Changes in Ventricular and Cortical Volumes following Shunt Placement in Patients with Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: While changes in ventricular and extraventricular CSF spaces have been studied following shunt placement in patients with idiopathic normal pressure hydrocephalus, regional changes in cortical volumes have not. These changes are important to better inform disease pathophysiology and evaluation for copathology. The purpose of this work is to investigate changes in ventricular and cortical volumes in patients with idiopathic normal pressure hydrocephalus following ventriculoperitoneal shunt placement. MATERIALS AND METHODS: This is a retrospective cohort study of patients with idiopathic normal pressure hydrocephalus who underwent 3D T1-weighted MR imaging before and after ventriculoperitoneal shunt placement. Images were analyzed using tensor-based morphometry with symmetric normalization to determine the percentage change in ventricular and regional cortical volumes. Ventricular volume changes were assessed using the Wilcoxon signed rank test, and cortical volume changes, using a linear mixed-effects model (P < .05). RESULTS: The study included 22 patients (5 women/17 men; mean age, 73 [SD, 6] years). Ventricular volume decreased after shunt placement with a mean change of -15.4% (P < .001). Measured cortical volume across all participants and cortical ROIs showed a mean percentage increase of 1.4% (P < .001). ROIs near the vertex showed the greatest percentage increase in volume after shunt placement, with smaller decreases in volume in the medial temporal lobes. CONCLUSIONS: Overall, cortical volumes mildly increased after shunt placement in patients with idiopathic normal pressure hydrocephalus with the greatest increases in regions near the vertex, indicating postshunt decompression of the cortex and sulci. Ventricular volumes showed an expected decrease after shunt placement.

Tau uptake in agrammatic primary progressive aphasia with and without apraxia of speech.

BACKGROUND AND PURPOSE: The non-fluent/agrammatic variant of primary progressive aphasia (agPPA) is a heterogeneous diagnosis wherein some individuals have apraxia of speech (AOS). When agPPA includes AOS, a tauopathy is the likely underlying pathology. Recently, [18F]AV-1451 was developed for the in-vivo assessment of tau. In this study, we compared patterns of tau tracer uptake in patients with agPPA with and without AOS. METHODS: Nine patients with agPPA (four without AOS) underwent tau positron emission tomography imaging with [18F]AV-1451. Uptake of [18F]AV-1451 was assessed as cortical to cerebellar crus ratio (standard uptake value ratio) in cortical regions of interest measured using the MCALT atlas and compared voxel-wise in SPM12. Each patient was age- and sex-matched to three controls. RESULTS: The agPPA without AOS showed uptake in the left frontal and temporal lobes, whereas agPPA with AOS showed uptake in the bilateral supplementary motor areas, frontal lobes, precuneus and precentral gyrus relative to controls. The left precentral gyrus had uptake in agPPA with AOS relative to those without AOS. CONCLUSIONS: This cross-sectional study suggests that [18F]AV-1451 uptake in the precentral gyrus is implicated in AOS in agPPA.

[18F] AV-1451 uptake in corticobasal syndrome: the influence of beta-amyloid and clinical presentation.

