Knopman, David S.

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63 Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of 63 Zn-zinc citrate (∼330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral 63 Zn clearances were compared with 11 C-Pittsburgh Compound B ( 11 C-PiB) and 18 F-fluorodeoxyglucose ( 18 F-FDG) imaging data. 63 Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in 63 Zn clearance kinetics in relationship with regions of high amyloid-β plaque burden ( 11 C-PiB) and 18 F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe 63 Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-β pathology, warranting further imaging studies of zinc homeostasis in patients with AD.

Objectives To determine the cross‐sectional association between cerebral amyloid‐beta (A β ) deposition and gait. Design Cross‐sectional. Setting Population‐based cohort study in Olmsted County, MN . Participants Cognitively normal individuals (n = 611), aged 50 to 69 years, enrolled in the Mayo Clinic Study of Aging with concurrent PiB‐ PET imaging and gait assessment. Participants with a history of stroke, alcoholism, Parkinson's disease, subdural hematoma, traumatic brain injury, or normal pressure hydrocephalus were excluded. Measurements PiB‐ PET SUVR was measured in prefrontal, orbitofrontal, parietal, temporal, anterior cingulate, posterior cingulate, and motor‐specific regions of interest ( ROI s). Gait parameters (speed, cadence, stride length, double support time, and intra‐individual stance time variability) were measured using GAITR ite ® instrumentation. Linear regression models were adjusted for age, sex, body mass index, education, APOE ε 4 allele, Charlson comorbidity index, and depression. In secondary analyses, we additionally adjusted for neurodegeneration (hippocampal volume, FDG PET SUVR , and cortical thickness) in AD ‐associated regions. Results In fully adjusted models including neuroimaging measures of neurodegeneration, higher PiB‐ PET SUVR across all ROI s was associated with slower gait speed ( P < .05 except for the parietal ROI ), lower cadence and longer double support time ( P ≤ .05 except for the motor ROI ), and greater stance time variability ( P < .05). In sex‐stratified analyses, the association between higher PiB‐ PET SUVR across all ROI s and measures of gait was only present among women. Conclusion PiB‐ PET SUVR across ROI s, independent of general measures of AD ‐associated neurodegeneration, is associated with poorer performance on multiple gait parameters among cognitively normal women, aged 50 to 69 years. Longitudinal studies are needed to determine whether A β predicts gait decline in both women and men.

ObjectivePatients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)‐related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV‐1451 uptake in patients with probable DLB, compared to AD, and its relationship to β‐amyloid deposition on PET.MethodsConsecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer's Disease Research Center underwent magnetic resonance imaging, AV‐1451, and Pittsburgh compound‐B (PiB) PET examinations. Age‐ and sex‐matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas‐ and voxel‐based analyses were performed.ResultsThe AD dementia group had significantly higher AV‐1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV‐1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006).InterpretationMedial temporal lobe AV‐1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV‐1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB. ANN NEUROL 2017;81:58–67

AimThe p.P301L mutation in microtubule‐associated protein tau (MAPT) is a common cause of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17). We compare clinicopathologic features of five unrelated and three related (brother, sister and cousin) patients with FTDP‐17 due to p.P301L mutation.MethodsGenealogical, clinical, neuropathologic and genetic data were reviewed from eight individuals.ResultsThe series consisted of five men and three women with an average age of death of 58 years (52–65 years) and average disease duration of 9 years (3–14 years). The first symptoms were those of behavioural variant frontotemporal dementia in seven patients and semantic variant of primary progressive aphasia in one. Three patients were homozygous for the MAPT H1 haplotype; five had H1/H2 genotype. The apolipoprotein E genotype was ϵ3/ϵ3 in seven and ϵ3/ϵ4 in one. The average brain weight was 1015 g (876–1188 g). All had frontotemporal lobar or more diffuse cortical atrophy. Except for one patient, the hippocampus and parahippocampal gyrus had minimal atrophy, whereas there was atrophy of middle and inferior temporal gyri. Dentate fascia neuronal dispersion was identified in three patients, two of whom had epilepsy. In one patient there was extensive white matter tau involvement with Gallyas‐positive globular glial inclusions typical of globular glial tauopathy (GGT).ConclusionsThis clinicopathologic study shows inter‐ and intra‐familial clinicopathologic heterogeneity of FTDP‐17 due to MAPT p.P301L mutation, including GGT in one patient.

