Amyloid-Related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population With and Without Cerebral Amyloid.

BACKGROUND: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies provide a unique opportunity to compare magnetic resonance imaging (MRI) findings such as amyloid-related imaging abnormalities (ARIA) in cognitively unimpaired elderly with and without elevated cerebral amyloid. OBJECTIVES: To compare screening MRI findings, such as ARIA, in the cognitively unimpaired potential participants of a clinical trial with and without elevated cerebral amyloid. DESIGN: Cross-sectional analysis of structural MRI findings in screening data from the A4 and LEARN studies. SETTING: The A4 Study is a multi-center international clinical trial. The LEARN Study is a multi center observational study in the United States. PARTICIPANTS: Clinically normal older adults (65-85 years) with elevated cerebral amyloid (Aß+; n = 1250, A4) and without elevated cerebral amyloid (Aß-; n = 538, LEARN). MEASUREMENTS: Participants underwent florbetapir positron emission tomography for Aß+/- classification. A centrally read 3T MRI to assess for study eligibility was conducted on study qualified MRI scanners. RESULTS: No ARIA-effusions (ARIA-E) was detected on screening MRI in the Aß+ or Aß- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aß+ cohort compared with 8% in Aß- (P < 0.001). In the Aß+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aß-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aß+ cohort increased the odds for presence of MCH (odds ratio [OR] = 2.03; 95% CI, 1.23 to 3.27, P = 0.004). Cortical infarctions (4% vs 0%) and subcortical infarctions (10% vs 1%) were observed at statistically significantly higher prevalence in the Aß+ cohort compared with Aß- (P < 0.001). Females showed reduced odds of MCH in the Aß+ cohort by a factor of 0.63 (95% CI, 0.47 to 0.84, P = 0.002). CONCLUSIONS: ARIA-E is rare in cognitively unimpaired Aß+ and Aß- populations prior to anti-amyloid drug intervention. ARIA-H in Aß+ was greater than in Aß- populations.

Lessons from KEEPS: the Kronos Early Estrogen Prevention Study.

The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17ß-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of ß-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Multiple sclerosis masquerading as Alzheimer-type dementia: Clinical, radiological and pathological findings.

BACKGROUND AND OBJECTIVES: We report a comprehensive clinical, radiological, neuropsychometric and pathological evaluation of a woman with a clinical diagnosis of AD dementia (ADem), but whose autopsy demonstrated widespread demyelination, without Alzheimer disease (AD) pathology. METHODS AND RESULTS: Initial neuropsychometric evaluation suggested amnestic mild cognitive impairment (aMCI). Serial magnetic resonance images (MRI) images demonstrated the rate of increase in her ventricular volume was comparable to that of 46 subjects with aMCI who progressed to ADem, without accumulating white matter disease. Myelin immunohistochemistry at autopsy demonstrated extensive cortical subpial demyelination. Subpial lesions involved the upper cortical layers, and often extended through the entire width of the cortex. CONCLUSIONS: Multiple sclerosis (MS) can cause severe cortical dysfunction and mimic ADem. Cortical demyelination is not well detected by standard imaging modalities and may not be detected on autopsy without myelin immunohistochemistry.

Cerebral Microbleeds, CSF p-Tau, and Cognitive Decline: Significance of Anatomic Distribution.

BACKGROUND AND PURPOSE: Cerebral microbleeds are associated with aging, hypertension, and Alzheimer disease. Microbleeds in a lobar distribution are believed to reflect underlying amyloid angiopathy, whereas microbleeds in the deep gray matter and infratentorial brain are commonly seen with hypertension. However, it is unknown how microbleeds in either distribution are related to Alzheimer pathogenesis. The purpose of this analysis was to test whether lobar and deep gray/infratentorial microbleeds demonstrate differential associations with CSF amyloid-ß and phosphorylated tau 181 protein levels and longitudinal cognitive decline. MATERIALS AND METHODS: A total of 626 subjects (151 cognitively normal, 389 with mild cognitive impairment, and 86 with Alzheimer disease) from the Alzheimer's Disease Neuroimaging Initiative who had undergone 3T MR imaging and lumbar puncture were included in the analysis. The number and location of microbleeds were assessed visually. Associations between lobar or deep gray/infratentorial microbleeds with CSF amyloid-ß levels, abnormal CSF phosphorylated tau 181 protein levels, and longitudinal cognitive decline were assessed by using ordinary least-squares, logistic, and mixed-effects regression models while adjusting for covariates. RESULTS: Having ≥3 lobar microbleeds was associated with lower levels of CSF amyloid-ß (P = .001). After adjusting for CSF amyloid-ß level, lobar microbleeds were independently associated with a higher likelihood of having an abnormal CSF phosphorylated tau 181 protein level (P = .004). Lobar microbleeds were associated with accelerated longitudinal cognitive decline (P = .007). Deep gray/infratentorial microbleeds revealed no significant associations. CONCLUSIONS: The distribution of microbleeds revealed different associations with amyloid-ß and phosphorylated tau 181 protein levels and cognition. Lobar and deep gray/infratentorial microbleeds should be considered separately with regard to Alzheimer disease pathogenesis.

