Objective

To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.

Design

Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Patients

Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.

Main Outcome Measures

The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).

Results

Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.

Conclusions

Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.

Objective

To examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age, gender and education-matched older adults.

Design

Case-control study.

Setting

Community-based sample

Subjects

Fifty-six cognitively normal APOE ε4 carriers and 56 age, gender and education-matched cognitively normal APOE ε4 non-carriers.

Main Outcome Measure

Alterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared to APOE ε4 non-carriers ranging from 63 to 91 years of age.

Results

A posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the ε4 carriers relative to APOE ε4 non-carriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network, including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE ε4 carriers vs. non-carriers. There were no group-wise differences in brain anatomy.

Conclusions

We found reductions in posterior default mode network connectivity but increased salience network connectivity in elderly cognitively normal APOE ε4 carriers relative to APOE ε4 non-carriers at rest. The observation of functional alterations in connectivity in the absence of structural changes between APOE e4 carriers and non-carriers suggests that alterations in connectivity may have the potential to serve as an early biomarker.

Objective

To empirically assess the concept that Alzheimer’s disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.

Design

Validation sample

Setting

Multi-site, referral centers

Patients

We studied 401 elderly cognitively normal (CN), Mild Cognitive Impairment (MCI) and AD dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative. We compared the proportions of three AD biomarkers – CSF Aβ42, CSF total tau (t-tau), and hippocampal volume adjusted by intra-cranial volume (HVa) - that were abnormal as cognitive impairment worsened. Cut-points demarcating normal vs. abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.

Interventions

None

Main Outcome measures

AD biomarkers

Results

Within each clinical group in the entire sample (n=401) CSF Aβ42 was abnormal more often than t-tau or HVa. Among the 298 subjects with both baseline and 12 month data, the proportion of subjects with abnormal Aβ42 did not change from baseline to 12 months in any group. The proportion of subjects with abnormal t-tau increased from baseline to 12 months in CN (p=0.05) but not in MCI or dementia. In 209 subjects with abnormal CSF AB42 at baseline, the percent abnormal HVa, but not t-tau, increased from baseline to 12 months in MCI.

Conclusions

Reduction in CSF Aβ42 denotes a pathophysiological process that significantly departs from normality (i.e., becomes dynamic) early, while t-tau and HVa are biomarkers of downstream pathophysiological processes. T-tau becomes dynamic before HVa, but HVa is more dynamic in the clinically symptomatic MCI and dementia phases of the disease than t-tau.

In the past 10 years, there has been a virtual explosion in the literature concerning the construct of mild cognitive impairment. The interest in this topic demonstrates the increasing emphasis on the identification of the earliest features of cognitive disorders such as Alzheimer’s disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiological, neuroimaging, biomarker, neuropathological, disease mechanism and clinical trials research. This review summarizes the progress that has been made while also recognizing the challenges that remain.

Background

Defining the nature of the contribution of stroke to cognitive impairment remains challenging.

Methods

We randomly selected Olmsted County, MN residents aged 70–89 years on October 1, 2004 and invited eligible non-demented subjects to participate. Participants (n = 2,050) were evaluated with an informant interview, a neurological evaluation, and neuropsychological testing. Neuropsychological testing included 9 tests to assess memory, attention and executive function, visuospatial cognition and language. Subjects were diagnosed by consensus as cognitively normal, MCI (either amnestic (a-) or non-amnestic (na-)), or dementia. A history of stroke was obtained from the subject and confirmed in the medical record. We computed the odds ratios (OR) for a clinical diagnosis of MCI or for scoring in the lowest quartile on each cognitive domain.

Results

There were 1640 cognitively normal and 329 MCI subjects, 241 a-MCI and 88 na-MCI. In fully adjusted models with non-demented subjects only, a history of stroke was associated with a higher odds ratio (OR) of na-MCI (OR= 2.85, 95% CI 1.61 – 5.04) than a-MCI (OR= 1.77, 95% CI 1.14 – 2.74). A history of stroke was also associated with impaired function in each cognitive domain except memory. The association was strongest for attention and executive function (OR=2.48, 95% CI 1.73 – 3.53). APOE e4 genotype was associated only with a-MCI and with impaired memory function.

Conclusions

In this population-based sample of non-demented persons, a history of stroke was particularly associated with na-MCI and with impairment in non-memory cognition. APOE e4 genotype was associated with memory impairment and a-MCI.

Objective

To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), emphasizing the unique clinical features in this kindred.

Design

Clinical, radiologic, pathologic, and genetic characterization of a kindred with a familial neurodegenerative disorder.

Setting

Multispecialty group academic medical center.

Patients

Affected members of a kindred with dementia +/- parkinsonism associated with a unique mutation in PGRN.

Main Outcome Measure

Genotype-phenotype correlation.

Results

Ten affected individuals were identified, among whom six presented with initial amnestic complaints resulting in initial diagnoses of AD or amnestic mild cognitive impairment (MCI). A minority of individuals presented with features characteristic of FTD. The ages of onset of generation II (mean 75.8 years, range 69-80 years) were far greater than those of generation III (mean 60.7 years, range 55-66 years). The pattern of cerebral atrophy varied widely among affected individuals. Neuropathology in six individuals showed frontotemporal lobar degeneration with ubiquitin positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U + NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), causing a frameshift (p.Thr52Hisfs×2) and therefore creation of a premature termination codon and likely null allele.

Conclusions

We describe a large kindred in which the majority of affected individuals had clinical presentations resembling AD or amnestic MCI in association with a mutation in PGRN and underlying FTLD-U + NII neuropathology. This is in distinct contrast to previously reported kindreds, where clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age of onset between generations will require further study.

Objective

To investigate the impact white matter hyperintensities (WMH) detected on MRI have on motor dysfunction and cognitive impairment in non-demented elderly subjects.

Design

Cross-sectional study.

Setting

Population-based study on the incidence and prevalence of cognitive impairment in Olmsted County, MN.

Participants

A total of 148 non-demented elderly (65 males) ranging in age from 73 to 91 years.

Main Outcome Measures

We measured the percentage of the total white matter volume classified as WMH (WMHp) in a priori defined brain regions (i.e. frontal, temporal, parietal, occipital, periventricular or subcortical). Motor impairment was evaluated qualitatively using the Unified Parkinson’s Disease Rating Scale (UPDRS) summary measures of motor skills and quantitatively using a digitized portable walkway system. Four cognitive domains were evaluated using z-scores of memory, language, executive function, and visuospatial reasoning.

Results

A higher WMHp in all regions except occipital was associated with lower executive function z-score (p-value<0.01). A higher WMHp in all regions, but most strongly for parietal lobe, correlated with higher gait/postural-stability/posture UPDRS sum (p-value<0.01). A higher WMHp whether periventricular, subcortical or lobar correlated with reduced velocity (p-value<0.001).

Conclusions

We conclude that executive function is the primary cognitive domain affected by WMH burden. The data suggests that WMH in the parietal lobe are chiefly responsible for reduced balance and postural support compared to the other three lobes and may alter integration of sensory information via parietal lobe dysfunction in the aging brain. It is of interest that parietal WM changes were not the predominant correlate with motor speed, lending evidence to a global involvement of neural networks in gait velocity.

Objective

Physical exercise was found to be associated with a decreased risk of dementia and Alzheimer disease. We investigated whether physical exercise is also associated with mild cognitive impairment (MCI).

Design

Population-based case-control study.

Setting

The Mayo Clinic Study of Aging, an ongoing population-based cohort study in Olmsted County, Minnesota, USA.

Participants

1324 non-demented subjects who completed a questionnaire on physical exercise.

Main Outcome Measures

An expert consensus panel classified each subject as either cognitively normal or affected by MCI using information from a Clinical Dementia Rating Scale administered to the subject and to an informant, a neurological evaluation, and neuropsychological testing to assess 4 cognitive domains.

