Vernon S. Pankratz

Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimers disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

Personal ViewTracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimers disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

Prevalence of mild cognitive impairment is higher in men The Mayo Clinic Study of Aging

Objective: We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria. Methods: We evaluated an age- and sex-stratified random sample of Olmsted County residents who were 70–89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria. Results: Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval [CI] 14.4–17.5) for any MCI, 11.1% (95% CI 9.8–12.3) for amnestic MCI, and 4.9% (95% CI 4.0–5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21–1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE ε3ε4 or ε4ε4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001). Conclusions: Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.

Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease

Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer’s dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer’s Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer’s dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were ‘amyloid positive’ (n = 165, with the assumption that Alzheimers pathology is dominant in this group) and those who were ‘amyloid negative’ (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan–Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer’s disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer’s disease co-existent with other pathologies.

Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging : Population-Based Study

CONTEXT Little is known about the population-based prevalence of neuropsychiatric symptoms in mild cognitive impairment (MCI). OBJECTIVE To estimate the prevalence of neuropsychiatric symptoms in MCI and normal cognitive aging in a defined population. DESIGN Cross-sectional study derived from an ongoing population-based prospective cohort study. SETTING The Mayo Clinic Study of Aging. PARTICIPANTS We studied a random sample of 1969 individuals without dementia from the target population of 9965 elderly persons residing in Olmsted County (Minnesota) on the prevalence date (October 1, 2004). Neuropsychiatric data were available for 319 of 329 subjects with MCI (97.0%) and 1590 of 1640 subjects with normal cognition (97.0%). Neurologic, cognitive, and neuropsychiatric data were obtained from the study participants. A classification of MCI, dementia, and normal cognitive aging was adjudicated by an expert consensus panel. Accordingly, 329 subjects were classified as having MCI and the remaining 1640 subjects were classified as having normal cognition. MAIN OUTCOME MEASURE Neuropsychiatric Inventory Questionnaire score. RESULTS Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. By considering both the odds ratio (OR) and the frequency of a symptom, the most distinguishing features between the 2 groups were apathy (OR, 4.53; 95% confidence interval [CI], 3.11-6.60; P < .001), agitation (3.60; 2.18-5.92; P < .001), anxiety (3.00; 2.01-4.48; P < .001), irritability 2.99; 2.11-4.22; P < .001), and depression (2.78; 2.06-3.76; P < .001). The OR was highest for delusion (8.12; 95% CI, 2.92-22.60; P < .001); however, it was rare in both subjects with MCI (11 of 319 [3.4%]) and those with normal cognition (6 of 1590 [0.4%]). Thus, the population attributable risk for delusion was only 2.62% compared with 14.60% for apathy. CONCLUSIONS Nonpsychotic symptoms affected approximately 50% of subjects with MCI and 25% of subjects with normal cognition. In contrast, psychotic symptoms were rare.

Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50–89 years: a cross-sectional study

BACKGROUND As preclinical Alzheimers disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimers disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimers disease overlap in terms of β-amyloidosis and neurodegeneration. METHODS We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50-89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, (18)F-fluorodeoxyglucose ((18)F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A(+)] or negative [A(-)]) was determined by amyloid PET with (11)C Pittsburgh compound B. Neurodegeneration status (positive [N(+)] or negative [N(-)]) was determined by an Alzheimers disease signature (18)F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A(-)N(-)], amyloid positive and neurodegeneration negative [A(+)N(-)], amyloid negative and neurodegeneration positive [A(-)N(+)], or amyloid positive and neurodegeneration positive [A(+)N(+)]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models. FINDINGS The study population consisted of 985 eligible participants. The population frequency of A(-)N(-) was 100% (n=985) at age 50 years and fell to 17% (95% CI 11-24) by age 89 years. The frequency of A(+)N(-) increased to 28% (24-32) at age 74 years, then decreased to 17% (11-25) by age 89 years. The frequency of A(-)N(+) increased from age 60 years, reaching 24% (16-34) by age 89 years. The frequency of A(+)N(+) increased from age 65 years, reaching 42% (31-52) by age 89 years. The results from our multinomial models suggest that A(+)N(-) and A(+)N(+) were more frequent in APOE ɛ4 carriers than in non-carriers and that A(+)N(+) was more, and A(+)N(-) less frequent in men than in women. INTERPRETATION Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals. FUNDING US National Institute on Aging and Alexander Family Professorship of Alzheimers Disease Research.