Molecular imaging of Alzheimer disease pathology.

Development of molecular imaging agents for fibrillar ß-amyloid positron-emission tomography during the past decade has brought molecular imaging of Alzheimer disease pathology into the spotlight. Large cohort studies with longitudinal follow-up in cognitively normal individuals and patients with mild cognitive impairment and Alzheimer disease indicate that ß-amyloid deposition can be detected many years before the onset of symptoms with molecular imaging, and its progression can be followed longitudinally. The utility of ß-amyloid PET in the differential diagnosis of Alzheimer disease is greatest when there is no pathologic overlap between 2 dementia syndromes, such as in frontotemporal lobar degeneration and Alzheimer disease. However ß-amyloid PET alone may be insufficient in distinguishing dementia syndromes that commonly have overlapping ß-amyloid pathology, such as dementia with Lewy bodies and vascular dementia, which represent the 2 most common dementia pathologies after Alzheimer disease. The role of molecular imaging in Alzheimer disease clinical trials is growing rapidly, especially in an era when preventive interventions are designed to eradicate the pathology targeted by molecular imaging agents.

Neuroimaging comparison of primary progressive apraxia of speech and progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Primary progressive apraxia of speech, a motor speech disorder of planning and programming, is a tauopathy that has overlapping histological features with progressive supranuclear palsy. We aimed to compare, for the first time, atrophy patterns, as well as white matter tract degeneration, between these two syndromes. METHODS: Sixteen primary progressive apraxia of speech subjects were age- and gender-matched to 16 progressive supranuclear palsy subjects and 20 controls. All subjects were prospectively recruited, underwent neurological and speech evaluations and 3.0-Tesla magnetic resonance imaging. Grey and white matter atrophy was assessed using voxel-based morphometry and atlas-based parcellation, and white matter tract degeneration was assessed using diffusion tensor imaging. RESULTS: All progressive supranuclear palsy subjects had typical oculomotor/gait impairments, but none had speech apraxia. Both syndromes showed grey matter loss in supplementary motor area, white matter loss in posterior frontal lobes and degeneration of the body of the corpus callosum. Whilst lateral grey matter loss was focal, involving superior premotor cortex, in primary progressive apraxia of speech, loss was less focal extending into prefrontal cortex in progressive supranuclear palsy. Caudate volume loss and tract degeneration of superior cerebellar peduncles were also observed in progressive supranuclear palsy. Interestingly, area of the midbrain was reduced in both syndromes compared to controls, although this was greater in progressive supranuclear palsy. CONCLUSIONS: Although neuroanatomical differences were identified between these distinctive clinical syndromes, substantial overlap was also observed, including midbrain atrophy, suggesting these two syndromes may have common pathophysiological underpinnings.

Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease.

OBJECTIVE: Recommendations for the diagnosis of preclinical Alzheimer disease (AD) have been formulated by a workgroup of the National Institute on Aging and Alzheimer's Association. Three stages of preclinical AD were described. Stage 1 is characterized by abnormal levels of ß-amyloid. Stage 2 represents abnormal levels of ß-amyloid and evidence of brain neurodegeneration. Stage 3 includes the features of stage 2 plus subtle cognitive changes. Stage 0, not explicitly defined in the criteria, represents subjects with normal biomarkers and normal cognition. The ability of the recommended criteria to predict progression to cognitive impairment is the crux of their validity. METHODS: Using previously developed operational definitions of the 3 stages of preclinical AD, we examined the outcomes of subjects from the Mayo Clinic Study of Aging diagnosed as cognitively normal who underwent brain MRI or [(18)F]fluorodeoxyglucose and Pittsburgh compound B PET, had global cognitive test scores, and were followed for at least 1 year. RESULTS: Of the 296 initially normal subjects, 31 (10%) progressed to a diagnosis of mild cognitive impairment (MCI) or dementia (27 amnestic MCI, 2 nonamnestic MCI, and 2 non-AD dementias) within 1 year. The proportion of subjects who progressed to MCI or dementia increased with advancing stage (stage 0, 5%; stage 1, 11%; stage 2, 21%; stage 3, 43%; test for trend, p < 0.001). CONCLUSIONS: Despite the short follow-up period, our operationalization of the new preclinical AD recommendations confirmed that advancing preclinical stage led to higher proportions of subjects who progressed to MCI or dementia.