Results

We compared the frequency of physical exercise in 198 subjects with MCI to the frequency in 1126 cognitively normal subjects and adjusted analyses for age, sex, years of education, medical comorbidity, and depression. The odds ratio (OR) for any frequency of moderate-intensity exercise was 0.61 (95% confidence interval [CI], 0.43–0.88; P=.008) for exercise in midlife (aged 50–65 years), and 0.68 (95% CI, 0.49–0.93; P=.02) for exercise in late life. The findings were consistent in men and women. Light exercise and vigorous exercise were not significantly associated with MCI.

Conclusions

In this population-based case-control study, any frequency of moderate-intensity exercise carried out in either midlife or late life was associated with a reduced OR of MCI.

Background

Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43– and ubiquitin-immunoreactive pathologic lesions.

Objective

To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis.

Design, Setting, and Patients

Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries.

Main Outcome Measures

Clinical phenotypes and survival patterns of patients.

Results

A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P<.001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P=.005).

Conclusions

Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.

Objective

To localize susceptibility genes for alterations in brain structure associated with risk of stroke and dementia. We conducted genomewide linkage analyses for magnetic resonance imaging (MRI) measures of brain atrophy, ventricular, and subcortical white matter hyperintensity (leukoaraiosis) in 689 non-Hispanic white (673 sibling pairs; median age, 61 years) and 544 non-Hispanic black participants (503 sibling pairs; median age, 64 years) from sibships with at least 2 members with essential hypertension.

Design, Setting, and Patients

We determined brain, ventricular, and leukoaraiosis volumes from axial fluid-attenuated inversion recovery MRI; we calculated brain atrophy as the difference between total intracranial and brain volumes. Microsatellite markers (n=451) distributed across the 22 autosomes were genotyped, and we used variance components methods to estimate heritability and assess evidence of genetic linkage for each MRI measure.

Main Outcome Measures

Brain atrophy ventricular volume, and leukoaraiosis determined from fluid-attenuated inversion recovery MRI.

Results

In both races, the heritability of each MRI measure was statistically greater than 0 (P< .001), ranging in magnitude from 0.42 (for ventricular volume in blacks) to 0.69 (for brain atrophy in blacks). Based on multipoint logarithm of odds scores (MLS), the strongest evidence of genetic linkage was observed for brain atrophy on chromosomes 1 (MLS, 3.49 at 161 cM; P< .001) and 17 (MLS, 3.08 at 18 cM; P< .001) in whites; for ventricular volume on chromosome 12 (MLS, 3.67 at 49 cM; P< .001) in blacks and chromosome 10 (MLS, 2.47 at 110 cM; P < .001) in whites; and for leukoaraiosis on chromosome 11 (MLS, 2.21 at 118 cM; P < .001) in whites and chromosome 22 (MLS, 2.02 at 36 cM; P= .001) in blacks.

Conclusions

The MRI measures of structural brain injury are heritable in non-Hispanic black and white sibships ascertained through hypertensive sibling pairs. The susceptibility loci for brain atrophy, ventricular volume, and leukoaraiosis identified by linkage analyses differ among MRI measures and between races.

Background

Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families.

Objective

To determine whether there is a difference in the patterns of atrophy in cases with FTLD-U with and without a mutation in PGRN.

Design

Case control study

Setting

Brain bank of a tertiary care medical center

Patients

All subjects that had screened positive for mutations in PGRN and had a volumetric MRI were identified (n=8, PGRN (+)). Subjects were then matched by clinical diagnosis to a group of eight subjects with a pathological diagnosis of FTLD-U that had screened negative for mutations in PGRN (PGRN (−)). All subjects were then age and gender-matched to a control subject.

Main outcome Measures

Voxel-based morphometry was used to assess the patterns of grey matter atrophy in the PGRN (+) and (−) groups compared to controls, and compared to each other.

Results

The PGRN (+) group showed a widespread and severe pattern of grey matter loss predominantly affecting the frontal, temporal and parietal lobes. In comparison, the PGRN (−) group showed a less severe pattern of loss restricted mainly to the temporal and frontal lobes. On direct comparison the PGRN (+) group showed greater loss in the frontal and parietal lobes compared to the PGRN (−) group.

Conclusions

This study suggests that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.

Objective

To compare clinical and imaging features of patients with posterior cortical atrophy (PCA) with and without well-formed visual hallucinations.

