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Background: The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the underlying genetic cause of many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychologic, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism, and ALS spectrum. Objective: To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72. Design: Clinical series. Setting: Tertiary care academic medical center. Patients: The members of a family affected by the mutation with features of FTD and/or ALS. Main Outcome Measures: Clinical, neuropsychologic, and neuroimaging assessments. Results: All 3 examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/ behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and 1 had ALS. Magnetic resonance imaging showed symmetric bilateral frontal, temporal, insular, and cingulate atrophy. Conclusions: This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the cliniconeuromagingneropathologic correlations. [ABSTRACT FROM AUTHOR]

Objective: To characterize the shape of the trajectories of Alzheimer disease biomarkers as a function of Mini-Mental State Examination (MMSE) score. Design and Setting: Longitudinal registries from the Mayo Clinic and the Alzheimer's Disease Neuroimaging Initiative. Patients: Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to Alzheimer disease 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 score, adjusted for age, was modeled and described as baseline (crosssectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebrospinal fluid (CSF) Aβ42 and tau levels, amyloid and fluorodeoxyglucose positron emission tomography imaging, and structural magnetic resonance imaging. Results: Baseline biomarker values generally worsened (ie, nonzero slope) with lower baseline MMSE score. Baseline hippocampal volume, amyloid positron emission tomography, and fluorodeoxyglucose positron emission tomography values plateaued (ie, nonlinear slope) with lower MMSE score in 1 or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE score. Nonconstant within-subject rates (deceleration) of biomarker change were found in only 1 model. Conclusions: Biomarker trajectory shapes by MMSE score were complex and were affected by interactions with age and APOE status. Nonlinearity was found in several baseline effects models. Nonconstant within-subject rates of biomarker change were found in only 1 model, likely owing to limited within-subject longitudinal follow-up. Creating reliable models that describe the full trajectories of Alzheimer disease biomarkers will require significant additional longitudinal data in individual participants. [ABSTRACT FROM AUTHOR]

Objective: To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner. Design: Validation sample. Setting: Multisite, referral centers. Participants: A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) 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. Main Outcome Measures: Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume). Results: Within each clinical group of the entire sample (n=401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P=.05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months. Conclusions: A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level. [ABSTRACT FROM AUTHOR]

Objective: To examine default mode and salience network functional connectivity as a function of APOE ε4 status in a group of cognitively normal age-, sex-, and education-matched older adults. Design: Case-control study. Subjects: Fifty-six cognitively normal APOE ε4 carriers and 56 age-, sex- and education-matched cognitively normal APOE ε4 noncarriers. Main Outcome Measure: Alterations in in-phase default mode and salience network connectivity in APOE ε4 carriers compared with APOE ε4 noncarriers ranging from 63 to 91 years of age. Results: A posterior cingulate seed revealed decreased inphase 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 noncarriers. 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 noncarriers. There were no groupwise differences in brain anatomy. Conclusions: The observation of functional alterations in default mode and salience network connectivity in the absence of structural changes between APOE ε4 carriers and noncarriers suggests that alterations in connectivity may have the potential to serve as an early biomarker. [ABSTRACT FROM AUTHOR]

Objective: To report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene, PRNP. Design: Clinical description of a kindred. Setting: Mayo Clinic Alzheimer Disease Research Center (Rochester, Minnesota). Subjects: Two pathologically confirmed cases and their relatives. Main Outcome Measures: Clinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses, and neuropathologic features. Results: The proband was a woman with clinical and neuroimaging features of atypical frontotemporal dementia and ataxia. Generalized tonic-clonic seizures developed later in the disease course, and electroencephalography revealed spike and wave discharges but no periodic sharpwave complexes. Her affected sister and father also exhibited frontotemporal dementia-like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in the disease course. Genetic analyses in the proband identified a novel defect in PRNP, with 1 mutated allele carrying a 288-base pair insertion consisting of 12 octapeptide repeats. Neuropathologic examination of the proband and her sister revealed prion protein-positive plaques and widespread tau-positive tangles. Conclusions: This kindred has a unique combination of clinical and neuropathologic features associated with the largest base pair insertion identified to date in PRNP and underscores the need to consider familial prion disease in the differential diagnosis of a familial frontotemporal dementia-like syndrome. [ABSTRACT FROM AUTHOR]