Similar clinical and neuroimaging features in monozygotic twin pair with mutation in progranulin.

OBJECTIVE: To report the phenotypic characterization of monozygotic twins with mutations encoding progranulin (PGRN). METHODS: We studied a twin pair with an exon 4 gene deletion in the PGRN gene. Both twins had clinical and neuropsychological examinations as well as structural MRI and fluorodeoxyglucose PET (FDG-PET) scans. PGRN gene sequencing was performed followed by progranulin ELISA in plasma. RESULTS: Both twins manifested symptoms within 3 years of each other, with early behavioral, language, dysexecutive, and memory problems. MRI and FDG-PET imaging demonstrated a strikingly similar topography of findings with clear left hemisphere predominance. Serum progranulin levels in both were well below those from a normal population sample. CONCLUSIONS: Compared with the heterogeneity seen in many families with PGRN mutations, these monozygotic twins demonstrated strong clinical, neuroimaging, and serum progranulin level similarities, demonstrating the importance of shared genetic profiles beyond environmental influences in the symptomatic expression of the disease.

APOE modifies the association between Aß load and cognition in cognitively normal older adults.

OBJECTIVE: To determine the relationship between ß-amyloid (Aß) load as measured by [(11)C]-Pittsburgh compound B (PiB) PET and cognitive function in cognitively normal older adults. METHODS: We studied 408 cognitively normal older adults who participated in the population-based Mayo Clinic Study of Aging (MCSA) from January 2009 through March 2011. The participants underwent PiB PET and neuropsychometric testing within 6 months. The association between PiB retention and cognitive function was measured by partial correlation and an interaction with APOE status was tested using linear regression after adjusting for age, sex, and education. RESULTS: Higher PiB retention was associated with cognitive performance (Spearman partial r = -0.18; p < 0.01), specifically the memory, language, attention/executive, and visual-spatial processing domains in the whole group of participants. The association between PiB retention and cognition was modified by the APOE status on linear regression analysis even after controlling for the differences in the distribution of PiB values among APOE ε4 carriers and noncarriers (p = 0.02). Cognitive performance was associated with the Aß deposition in the frontal, temporal, and parietal lobe association cortices in APOE ε4 carriers on SPM analysis (p < 0.001). CONCLUSION: There is a modest association between PiB retention and cognitive function in cognitively normal older adults and this relationship between Aß load and cognitive function is modified by APOE status. Whereas Aß load is associated with greater cognitive impairment in APOE ε4 carriers, the cognitive function in APOE ε4 noncarriers is influenced less by the Aß load, suggesting that APOE isoforms modulate the harmful effects of Aß on cognitive function.

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.

Diffusion tensor imaging and cognitive function in older adults with no dementia.

OBJECTIVE: To determine the patterns of diffusivity associated with cognitive domain functions in older adults without dementia. METHODS: We studied older adults without dementia (n = 220) who underwent neuropsychometric testing and a diffusion tensor imaging (DTI) examination at 3 T in a cross-sectional study. Memory, language, attention/executive function, and visual-spatial processing domains were assessed within 4 months of the MRI examination. A fluid-attenuated inversion recovery-based DTI sequence that enabled uncontaminated cortical diffusion measurements was performed. Associations between cortical mean diffusivity (MD) and cognitive function were tested using voxel-based regression analysis. Association between tract diffusivity and cognitive function was tested with regions of interest drawn on color-coded fractional anisotropy (FA) maps. RESULTS: Memory function was associated with the medial temporal lobe cortical MD on voxel-based analysis (p < 0.001, corrected for multiple comparisons), and inferior longitudinal fasciculus and posterior and anterior cingulum FA on tract-based analysis (p < 0.001). Language function was associated with the left temporal lobe cortical MD (p < 0.001, corrected for multiple comparisons), inferior longitudinal fasciculus, fornix, and posterior cingulum FA (p < 0.05). Attention and executive function was associated with the posterior and anterior cingulum FA, and visual-spatial function was associated with posterior cingulum FA (p < 0.01). CONCLUSION: Specific cognitive domain functions are associated with distinct patterns of cortical and white matter diffusivity in elderly with no dementia. Posterior cingulum tract FA was associated with all 4 cognitive domain functions, in agreement with the hypothesis that the posterior cingulate cortex is the main connectivity hub for cognitive brain networks. Microstructural changes identified on DTI may be associated with neurodegenerative pathologies underlying cognitive changes in older adults without dementia.