Corticobasal syndrome (CBS) is a phenotypic manifestation of diverse pathologies, including Alzheimer's disease and 4-repeat tauopathies. Predicting pathology in CBS is unreliable and, hence, molecular neuroimaging may prove to be useful. The aim of this study was to assess regional patterns of uptake on [18F] AV-1451 PET in CBS and determine whether patterns of uptake differ according to beta-amyloid deposition or differing clinical presentations. Fourteen patients meeting criteria for CBS underwent Pittsburgh Compound B (PiB) and [18F] AV-1451 PET. Seven patients presented as CBS and seven presented with apraxia of speech (AOS) and later evolved into CBS. A global PiB summary was calculated and used to classify patients as PiB (-) or PiB (+). AV-1451 uptake was calculated in fourteen regions-of-interest, with values divided by uptake in cerebellar crus grey matter to generate standard uptake value ratios. AV-1451 uptake was considered elevated if it fell above the 95th percentile from a group of 476 cognitively unimpaired normal controls. Six of the 14 CBS patients (43%) were PiB (+), with three of these patients showing strikingly elevated AV-1451 uptake across many cortical regions. Of the eight PiB (-) patients, only those with AOS showed elevated AV-1451 uptake in supplementary motor area and precentral cortex compared to controls. No region of elevated AV-1451 uptake were observed in PiB (-) typical CBS patients without AOS. These results suggest that regional [18F] AV-1451 is variable in CBS and depends on the presence of beta-amyloid as well as clinical presentation such as AOS. PiB (+) CBS does not necessarily reflect underlying Alzheimer's disease; however, the possibility some of these patients will evolve into Alzheimer's disease over time cannot be excluded.

MR Elastography Demonstrates Increased Brain Stiffness in Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: Normal pressure hydrocephalus is a reversible neurologic disorder characterized by a triad of cognitive impairment, gait abnormality, and urinary incontinence that is commonly treated with ventriculoperitoneal shunt placement. However, multiple overlapping symptoms often make it difficult to differentiate normal pressure hydrocephalus from other types of dementia, and improved diagnostic techniques would help patient management. MR elastography is a novel diagnostic tool that could potentially identify patients with normal pressure hydrocephalus. The purpose of this study was to assess brain stiffness changes in patients with normal pressure hydrocephalus compared with age- and sex-matched cognitively healthy individuals. MATERIALS AND METHODS: MR elastography was performed on 10 patients with normal pressure hydrocephalus and 21 age- and sex-matched volunteers with no known neurologic disorders. Image acquisition was conducted on a 3T MR imaging scanner. Shear waves with 60-Hz vibration frequency were transmitted into the brain by a pillowlike passive driver. A novel postprocessing technique resistant to noise and edge artifacts was implemented to determine regional brain stiffness. The Wilcoxon rank sum test and linear regression were used for statistical analysis. RESULTS: A significant increase in stiffness was observed in the cerebrum (P = .001), occipital lobe (P < .001), parietal lobe (P = .001), and the temporal lobe (P = .02) in the normal pressure hydrocephalus group compared with healthy controls. However, no significant difference was noted in other regions of the brain, including the frontal lobe (P = .07), deep gray and white matter (P = .43), or cerebellum (P = .20). CONCLUSIONS: This study demonstrates increased brain stiffness in patients with normal pressure hydrocephalus compared with age- and sex-matched healthy controls; these findings should motivate future studies investigating the use of MR elastography for this condition and the efficacy of shunt therapy.

Regional ß-amyloid burden does not correlate with cognitive or language deficits in Alzheimer's disease presenting as aphasia.

BACKGROUND AND PURPOSE: A subset of patients with Alzheimer's disease (AD) present with early and prominent language impairment (aphasic AD). Our previous study demonstrated an association between global ß-amyloid burden measured on [(11)C] Pittsburgh compound B (PiB) positron emission tomography and general cognitive impairment, but not with aphasia, in such subjects. As a follow-up, whether there is any association between regional ß-amyloid burden, atrophy on magnetic resonance imaging (MRI) and global cognitive impairment, aphasia or other cognitive and functional impairment in aphasic AD is assessed. METHODS: Forty-four aphasic AD subjects who underwent PiB scanning and volumetric MRI and were determined to be positive for ß-amyloid deposition were analyzed. All had completed detailed neurological, neuropsychological and language batteries. Spearman's rank-order correlation was utilized to assess for associations. RESULTS: Greater visuospatial impairment was associated with increased ß-amyloid burden in the primary visual cortex (P = 0.001). Although there were many trends for associations between neurocognitive and language deficits and regional ß-amyloid burden, there were no strong associations that survived correction for multiple comparisons. However, neurocognitive and language impairment in these subjects strongly correlated with the degree of left lateral temporal and inferior parietal atrophy (P < 0.004). CONCLUSIONS: The findings from this study suggest a close relation between the severity of regional atrophy and cognitive and language impairment, but argue against a strong association between regional ß-amyloid burden and such deficits in aphasic AD subjects. Hence, other pathological factors may be driving the previously identified association between global ß-amyloid deposition and general cognitive impairment in aphasic AD.

Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images.

BACKGROUND AND PURPOSE: The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD. METHODS: In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated. RESULTS: Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD. CONCLUSION: These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.

Amyloid burden correlates with cognitive decline in Alzheimer's disease presenting with aphasia.

BACKGROUND AND PURPOSE: A subset of patients with Alzheimer's disease (AD) present with early and prominent language deficits. It is unclear whether the burden of underlying ß-amyloid pathology is associated with language or general cognitive impairment in these subjects. METHODS: The relationship between cortical ß-amyloid burden on [(11) C]Pittsburgh compound B (PiB) positron emission tomography (PET) and performance on the Montreal Cognitive Assessment (MoCA), the Wechsler Memory Scale - Third Edition (WMS-III), the Boston Naming Test (BNT) and the Western Aphasia Battery (WAB) was assessed using regression and correlation analyses in subjects presenting with aphasia who showed ß-amyloid deposition on PiB PET. RESULTS: The global PiB ratio was inversely correlated with MoCA (P = 0.02) and the WMS-III Visual Reproduction (VR) subtest (VR I, P = 0.02; VR II, P = 0.04). However, the correlations between PiB ratio, BNT (P = 0.13), WAB aphasia quotient (P = 0.11) and WAB repetition scores (P = 0.34) were not significant. CONCLUSION: This study demonstrates that an increased cortical ß-amyloid burden is associated with cognitive impairment, but not language deficits, in AD subjects presenting with aphasia. The results suggest that ß-amyloid deposition could be partly contributing to impaired cognition in such patients whilst language dysfunction may be more influenced by other pathological mechanisms, perhaps downstream pathways of ß-amyloid deposition.

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.

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.

Age-related changes in the default mode network are more advanced in Alzheimer disease.

OBJECTIVE: To investigate age-related default mode network (DMN) connectivity in a large cognitively normal elderly cohort and in patients with Alzheimer disease (AD) compared with age-, gender-, and education-matched controls. METHODS: We analyzed task-free-fMRI data with both independent component analysis and seed-based analysis to identify anterior and posterior DMNs. We investigated age-related changes in connectivity in a sample of 341 cognitively normal subjects. We then compared 28 patients with AD with 56 cognitively normal noncarriers of the APOE ε4 allele matched for age, education, and gender. RESULTS: The anterior DMN shows age-associated increases and decreases in fontal lobe connectivity, whereas the posterior DMN shows mainly age-associated declines in connectivity throughout. Relative to matched cognitively normal controls, subjects with AD display an accelerated pattern of the age-associated changes described above, except that the declines in frontal lobe connectivity did not reach statistical significance. These changes survive atrophy correction and are correlated with cognitive performance. CONCLUSIONS: The results of this study indicate that the DMN abnormalities observed in patients with AD represent an accelerated aging pattern of connectivity compared with matched controls.

Magnetic resonance spectroscopy, ß-amyloid load, and cognition in a population-based sample of cognitively normal older adults.