Objectives: To use diffusion tensor imaging to assess white matter tract degeneration in progressive supranuclear palsy (PSP) and to investigate correlates between tract integrity and clinical measures. Design: Case-control study. Setting: Tertiary care medical center. Patients/Participants: Twenty patients with probable PSP and 20 age- and sex-matched healthy controls were enrolled. All patients with PSP underwent standardized clinical testing, including the Frontal Behavioral Inventory and Frontal Assessment Battery to assess behavioral change, the PSP Rating Scale to measure disease severity, the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (parts II and III) to measure motor function, and the PSP Saccadic Impairment Scale to measure eye movement abnormalities. Methods: Fractional anisotropy and mean diffusivity were measured using region of interest analysis and tractbased spatial statistics. Results: Compared with controls, abnormal diffusivity was observed predominantly in the superior cerebellar peduncles, body of the corpus callosum, inferior longitudinal fasciculus, and superior longitudinal fasciculus in patients with PSP. Fractional anisotropy values in the superior cerebellar peduncles correlated with disease severity (r=-0.59, P=.006), inferior longitudinal fasciculus correlated with motor function (r=-0.51, P=.02), and superior longitudinal fasciculus correlated with severity of saccadic impairments (r=-0.45, P=.047). Conclusions: The results of this study demonstrate that PSP is associated with degeneration of the brainstem, association, and commissural fibers and that this degeneration likely plays an important role in clinical dysfunction. [ABSTRACT FROM AUTHOR]

Objective: To evaluate relationships between magnetic resonance imaging (MRI)-based measures of white matter hyperintensities (WMHs), measured at baseline and longitudinally, and 1-year cognitive decline using a large convenience sample in a clinical trial design with a relatively mild profile of cardiovascular risk factors. Design: Convenience sample in a clinical trial design. Subjects: A total of 804 participants in the Alzheimer Disease Neuroimaging Initiative who received MRI scans, cognitive testing, and clinical evaluations at baseline, 6-month follow-up, and 12-month follow-up visits. For each scan, WMHs were detected automatically on coregistered sets of T1, proton density, and T2 MRI images using a validated method. Mixed-effects regression models evaluated relationships between risk factors for WMHs, WMH volume, and change in outcome measures including Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subscale (ADASCog), and Clinical Dementia Rating Scale sum of boxes scores. Covariates in these models included race, sex, years of education, age, apolipoprotein E genotype, baseline clinical diagnosis (cognitively normal, mild cognitive impairment, or Alzheimer disease), cardiovascular risk score, and MRI-based hippocampal and brain volumes. Results: Higher baseline WMH volume was associated with greater subsequent 1-year increase in ADAS-Cog and decrease in MMSE scores. Greater WMH volume at follow-up was associated with greater ADAS-Cog and lower MMSE scores at follow-up. Higher baseline age and cardiovascular risk score and more impaired baseline clinical diagnosis were associated with higher baseline WMH volume. Conclusions: White matter hyperintensity volume predicts 1-year cognitive decline in a relatively healthy convenience sample that was similar to clinical trial samples, and therefore should be considered as a covariate of interest at baseline and longitudinally in future AD treatment trials. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact white matter hyperintensities (WMH) detected on magnetic resonance imaging have on motor dysfunction and cognitive impairment in elderly subjects without dementia. Design: Cross-sectional study. Setting: Population-based study on the incidence and prevalence of cognitive impairment in Olmsted County, Minnesota. Participants: A total of 148 elderly subjects (65 men) without dementia ranging in age from 73 to 91 years. Main Outcome Measures: We measured the percentage of the total white matter volume classified as WMH in a priori-defined brain regions (ie, frontal, temporal, parietal, occipital, periventricular, or subcortical). Motor impairment was evaluated qualitatively using the Unified Parkinson's Disease Rating Scale 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 WMH proportion in all regions except the occipital lobe was associated with lower executive function z score (P value<.01). A higher WMH proportion in all regions, but most strongly for the parietal lobe, correlated with higher Unified Parkinson's Disease Rating Scale gait, posture, and postural stability sum(P value<.01).A higher WMH proportion, whether periventricular, subcortical, or lobar, correlated with reduced velocity (P value<.001). Conclusions: We conclude that executive function is the primary cognitive domain affected by WMH burden. The data suggest that WMH in the parietal lobe are chiefly responsible for reduced balance and postural support compared with the other 3 lobes and may alter integration of sensory information via parietal lobe dysfunction in the aging brain. Parietal white matter changes were not the predominant correlate with motor speed, lending evidence to a global involvement of neural networks in gait velocity. [ABSTRACT FROM AUTHOR]