MRS in presymptomatic MAPT mutation carriers: a potential biomarker for tau-mediated pathology.

OBJECTIVE: To determine the proton magnetic resonance spectroscopy ((1)H MRS) changes in carriers of microtubule-associated protein (MAPT) mutations in a case-control study. METHODS: Patients with MAPT mutations (N279K, V337M, R406W, IVS9-10G>T, P301L) from 5 different families (n = 24) underwent MRI and single voxel (1)H MRS from the posterior cingulate gyrus inferior precuneus at 3 T. Ten of the patients were symptomatic with median Clinical Dementia Rating sum of boxes score (CDR-SOB) of 6.5 and 14 patients were presymptomatic with CDR-SOB of 0. Age- and sex-matched controls (n = 24) were recruited. RESULTS: Symptomatic MAPT mutation carriers were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) ratio, an index of neuronal integrity, increased myoinositol (mI)/Cr ratio, a possible marker for glial activity, decreased NAA/mI, and hippocampal atrophy (p < 0.001). Whereas presymptomatic MAPT mutation carriers had elevated mI/Cr and decreased NAA/mI (p < 0.001), NAA/Cr levels and hippocampal volumes were not different from controls. Decrease in NAA/Cr (R(2) = 0. 22; p = 0.021) and hippocampal volumes (R(2) = 0.46; p < 0.001) were associated with proximity to the expected or actual age at symptom onset in MAPT mutation carriers. CONCLUSION: (1)H MRS metabolite abnormalities characterized by an elevated mI/Cr and decreased NAA/mI are present several years before the onset of symptoms in MAPT mutation carriers. The data suggest an ordered sequencing of the (1)H MRS and MRI biomarkers. MI/Cr, a possible index of glial proliferation, precedes the decrease in neuronal integrity marker NAA/Cr and hippocampal atrophy. (1)H MRS may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies.

Dementia with Lewy bodies and Alzheimer disease: neurodegenerative patterns characterized by DTI.

OBJECTIVE: To identify the patterns of diffusivity changes in patients with dementia with Lewy bodies (DLB) and Alzheimer disease (AD) and to determine whether diffusion tensor MRI (DTI) is complementary to structural MRI in depicting the tissue abnormalities characteristic of DLB and AD. METHODS: We studied clinically diagnosed age-, gender-, and education-matched subjects with DLB (n = 30), subjects with AD (n = 30), and cognitively normal (CN) subjects (n = 60) in a case-control study. DTI was performed at 3T with a fluid-attenuated inversion recovery-based DTI sequence that enabled cortical diffusion measurements. Mean diffusivity (MD) and gray matter (GM) density were measured from segmented cortical regions. Tract-based diffusivity was measured using color-coded fractional anisotropy (FA) maps. RESULTS: Patients with DLB were characterized by elevated MD in the amygdala and decreased FA in the inferior longitudinal fasciculus (ILF). ILF diffusivity was associated with the presence of visual hallucinations (p = 0.007), and amygdala diffusivity was associated with Unified Parkinson's Disease Rating Scale (r = 0.50; p = 0.005) in DLB. In contrast, patients with AD were characterized by elevated MD in the medial temporal, temporal, and parietal lobe association cortices and decreased FA in the fornix, cingulum, and ILF. Amygdala diffusivity was complementary to GM density in discriminating DLB from CN; hippocampal and parahippocampal diffusivity was complementary to GM density in discriminating AD from CN. CONCLUSION: Increased amygdalar diffusivity in the absence of tissue loss in dementia with Lewy bodies (DLB) may be related to microvacuolation, a common pathology associated with Lewy body disease in the amygdala. Diffusivity measurements were complementary to structural MRI, demonstrating that measures of diffusivity on diffusion tensor MRI are valuable tools for characterizing the tissue abnormalities characteristic of Alzheimer disease and DLB.

Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia.