OBJECTIVE: To determine the relationship between proton magnetic resonance spectroscopy ((1)H MRS) metabolites and ß-amyloid (Aß) load and the effects of Aß load on the association between (1)H MRS metabolites and cognitive function in cognitively normal older adults. METHODS: We studied 311 cognitively normal older adults who participated in the population-based Mayo Clinic Study of Aging from January 2009 through September 2010. Participants underwent (11)C-Pittsburgh compound B (PiB) PET, (1)H MRS from the posterior cingulate gyri, and neuropsychometric testing to assess memory, attention/executive, language, and visual-spatial domain functions within 6 months. Partial Spearman rank order correlations were adjusted for age, sex, and education. RESULTS: Higher PiB retention was associated with abnormal elevations in myoinositol (mI)/creatine (Cr) (partial r(s) = 0.17; p = 0.003) and choline (Cho)/Cr (partial r(s) = 0.13; p = 0.022) ratios. Higher Cho/Cr was associated with worse performance on Auditory Verbal Learning Test Delayed Recall (partial r(s) = -0.12; p = 0.04), Trail Making Test Part B (partial r(s) = 0.12; p = 0.04), Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol (partial r(s) = -0.18; p < 0.01), and WAIS-R Block Design (partial r(s) = -0.12; p = 0.03). Associations between (1)H MRS metabolites and cognitive function were not different among participants with high vs low PiB retention. CONCLUSION: In cognitively normal older adults, the (1)H MRS metabolite ratios mI/Cr and Cho/Cr are associated with the preclinical pathologic processes in the Alzheimer disease cascade. Higher Cho/Cr is associated with worse performance on domain-specific cognitive tests independent of Aß load, suggesting that Cho/Cr elevation may also be dependent on other preclinical dementia pathologies characterized by Cho/Cr elevation such as Lewy body or ischemic vascular disease in addition to Aß load.

Altered functional connectivity in asymptomatic MAPT subjects: a comparison to bvFTD.

OBJECTIVE: To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD). METHODS: In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest. RESULTS: The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects. CONCLUSIONS: Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.

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.

Does TDP-43 type confer a distinct pattern of atrophy in frontotemporal lobar degeneration?

OBJECTIVE: To determine whether TDP-43 type is associated with distinct patterns of brain atrophy on MRI in subjects with pathologically confirmed frontotemporal lobar degeneration (FTLD). METHODS: In this case-control study, we identified all subjects with a pathologic diagnosis of FTLD with TDP-43 immunoreactive inclusions (FTLD-TDP) and at least one volumetric head MRI scan (n = 42). In each case we applied published criteria for subclassification of FTLD-TDP into FTLD-TDP types 1-3. Voxel-based morphometry was used to compare subjects with each of the different FTLD-TDP types to age- and gender-matched normal controls (n = 30). We also assessed different pathologic and genetic variants within, and across, the different types. RESULTS: Twenty-two subjects were classified as FTLD-TDP type 1, 9 as type 2, and 11 as type 3. We identified different patterns of atrophy across the types with type 1 showing frontotemporal and parietal atrophy, type 2 predominantly anterior temporal lobe atrophy, and type 3 predominantly posterior frontal atrophy. Within the FTLD-TDP type 1 group, those with a progranulin mutation had significantly more lateral temporal lobe atrophy than those without. All type 2 subjects were diagnosed with semantic dementia. Subjects with a pathologic diagnosis of FTLD with motor neuron degeneration had a similar pattern of atrophy, regardless of whether they were type 1 or type 3. CONCLUSIONS: Although there are different patterns of atrophy across the different FTLD-TDP types, it appears that genetic and pathologic factors may also affect the patterns of atrophy.

Imaging correlates of pathology in corticobasal syndrome.

BACKGROUND: Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS. METHODS: This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls. RESULTS: All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD. CONCLUSIONS: Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology.

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.

Effects of age on the glucose metabolic changes in mild cognitive impairment.

BACKGROUND AND PURPOSE: Decreased glucose metabolism in the temporal and parietal lobes on FDG-PET is recognized as an early imaging marker for the AD pathology. Our objective was to investigate the effects of age on FDG-PET findings in aMCI. MATERIALS AND METHODS: Twenty-five patients with aMCI at 55-86 years of age (median = 73 years) and 25 age- and sex-matched CN subjects underwent FDG-PET. SPM5 was used to compare the FDG uptake in patients in aMCI-old (>73 years) and aMCI-young (