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 disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiologic, 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. [ABSTRACT FROM AUTHOR]

Objective: To localize susceptibility genes for alterations in brain structure associated with risk of stroke and dementia.Weconducted 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 fluidattenuated 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 fluidattenuated 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). Basedonmultipoint logarithm of odds scores (MLS), the strongest evidence of genetic linkage was observed for brain atrophy on chromosomes1( MLS, 3.49 at 161cM; P<.001) and17(MLS, 3.08 at 18cM;P<.001) inwhites; for ventricularvolumeonchromosome 12 (MLS, 3.67 at 49 cM; P<.001) in blacks and chromosome10 (MLS,2.47 at 110 cM;P<.001) in whites; and for leukoaraiosison chromosome 11(MLS, 2.21 at118 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. [ABSTRACT FROM AUTHOR]

Background: Semantic dementia is a syndrome within the spectrum of frontotemporal lobar degenerations characterized by fluent progressive aphasia (particularly anomia) and loss of word meaning. Objective: To report a unique case of very early semantic dementia with a slowly progressive course, allowing insights into the early natural history of this disorder. Design: Case report. Setting: A tertiary care center. Patient: A 62-year-old woman who presented with "memory loss" complaints. Main Outcome Measures: Clinical course, neuropsychological data, and magnetic resonance imaging results. Results: The patient was first evaluated when the results of standard neuropsychological measures were normal but subtle left anterior temporal lobe atrophy was present. During the follow-up period of 8 years, she developed profound anomia and loss of word meaning associated with progressive left anterior temporal lobe atrophy, consistent with semantic dementia. In more recent years, anterograde memory impairment and mild prosopagnosia evolved in association with left hippocampal atrophy and subtle atrophy in the homologous gyri of the right anterior temporal lobe. She remains functionally independent despite her current deficits. Conclusions: Early identification of patients who will develop semantic dementia is difficult and might be missed with standard clinical, neuropsychological, and structural neuroimaging evaluations. Recognition of this relatively rare syndrome is important for early diagnosis and prognostication and particularly for therapeutic interventions in the future. [ABSTRACT FROM AUTHOR]

Background: Although a majority of patients with amnestic mild cognitive impairment (aMCI) progress to Alzheimerdisease, 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 1HMRS 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 ¹HMRS 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, 1HMRS 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. [ABSTRACT FROM AUTHOR]

Background: In most patients, mild cognitive impairment (MCI) represents the clinically evident prodromal phase of dementia. This is most well established in amnestic MCI, which is most commonly a precursor to Alzheimer disease (AD). It follows, however, that subjects with MCI who have impairment in nonmemory domains may progress to non-AD degenerative dementias. Objective: To investigate patterns of cerebral atrophy associated with specific subtypes of MCI. Design: Case-control study. Setting: Community-based sample at a tertiary referral center. Patients: One hundred forty-five subjects with MCI and 145 age- and sex-matched cognitively normal control subjects. Mild cognitive impairment was classified as amnestic, single cognitive domain; amnestic, multiple domain; nonamnestic, single domain; and nonamnestic, multiple domain. Subjects with nonamnestic singledomain MCI were classified into language, attention/ executive, and visuospatial subgroups on the basis of specific cognitive impairment. Main Outcome Measure: Patterns of gray matter loss in the MCI groups compared with control subjects, assessed using voxel-based morphometry. Results: Subjects in the amnestic single- and multipledomain groups showed loss in the medial and inferior temporal lobes compared with control subjects, and those in the multiple-domain group also had involvement of the posterior temporal lobe, parietal association cortex, and posterior cingulate. Subjects in the nonamnestic single-domain group with language impairment showed loss in the left anterior inferior temporal lobe. The group with attention/executive deficits showed loss in the basal forebrain and hypothalamus. No coherent patterns of loss were observed in the other subgroups. Conclusions: The pattern of atrophy in the amnestic MCI groups is consistent with the concept that MCI in most of these subjects represents prodromal AD. However, the varying patterns in the language and attention/ executive subgroups suggest that these subjects may have a different underlying disorder. [ABSTRACT FROM AUTHOR]