A Comparison of BTA Stat, Hemoglobin Dipstick, Telomerase and Vysis Urovysion Assays for the Detection of Urothelial Carcinoma in Urine

PURPOSE We determine the sensitivity and specificity of various assays for the detection of urothelial carcinoma. MATERIALS AND METHODS A total of 280 voided urine specimens from 265 patients were obtained immediately before cystoscopy for BTA stat, (Bard Diagnostic, Redmond, Washington) hemoglobin dipstick, (Bayer, Elkhart, Indiana) telomerase and UroVysion (Vysis, a wholly owned subsidiary of Abbott Laboratories, Abbott Park, Illinois) analysis. RESULTS Of the 265 patients 75 had biopsy proven urothelial carcinoma, and the sensitivity of the assays was determined from these patients. From most sensitive to least sensitive, the overall sensitivity of UroVysion (73 cases), BTA stat (72), hemoglobin dipstick (73) and telomerase (70) was 81%, 78%, 74%, and 46%, respectively. Each of the first 3 tests was statistically significantly more sensitive than the telomerase assay (p <0.05). However, the differences in overall sensitivity of UroVysion, BTA stat and hemoglobin dipstick were not statistically significant. The specificity of the tests was calculated for 80 of the 265 patients in this study who had no history of urothelial carcinoma and negative cystoscopy findings despite common urological complaints. From most specific to least specific, the specificity of UroVysion, telomerase, BTA stat and hemoglobin dipstick was 96%, 91%, 74% and 51%, respectively. UroVysion and telomerase were statistically significantly (p <0.01) more specific than the BTA stat and hemoglobin dipstick assays, and all of the assays were more specific than hemoglobin dipstick testing (p <0.001). CONCLUSIONS Our study reveals that UroVysion is the most sensitive and specific assay among those tested for the detection of urothelial carcinoma. Telomerase testing had good specificity but poor sensitivity. The BTA stat and hemoglobin dipstick tests had good sensitivity but relatively poor specificity. UroVysion is a promising new assay for the detection of urothelial carcinoma in urine specimens. However, further studies are needed to explore the role of the various assays in the treatment of patients with superficial urothelial carcinoma.

Assessing the Temporal Relationship Between Cognition and Gait: Slow Gait Predicts Cognitive Decline in the Mayo Clinic Study of Aging

BACKGROUND The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals. METHODS The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70-89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions. RESULTS Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed. CONCLUSIONS Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline.

Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies

Objective: To determine whether adding REM sleep behavior disorder (RBD) to the dementia with Lewy bodies (DLB) diagnostic criteria improves classification accuracy of autopsy-confirmed DLB. Methods: We followed 234 consecutive patients with dementia until autopsy with a mean of 4 annual visits. Clinical diagnoses included DLB, Alzheimer disease (AD), corticobasal syndrome, and frontotemporal dementia. Pathologic diagnoses used the 2005 DLB consensus criteria and included no/low likelihood DLB (non-DLB; n = 136) and intermediate/high likelihood DLB (DLB; n = 98). Regression modeling and sensitivity/specificity analyses were used to evaluate the diagnostic role of RBD. Results: Each of the 3 core features increased the odds of autopsy-confirmed DLB up to 2-fold, and RBD increased the odds by 6-fold. When clinically probable DLB reflected dementia and 2 or more of the 3 core features, sensitivity was 85%, and specificity was 73%. When RBD was added and clinically probable DLB reflected 2 or more of 4 features, sensitivity improved to 88%. When dementia and RBD were also designated as probable DLB, sensitivity increased to 90% while specificity remained at 73%. The VH, parkinsonism, RBD model lowered sensitivity to 83%, but improved specificity to 85%. Conclusions: Inclusion of RBD as a core clinical feature improves the diagnostic accuracy of autopsy-confirmed DLB.

Brain β-amyloid load approaches a plateau

Objective: To model the temporal trajectory of β-amyloid accumulation using serial amyloid PET imaging. Methods: Participants, aged 70–92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimers Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association. Results: Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined—reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5–2.5 is approximately 15 years. Conclusion: This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions.