pathological cascades leading to clinical symptoms remain unknown. Lipids and lipid peroxidation products have important roles in the homeostasis of the central nervous system. As well, lipid transport genes and vascular changes associated with peripheral dyslipidemia have been associated with an increased risk of AD. The present review discusses ways in which lipids may be involved in the pathogenesis of AD-associated neurodegeneration through their roles as neuronal structural components, cell modulators, or second messengers. Given the many possibilities through which lipids may be directly involved in or contribute to the pathogenesis of AD, the use of lipids as biomarkers for disease progression is discussed, as are other avenues for future research.

Effects of general medical health on Alzheimer's progression: The Cache County Dementia Progression Study

BACKGROUNDnSeveral observational studies have suggested a link between health status and rate of decline among individuals with Alzheimers disease (AD). We sought to quantify the relationship in a population-based study of incident AD, and to compare global comorbidity ratings to counts of comorbid conditions and medications as predictors of AD progression.nnnMETHODSnThis was a case-only cohort study arising from a population-based longitudinal study of memory and aging, in Cache County, Utah. Participants comprised 335 individuals with incident AD followed for up to 11 years. Patient descriptors included sex, age, education, dementia duration at baseline, and APOE genotype. Measures of health status made at each visit included the General Medical Health Rating (GMHR), number of comorbid medical conditions, and number of non-psychiatric medications. Dementia outcomes included the Mini-Mental State Examination (MMSE), Clinical Dementia Rating - sum of boxes (CDR-sb), and the Neuropsychiatric Inventory (NPI).nnnRESULTSnHealth status tended to fluctuate over time within individuals. None of the baseline medical variables (GMHR, comorbidities, and non-psychiatric medications) was associated with differences in rates of decline in longitudinal linear mixed effects models. Over time, low GMHR ratings, but not comorbidities or medications, were associated with poorer outcomes (MMSE: β = -1.07 p = 0.01; CDR-sb: β = 1.79 p < 0.001; NPI: β = 4.57 p = 0.01).nnnCONCLUSIONSnGiven that time-varying GMHR, but not baseline GMHR, was associated with the outcomes, it seems likely that there is a dynamic relationship between medical and cognitive health. GMHR is a more sensitive measure of health than simple counts of comorbidities or medications. Since health status is a potentially modifiable risk factor, further study is warranted.

Disturbance in cerebral spinal fluid sphingolipid content is associated with memory impairment in subjects infected with the human immunodeficiency virus

Despite widespread use of antiretroviral therapies to control replication of the human immunodeficiency virus (HIV), dysfunctions of cognition that are collectively termed HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of those infected by the virus. Currently there is not a biomarker that can identify HIV-infected people who are at risk for the development of HAND. Previous studies have identified particular sphingolipid species that are dysregulated in HAND, but the neurocognitive correlates of these biochemical findings are not currently understood. To address this question, we compared cerebrospinal fluid (CSF) levels of sphingomyelin, ceramide, and sterol species with performance on standard neurological tests designed to assess the function of multiple cognitive and motor domains in HIV-infected subjects. We found that sphingomyelin:ceramide ratios for acyl chain lengths of C16:0, C18:0, C22:0, and C24:0 were associated with worse performance on several indices of memory. The most striking finding was for the acyl chain of C18:0 that consistently associated with performance on multiple tests of memory. These findings suggest that the sphingomyelin:ceramide ratio for C18:0 may be a reasonable surrogate marker for memory dysfunction in HIV-infected subjects.