Objectives To investigate the timing (mid‐ vs late life) of physical activity, apolipoprotein ( APO )E ε 4, and risk of incident mild cognitive impairment ( MCI ). Design Prospective cohort study. Setting Mayo Clinic Study of Aging (Olmsted County, MN ). Participants Cognitively normal elderly adults (N = 1,830, median age 78, 50.2% female). Measurements Light, moderate, and vigorous physical activities in mid‐ and late life were assessed using a validated questionnaire. An expert consensus panel measured MCI based on published criteria. Cox proportional hazards models were used to calculate hazard ratios ( HR s) and 95% confidence intervals ( CI s) with age as a time scale after adjusting for sex, education, medical comorbidity, and depression. Results Light ( HR = 0.58, 95% CI = 0.43–0.79) and vigorous ( HR = 0.78, 95% CI = 0.63–0.97) physical activity in midlife were associated with lower risk of incident MCI . The association between moderate activity and incident MCI was not significant ( HR = 0.85, 95% CI = 0.67–1.09). In late life, light ( HR = 0.75, 95% CI = 0.58–0.97) and moderate ( HR = 0.81, 95% CI = 0.66–0.99) but not vigorous physical activity were associated with lower risk of incident MCI . A synergistic interaction was also observed between mid‐ and late‐life activity in reducing risk of incident MCI . Furthermore, APOE ε 4 carriers who did not exercise had a higher risk of incident MCI than noncarriers who reported physical activity. Conclusion Physical activity reduced the risk of incident MCI . Exercising in mid‐ and late life had an additive synergistic interaction in reducing the risk of MCI .

AbstractIntroductionThe objective of this study was to investigate whether 10 phospholipids/metabolites previously identified as prospectively predictive of mild cognitive impairment (MCI) or dementia in whites would also be predictive in a mostly African‐American cohort.MethodsWe repeatedly measured 188 phospholipids/metabolites in plasma samples of 221 participants of the Atherosclerosis Risk in Communities study, 97% African American, who were followed between 2004–2006 and 2011–2013.ResultsAfter a mean follow‐up of 7.3 years, 77 were classified as having MCI and 18 as having dementia. Our study failed to replicate previous findings in this mostly African American cohort, in that the 10 phospholipids/metabolites only achieved a C statistic/AUC of 0.609 in predicting development of MCI or dementia (compared to 0.96) and 0.607 in distinguishing normal from MCI or dementia at the follow‐up visit.ConclusionA panel of 10 phospholipids/metabolites previously associated with incident dementia was not predictive of MCI or dementia in an independent cohort.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by impairment in memory, behavioral changes, and gradual loss of autonomy. Since there is a long latent period prior to diagnosis, the aim of this study was to determine whether twenty single nucleotide polymorphisms identified in genome‐wide association analyses of AD are associated with cognitive change in 8,320 white and 2,039 African‐American middle‐aged adults enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study. Cognition was evaluated using the Delayed Word Recall Test (DWRT; verbal memory), Digit Symbol Substitution Test (DSST; processing speed), and Word Fluency Test (WFT; executive function). General linear models were used to assess mean differences in 6‐year change in test scores among individuals categorized by genotype after adjusting for age, gender, and years of education. Addition of the minor allele for rs670139 (MS4A4E), rs9331896 (CLU), and rs12155159 (NME8) was nominally associated with change on the DWRT, DSST, and WFT, respectively, in whites. The ZCWPW1(rs1476679) andCDS33(rs3865444) variants were nominally associated with change on the DWRT and WFT in African‐Americans. For rs670139 and rs9331896 the association was only significant in individuals bearing at least oneAPOEϵ4 allele in stratified analyses. An unweighted genetic risk score aggregating the risk alleles for 15 polymorphisms was not associated with change in cognitive function. Although the AD‐associated genetic variants appear to have small effects on early cognitive change, replication will be required to establish whether there is a discernible influence on cognitive status in midlife. © 2016 Wiley Periodicals, Inc.