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 FTLD-U cases with and without PGRN mutations. Design: Case-control study. Setting: Brain bank of a tertiary care medical center. Patients: Eight subjects who had screened positive for PGRN mutations (PGRN-positive) and who underwent volumetric magnetic resonance imaging were identified. Subjects were then matched by clinical diagnosis to a group of 8 subjects with a pathological diagnosis of FTLD-U who had screened negative for PGRN mutations (PGRN-negative). All subjects were then age-matched and sex-matched to a control subject. Main Outcome Measures: Voxel-based morphometry was used to assess the patterns of gray matter atrophy in the PGRN-positive group compared with the PGRN-negative group and compared with controls. Results: The PGRN-positive group showed a widespread and severe pattern of gray matter loss predominantly affecting the frontal, temporal, and parietal lobes. The PGRN-negative group showed a less severe pattern of gray matter loss restricted mainly to the temporal and frontal lobes. On direct comparison, the PGRN-positive group showed greater gray matter loss in the frontal and parietal lobes compared with the PGRN-negative group. Conclusion: Findings from this study suggest that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U. [ABSTRACT FROM AUTHOR]

Background: Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician. Objective: To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia. Design: A 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study initially designed to evaluate the efficacy of donepezil hydrochloride or vitamin E vs placebo to delay progression of MCI to dementia. Setting: Memory assessment centers. Patients: A total of 190 individuals with MCI. Main Outcome Measures: Ratings of MTA performed using magnetic resonance images obtained at baseline. Log-rank tests and Cox proportional hazards ratios examining the significance of MTA estimates in predicting progression of MCI to dementia. Results: A mean MTA score greater than 2.0 was associated with a greater than 2-fold increased likelihood of progression to dementia during the observation period (hazards ratio, 2.30; 95% confidence interval, 1.09-4.92; P = .03) after controlling for age, education, sex, and baseline Mini-Mental State Examination score. Conclusions: Adjusted estimates of MTA were associated with significantly increased risk of developing dementia within 3 years, suggesting that obtaining a magnetic resonance image during the evaluation of MCI may offer additional independent information about the risk of progression to dementia. Given the relatively high prevalence of MCI in the general population, use of this method as part of routine clinical evaluation may help identify individuals who might benefit from increased surveillance and future treatment. [ABSTRACT FROM AUTHOR]

Background: Visual hallucinations have been reported to occur in up to 25% of patients who meet the criteria for posterior cortical atrophy (PCA). It is not known, however, whether patients who meet the criteria for PCA and have hallucinations are different from those who meet the criteria and do not have hallucinations. Objective: To compare the clinical and imaging features of patients with PCA with and without wellformed visual hallucinations. Design: Case-control study. Setting: Tertiary care medical center. Patients: Fifty-nine patients fulfilling the criteria for PCA were retrospectively identified and divided into 2 groups based on the presence (n = 13) or absence (n = 46) of visual hallucinations. Main Outcome Measures: Statistically significant clinical differences and imaging differences using voxelbased morphometry between the 2 groups. Results: In patients with PCA and hallucinations, parkinsonism and rapid eye movement sleep behavior disorder occurred more frequently, as did myoclonic jerks (P< .001 for both). Voxel-based morphometry showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain, and midbrain, in patients with hallucinations. Conclusions: Hallucinations in patients with PCA are associated with parkinsonism, rapid eye movement sleep behavior disorder, and myoclonic jerks. The voxelbased morphometry results suggest that hallucinations in PCA cannot be exclusively attributed to atrophy of the posterior association cortices and may involve a circuit of thalamocortical connections. [ABSTRACT FROM AUTHOR]