OBJECTIVE: To use diffusion tensor imaging (DTI) to assess gray matter and white matter tract diffusion in behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SMD), and progressive nonfluent aphasia (PNFA). METHODS: This was a case-control study where 16 subjects with bvFTD, 7 with PNFA, and 4 with SMD were identified and matched by age and gender to 19 controls. All subjects had 3-T head MRI with a DTI sequence with diffusion encoding in 21 directions. Gray matter mean diffusivity (MD) was assessed using a region-of-interest (ROI) and voxel-level approach, and voxel-based morphometry was used to assess patterns of gray matter loss. White matter tract diffusivity (fractional anisotropy and radial diffusivity) was assessed by placing ROIs on tracts of interest. RESULTS: In bvFTD, increased gray matter MD and gray matter loss were identified bilaterally throughout frontal and temporal lobes, with abnormal diffusivity observed in white matter tracts that connect to these regions. In SMD, gray matter loss and increased MD were identified predominantly in the left temporal lobe, with tract abnormalities observed in the inferior longitudinal fasciculus and uncinate fasciculus. In PNFA, gray matter loss and increased MD were observed in left inferior frontal lobe, insula, and supplemental motor area, with tract abnormalities observed in the superior longitudinal fasciculus. CONCLUSIONS: The diffusivity of gray matter is increased in regions that are atrophic in frontotemporal dementia, suggesting disruption of the cytoarchitecture of remaining tissue. Furthermore, damage was identified in white matter tracts that interconnect these regions, supporting the hypothesis that these diseases involve different and specific brain networks.

Risk of dementia in MCI: combined effect of cerebrovascular disease, volumetric MRI, and 1H MRS.

OBJECTIVE: To investigate the combined ability of hippocampal volumes, 1H magnetic resonance spectroscopy (MRS) metabolites, and cerebrovascular disease to predict the risk of progression to dementia in mild cognitive impairment (MCI). METHODS: We identified 151 consecutively recruited subjects with MCI from the Mayo Clinic Alzheimer's Disease Research Center and Patient Registry who underwent MRI and 1H MRS studies at baseline and were followed up with approximately annual clinical examinations. A multivariable proportional hazards model that considered all imaging predictors simultaneously was used to determine whether hippocampal volumes, posterior cingulate gyrus 1H MRS metabolites, white matter hyperintensity load, and presence of cortical and subcortical infarctions are complementary in predicting the risk of progression from MCI to dementia. RESULTS: Seventy-five subjects with MCI progressed to dementia by last follow-up. The model that best predicted progression to dementia included age, sex, hippocampal volumes, N-acetylaspartate (NAA)/creatine (Cr) on 1H MRS, and cortical infarctions. Based on age- and sex-adjusted Kaplan-Meier plots, we estimated that by 3 years, 26% of the MCI patients with normal hippocampal volumes, NAA/Cr ratios >1 SD, and no cortical infarctions will progress to dementia, compared with 78% of the MCI patients with hippocampal atrophy, low NAA/Cr (< or =1 SD), and cortical infarction. CONCLUSIONS: Multiple magnetic resonance (MR) markers of underlying dementia pathologies improve the ability to identify patients with prodromal dementia over a single MR marker, supporting the concept that individuals with multiple brain pathologies have increased odds of dementia compared with individuals with a single pathology.

MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study.

BACKGROUND: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. METHODS: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). RESULTS: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. CONCLUSIONS: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.

1H magnetic resonance spectroscopy in dementia.

Present data support the concept that (1)H magnetic resonance spectroscopy ((1)H MRS) may become an adjunct to clinical evaluation for differential diagnosis of dementia in the future. The value of (1)H MRS in monitoring the disease progression in dementia is expected to be in areas where group effects are sought such as monitoring effectiveness of therapies in drug trials. Elevation of myoinositol to creatine (mI/Cr) and choline to creatine (Cho/Cr) and reduction in the neuronal integrity marker N-acetylaspartate to creatine (NAA/Cr) levels in individuals with mild cognitive impairment and pre-symptomatic Alzheimer's disease suggests that (1)H MRS may also be valuable in predicting future development of dementia and monitoring early disease progression for preventive therapies. Investigations of in vivo (1)H MRS as a marker for differential diagnosis and progression of dementia, however, has been limited to clinically confirmed cohorts and remains to be validated by histopathology at autopsy. Overall, MRS is a promising investigational technique in ageing and dementia at this time. The potential clinical application of MRS in ageing and dementia, however, is growing with technical advances in the field.

DWI predicts future progression to Alzheimer disease in amnestic mild cognitive impairment.

The authors assessed whether measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer disease (AD) in amnestic mild cognitive impairment (aMCI). Higher baseline hippocampal diffusivity was associated with a greater risk of progression to AD in aMCI (p = 0.002). Magnetic resonance diffusion-weighted imaging may help identify patients with aMCI who will progress to AD as well as or better than structural MRI measures of hippocampal atrophy.