Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers.

PURPOSE: The increasing use of amyloid PET in Alzheimer's disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the (11)C radiotracer Pittsburgh Compound B (PiB) and that of two (18)F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two (18)F tracers. METHODS: One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each (18)F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers. RESULTS: Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB-flutemetamol, ρ = 0.84-0.99; PiB-florbetapir, ρ = 0.83-0.97) and analysis method (ρ = 0.90-0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs. CONCLUSION: Despite differing white and grey matter retention characteristics, cortical retention for each (18)F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers.

APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.

Deposition of amyloid-ß (Aß) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aß load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aß levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aß load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aß levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aß deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aß burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD.

OBJECTIVE: To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls. RESULTS: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10). CONCLUSIONS: PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution.

BACKGROUND/OBJECTIVE: Patients with posterior cortical atrophy (PCA) often have Alzheimer disease (AD) at autopsy, yet are cognitively and anatomically distinct from patients with clinical AD. We sought to compare the distribution of ß-amyloid and glucose metabolism in PCA and AD in vivo using Pittsburgh compound B (PiB) and FDG-PET. METHODS: Patients with PCA (n = 12, age 57.5 ± 7.4, Mini-Mental State Examination [MMSE] 22.2 ± 5.1), AD (n = 14, age 58.8 ± 9.6, MMSE 23.8 ± 6.7), and cognitively normal controls (NC, n = 30, age 73.6 ± 6.4) underwent PiB and FDG-PET. Group differences in PiB distribution volume ratios (DVR, cerebellar reference) and FDG uptake (pons-averaged) were assessed on a voxel-wise basis and by comparing binding in regions of interest (ROIs). RESULTS: Compared to NC, both patients with AD and patients with PCA showed diffuse PiB uptake throughout frontal, temporoparietal, and occipital cortex (p < 0.0001). There were no regional differences in PiB binding between PCA and AD even after correcting for atrophy. FDG patterns in PCA and AD were distinct: while both groups showed hypometabolism compared to NC in temporoparietal cortex and precuneus/posterior cingulate, patients with PCA further showed hypometabolism in inferior occipitotemporal cortex compared to both NC and patients with AD (p < 0.05). Patients with AD did not show areas of relative hypometabolism compared to PCA. CONCLUSIONS: Fibrillar amyloid deposition in PCA is diffuse and similar to AD, while glucose hypometabolism extends more posteriorly into occipital cortex. Further studies are needed to determine the mechanisms of selective network degeneration in focal variants of AD.

Comparing predictors of conversion and decline in mild cognitive impairment.

OBJECTIVE: A variety of measurements have been individually linked to decline in mild cognitive impairment (MCI), but the identification of optimal markers for predicting disease progression remains unresolved. The goal of this study was to evaluate the prognostic ability of genetic, CSF, neuroimaging, and cognitive measurements obtained in the same participants. METHODS: APOE epsilon4 allele frequency, CSF proteins (Abeta(1-42), total tau, hyperphosphorylated tau [p-tau(181p)]), glucose metabolism (FDG-PET), hippocampal volume, and episodic memory performance were evaluated at baseline in patients with amnestic MCI (n = 85), using data from a large multisite study (Alzheimer's Disease Neuroimaging Initiative). Patients were classified as normal or abnormal on each predictor variable based on externally derived cutoffs, and then variables were evaluated as predictors of subsequent conversion to Alzheimer disease (AD) and cognitive decline (Alzheimer's Disease Assessment Scale-Cognitive Subscale) during a variable follow-up period (1.9 +/- 0.4 years). RESULTS: Patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7 times more likely to convert to AD than subjects who had normal results on both measures (p

Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization.

BACKGROUND: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally. OBJECTIVE: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures. METHODS: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials. RESULTS: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures. CONCLUSION: The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.

Relationships between biomarkers in aging and dementia.

BACKGROUND: PET imaging using [(18)F]fluorodeoxyglucose (FDG) and [(11)C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid beta-amyloid protein (Abeta(1-42)) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood. METHODS: Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Abeta(1-42), t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as "positive" or "negative" for AD based on cutoffs established in patients with AD and controls from other cohorts. RESULTS: Dichotomous categorization showed substantial agreement between PIB-PET and CSF Abeta(1-42) measures (91% agreement, kappa = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, kappa = 0.50), and minimal agreement for other comparisons (kappa <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Abeta(1-42). Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Abeta(1-42), t-tau, and p-tau(181p), whereas FDG-PET was correlated only with Abeta(1-42). CONCLUSIONS: PET and CSF biomarkers of Abeta agree with one another but are not related to cognitive impairment. [(18)F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.

Safety and tolerability of putaminal AADC gene therapy for Parkinson disease.

BACKGROUND: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial. METHODS: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression. RESULTS: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort. CONCLUSION: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo.

Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET) with (11)carbon-labelled Pittsburgh Compound-B ((11)C-PIB), the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Abeta) deposits, and is a sensitive marker for Abeta pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.

Performance of FDG PET for detection of Alzheimer's disease in two independent multicentre samples (NEST-DD and ADNI).