Setting

Tertiary care medical center

Methods

Fifty-nine patients fulfilling criteria for PCA were retrospectively identified, and divided into two groups based on the presence (N=13) and absence (N=46) of visual hallucinations. Both groups were then compared statistically for clinical differences, as well as with voxel-based morphometry (VBM) for imaging differences.

Results

In PCA patients with hallucinations, parkinsonism and rapid eye movement sleep behavior disorder occurred more frequently (p<0.0001), as did myoclonic jerks (p=0.0002). VBM analysis showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain and midbrain in the patients with hallucinations.

Conclusions

Hallucinations in patients with PCA are associated with parkinsonism, rapid eye movement sleep behavior disorder, and myoclonic jerks. The results from the VBM analysis suggest that hallucinations in PCA cannot be exclusively attributed to atrophy of the posterior association cortices and may involve a circuit of thalamocortical connections.

Background

Although a majority of patients with amnestic mild cognitive impairment (aMCI) progress to Alzheimer disease, the natural history of nonamnestic MCI (naMCI) is less clear. Noninvasive imaging surrogates for underlying pathological findings in MCI would be clinically useful for identifying patients who may benefit from disease-specific treatments at the prodromal stage of dementia.

Objective

To determine the characteristic magnetic resonance imaging (MRI) and proton MR spectroscopy (1H MRS) profiles of MCI subtypes.

Design

Case-control study.

Setting

Community-based sample at a tertiary referral center.

Patients

Ninety-one patients with single-domain aMCI, 32 patients with multiple-domain aMCI, 20 patients with single- or multiple-domain naMCI, and 100 cognitively normal elderly subjects frequency-matched by age and sex.

Main Outcome Measures

Posterior cingulate gyrus 1H MRS metabolite ratios, hippocampal volumes, and cerebrovascular disease on MRI.

Results

Patients with single-domain aMCI were characterized by small hippocampal volumes and elevated ratios of myo-inositol to creatine levels. Patients with naMCI on average had normal hippocampal volumes and 1H MRS metabolite ratios, but a greater proportion (3 of 20 patients [15%]) had cortical infarctions compared with patients with single-domain aMCI (6 of 91 [7%]). For characterization of MCI subtypes, 1H MRS and structural MRI findings were complementary.

Conclusions

The MRI and 1H MRS findings in singledomain aMCI are consistent with a pattern similar to that of Alzheimer disease. Absence of this pattern on average in patients with naMCI suggests that cerebrovascular disease and other neurodegenerative diseases may be contributing to the cognitive impairment in many individuals with naMCI.

Background

It remains unknown whether diabetes mellitus is a risk factor for mild cognitive impairment (MCI).

Objective

To investigate the association of diabetes mellitus with MCI using a population-based case-control design.

Design, Setting, and Participants

Our study was conducted in subjects aged 70 through 89 years on October 1, 2004, who were randomly selected from the Olmsted County, MN, population.

Main Outcome Measure

We administered to all participants the Clinical Dementia Rating Scale, a neurological exam, and a neuropsychological evaluation including 9 tests in 4 cognitive domains to diagnose normal cognition, MCI, or dementia. We assessed history of diabetes, diabetes treatment, and complications by interview and we measured fasting blood glucose. History of diabetes was also confirmed using a medical records-linkage system.

Results

We compared 329 patients with MCI to 1640 subjects free of MCI and of dementia. The frequency of diabetes was similar in subjects with MCI (20.1%) and in subjects without MCI (17.7%; odds ratio [OR], 1.16; 95% confidence interval [CI], 0.85-1.57). However, MCI was associated with onset of diabetes before age 65 years (OR, 2.20; 95% CI, 1.29-3.73), diabetes duration ≥10 years (OR, 1.76; 95% CI, 1.16-2.68), treatment with insulin (OR, 2.01; 95% CI, 1.22-3.31), and presence of complications (OR, 1.80; 95% CI, 1.13-2.89) after adjustment for age, sex, and education. Analyses using alternative definitions of diabetes yielded consistent findings.

Conclusions

These findings suggest an association between earlier onset, longer duration, and greater severity of diabetes and MCI.