AIM: We investigated the performance of FDG PET using an automated procedure for discrimination between Alzheimer's disease (AD) and controls, and studied the influence of demographic and technical factors. METHODS: FDG PET data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) [102 controls (76.0 +/- 4.9 years) and 89 AD patients (75.7 +/- 7.6 years, MMSE 23.5 +/- 2.1) and the Network for Standardisation of Dementia Diagnosis (NEST-DD) [36 controls (62.2 +/- 5.0 years) and 237 AD patients (70.8 +/- 8.3 years, MMSE 20.9 +/- 4.4). The procedure created t-maps of abnormal voxels. The sum of t-values in predefined areas that are typically affected by AD (AD t-sum) provided a measure of scan abnormality associated with a preset threshold for discrimination between patients and controls. RESULTS: AD patients had much higher AD t-sum scores compared to controls (p < 0.01), which were significantly related to dementia severity (ADNI: r = -0.62, p < 0.01; NEST-DD: r = -0.59, p < 0.01). Early-onset AD patients had significantly higher AD t-sum scores than late-onset AD patients (p < 0.01). Differences between databases were mainly due to different age distributions. The predefined AD t-sum threshold yielded a sensitivity and specificity of 83 and 78% in ADNI and 78 and 94% in NEST-DD, respectively. CONCLUSION: The automated FDG PET analysis procedure provided good discrimination power, and was most accurate for early-onset AD.

An inverse association of cardiovascular risk and frontal lobe glucose metabolism.

OBJECTIVE: To investigate associations between vascular risk profile and cerebral glucose metabolism. METHODS: Subjects ranged from normal to having dementia (age >55 years) and underwent neuropsychological testing, MRI, and FDG PET scanning (n = 58). The Framingham Cardiovascular Risk Profile (FCRP) and its individual components were used as covariates in regression analyses with each PET scan using SPM2. RESULTS: Analyses revealed broad areas of the frontal lobe in which higher FCRP was associated with lower normalized glucose metabolism including the superior medial frontal, superior frontal and superior orbital frontal cortex and the ventrolateral prefrontal cortex. Significant associations were predominately found in the left hemisphere. Independent component analyses revealed interesting regions but further confirm the relevance of the integrative measure of coronary risk. CONCLUSIONS: Although the mechanism of this association bears further investigation, this finding provides further evidence that vascular risk factors have malignant effects on the brain, particularly in the prefrontal cortex.

Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects.

Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.

Results from a phase I safety trial of hAADC gene therapy for Parkinson disease.

BACKGROUND: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. METHODS: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. RESULTS: PET results showed an average 30% increase in FMT uptake (K(i)(c)) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. CONCLUSIONS: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.

What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia?

BACKGROUND: Few studies have compared the accuracy of [(18)F]fluorodeoxyglucose (FDG) PET to the accuracy of clinical and pathologic diagnosis in dementia patients. METHODS: Forty-four individuals with dementia, cognitive impairment, or normal cognitive function underwent clinical initial evaluation (IE) and PET scanning and were followed up for approximately 4 years until a final evaluation (FE) and 5 years until death and autopsy. Clinical, pathologic, and imaging diagnoses were categorized as Alzheimer disease (AD) or not AD. RESULTS: Sensitivity of the IE for the pathologic diagnosis of AD was 0.76, and specificity was 0.58; PET had values of 0.84 and 0.74, and FE had values of 0.88 and 0.63. Positive predictive values for IE, PET, and FE were 0.70, 0.81, and 0.76. Negative predictive values were 0.65, 0.78, and 0.80. The diagnosis of AD was associated with a 70% probability of detecting AD pathology; with a positive PET scan this increased to 84%, and with a negative PET scan this decreased to 31%. A diagnosis of not AD at IE was associated with a 35% probability of AD pathology, increasing to 70% with a positive PET scan. CONCLUSIONS: As a diagnostic tool, PET is superior to a baseline clinical evaluation and similar to an evaluation performed 4 years later. Although the addition of [(18)F]fluorodeoxyglucose PET to a clinical diagnosis provides useful information that can affect the likelihood of detecting Alzheimer disease pathology, the value of this technique in the current clinical environment with limited therapeutic options is likely to be modest.

Amyloid imaging in distinguishing atypical prion disease from Alzheimer disease.

OBJECTIVE: To compare the in vivo uptake of two amyloid-binding PET agents, PIB and FDDNP, in human subjects with a prion protein (PrP) gene (PRNP) mutation that produces a clinical syndrome similar to Alzheimer disease (AD). BACKGROUND: Amyloid imaging with specific PET ligands offers great promise for early detection and differential diagnosis of AD. Genetic forms of prion disease can present with clinical features that resemble AD, and at autopsy may show deposition of mutant PrP-amyloid. FDDNP binds to PrP-amyloid in postmortem human specimens, but has not been reported in vivo in prion disease. The ability of PIB to bind PrP-amyloid is not known. METHODS: Two brothers with a 6 octapeptide repeat insertion mutation (6-OPRI) in the PRNP gene underwent clinical, structural MRI, and FDG-PET evaluations. One brother received a PIB-PET evaluation, while the other received an FDDNP-PET scan. PET results were compared with five normal subjects and five individuals with AD scanned with either agent. RESULTS: PIB uptake was similar to controls in one brother, while FDDNP uptake was intermediate between AD and controls in the other brother. CONCLUSIONS: Different amyloid-binding agents may have differential sensitivity to prion-related brain pathology. A combination of amyloid imaging agents may be useful in the diagnosis of early-onset dementia.

11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration.

BACKGROUND: The PET tracer (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) specifically binds fibrillar amyloid-beta (Abeta) plaques and can be detected in Alzheimer disease (AD). We hypothesized that PET imaging with (11)C-PIB would discriminate AD from frontotemporal lobar degeneration (FTLD), a non-Abeta dementia. METHODS: Patients meeting research criteria for AD (n = 7) or FTLD (n = 12) and cognitively normal controls (n = 8) underwent PET imaging with (11)C-PIB (patients and controls) and (18)F-fluorodeoxyglucose ((18)F-FDG) (patients only). (11)C-PIB whole brain and region of interest (ROI) distribution volume ratios (DVR) were calculated using Logan graphical analysis with cerebellum as a reference region. DVR images were visually rated by a blinded investigator as positive or negative for cortical (11)C-PIB, and summed (18)F-FDG images were rated as consistent with AD or FTLD. RESULTS: All patients with AD (7/7) had positive (11)C-PIB scans by visual inspection, while 8/12 patients with FTLD and 7/8 controls had negative scans. Of the four PIB-positive patients with FTLD, two had (18)F-FDG scans that suggested AD, and two had (18)F-FDG scans suggestive of FTLD. Mean DVRs were higher in AD than in FTLD in whole brain, lateral frontal, precuneus, and lateral temporal cortex (p < 0.05), while DVRs in FTLD did not significantly differ from controls. CONCLUSIONS: PET imaging with (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) helps discriminate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). Pathologic correlation is needed to determine whether patients with PIB-positive FTLD represent false positives, comorbid FTLD/AD pathology, or AD pathology mimicking an FTLD clinical syndrome.

Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease.

BACKGROUND: Neuroimaging in mild cognitive impairment (MCI) and Alzheimer disease (AD) generally shows medial temporal lobe atrophy and diminished glucose metabolism and cerebral blood flow in the posterior cingulate gyrus. However, it is unclear whether these abnormalities also impact the cingulum fibers, which connect the medial temporal lobe and the posterior cingulate regions. OBJECTIVE: To use diffusion tensor imaging (DTI), by measuring fractional anisotropy (FA), to test 1) if MCI and AD are associated with DTI abnormalities in the parahippocampal and posterior cingulate regions of the cingulum fibers; 2) if white matter abnormalities extend to the neocortical fiber connections in the corpus callosum (CC); 3) if DTI improves accuracy to separate AD and MCI from healthy aging vs structural MRI. METHODS: DTI and structural MRI were preformed on 17 patients with AD, 17 with MCI, and 18 cognitively normal (CN) subjects. RESULTS: FA of the cingulum fibers was significantly reduced in MCI, and even more in AD. FA was also significantly reduced in the splenium of the CC in AD, but not in MCI. Adding DTI to hippocampal volume significantly improved the accuracy to separate MCI and AD from CN. CONCLUSION: Assessment of the cingulum fibers using diffusion tensor imaging may aid early diagnosis of Alzheimer disease.

Neuropsychological characteristics of mild cognitive impairment subgroups.

OBJECTIVE: To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study. METHODS: MCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition. RESULTS: MCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits. CONCLUSIONS: The most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.

Rate of progression differs in frontotemporal dementia and Alzheimer disease.

OBJECTIVE: To compare survival and rates of cognitive and functional decline in patients with autopsy-confirmed frontotemporal dementia (FTD) and Alzheimer disease (AD) in a large multicenter study. BACKGROUND: Despite advances in the clinical characterization of FTD, little is known about its rate of progression. Characterizing survival and rate of decline in FTD is important because it can provide prognostic guidelines and benchmarks to use in the evaluation of disease-modifying drugs. METHODS: Seventy patients with FTD and 70 patients with AD who were followed by seven Alzheimer disease research centers until confirmation of diagnosis at autopsy were matched for overall age, education, and Mini-Mental State Examination (MMSE) score at initial evaluation. Survival and rates of cognitive and functional decline were compared. RESULTS: Patients with FTD had significantly shorter survival from initial evaluation to death than patients with AD (FTD = 4.2 years, AD = 6.0 years; log-rank test = 5.17, p < 0.05), and they declined significantly faster over one year on the MMSE (mean annual rate of change: -6.7 points for FTD vs -2.3 points for AD). A significantly greater proportion of patients with FTD were impaired in basic activities of daily living (ADLs) at initial evaluation, and lost the capacity for independent or minimally-assisted ADLs over the subsequent year. CONCLUSIONS: The results are consistent with shorter survival and faster rates of cognitive and functional decline in patients with frontotemporal dementia (FTD) compared to those with Alzheimer disease (AD). This suggests that FTD follows a more malignant disease course than AD once dementia is clinically recognized.