Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

Presymptomatic studies in genetic frontotemporal dementia.

Approximately 20% of patients with the neurodegenerative disorder frontotemporal dementia (FTD) have an autosomal dominant pattern of inheritance. Genetic FTD is caused by mutations in three genes in most cases (progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72) although a number of other genes are rare causes. Studies of other neurodegenerative diseases have shown imaging and biomarker evidence of disease onset many years prior to the development of symptoms. Similar studies in genetic FTD are now revealing evidence of a series of presymptomatic changes, initially in plasma biomarkers followed by MR imaging abnormalities of functional and structural connectivity and then grey matter atrophy. Lastly, neuropsychometric tests become abnormal in proximity to the onset of symptoms. Such studies have been relatively small until now but research centres with an expertise in genetic FTD are now forming consortia such as the Genetic Frontotemporal Dementia Initiative (GenFI) to create larger cohorts that can form the basis of future clinical trials.

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia.

BACKGROUND AND OBJECTIVES: The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS AND CONCLUSIONS: New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised as compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

Acceleration of cortical thinning in familial Alzheimer's disease.

BACKGROUND: MRI in presymptomatic autosomal dominant Alzheimer's disease mutation carriers (MC) provides an opportunity to detect changes that pre-date symptoms or clinical diagnosis. We used automated cortical thickness (CTh) measurement to compare the grey matter of such a group with cognitively normal controls. METHODS: 9 presymptomatic mutation carriers (4 PSEN1, 5 APP) and 25 healthy, age and sex-matched controls underwent longitudinal volumetric MRI brain imaging. CTh measurement was performed across the whole brain using a validated, automated technique. Four regions of interest (ROI) (entorhinal cortex (ERC), parahippocampal gyrus (PHG), posterior cingulate cortex and precuneus) and two control regions (paracentral and pericalcarine) were selected on the basis of imaging data in existing Alzheimer's disease (AD) literature. Linear mixed models were used to describe normal ageing in controls and the extent to which mean CTh in cases differed from controls according to time since clinical diagnosis, adjusting for normal ageing. RESULTS: An accelerating decline in CTh was observed across all ROI in the MC group. No such decline was demonstrated in the control regions for the MC group. Relative to controls, and adjusting for normal ageing, there was evidence (p=0.05, one-sided test) of lower CTh in the posterior cingulate up to 1.8 years prior to diagnosis and in the precuneus up to 4.1 years prior to diagnosis in the MC group. DISCUSSION: Automated CTh analysis is a relatively practical, rapid and effective technique for assessing subtle structural change in AD. There is evidence that cortical thickness is reduced in mutation carriers a number of years prior to clinical diagnosis.

Measuring disease progression in frontotemporal lobar degeneration: a clinical and MRI study.

OBJECTIVES: There is currently much interest in biomarkers of disease activity in frontotemporal lobar degeneration (FTLD). We assessed MRI and behavioral measures of progression in a longitudinal FTLD cohort. METHODS: Thirty-two patients with FTLD (11 behavioral variant frontotemporal dementia [bvFTD], 11 semantic dementia [SemD], 10 progressive nonfluent aphasia [PNFA]) and 24 age-matched healthy controls were assessed using volumetric brain MRI and standard behavioral measures (Mini-Mental State Examination, Frontal Assessment Battery, Clinical Dementia Rating Scale, Neuropsychiatric Inventory with Caregiver Distress scale) at baseline and 1 year later. A semi-automated image registration protocol was used to calculate annualized rates of brain atrophy (brain boundary shift integral [BBSI]) and ventricular expansion (ventricular boundary shift integral [VBSI]). Associations between these rates and changes in behavioral indices were investigated. RESULTS: Rates of whole brain atrophy were greater in the entire FTLD cohort and in each subgroup compared with controls (all p < or = 0.004). Rates of ventricular expansion were greater in the entire cohort (p < 0.001) and the SemD (p = 0.002) and PNFA (p = 0.05) subgroups compared with controls. Changes in Mini-Mental State Examination, Frontal Assessment Battery, and Clinical Dementia Rating Scale scores were associated with MRI measures of progression, though not uniformly across FTLD subgroups. Both BBSI and VBSI yielded feasible sample size estimates for detecting meaningful treatment effects in SemD and PNFA language subgroups. Sample sizes were substantially larger using MRI biomarkers for the bvFTD subgroup, and using behavioral biomarkers in general. CONCLUSIONS: Semi-automated MRI atrophy measures are potentially useful objective biomarkers of progression in frontotemporal lobar degeneration (FTLD); however, careful stratification of FTLD subtypes will be important in future clinical trials of disease-modifying therapies.

Memory complaints and increased rates of brain atrophy: risk factors for mild cognitive impairment and Alzheimer's disease.

AIM: To determine rates of cerebral atrophy in individuals with symptoms of memory loss but no objective cognitive impairment (SNCI) and their association with future cognitive decline. METHODS: Thirty-two SNCI subjects, 16 with mild cognitive impairment (MCI) and 27 control subjects had clinical assessment and magnetic resonance imaging at baseline and 1 year later. Rates of whole brain atrophy (WBA), hippocampal atrophy (HA) and ventricular enlargement (VE) were measured. Our outcome was clinical diagnosis at 2 years after entry into the study. RESULTS: The MCI group had greater rates of WBA, HA and VE than both controls and SNCI subjects. As a group SNCI subjects did not have significantly greater rates of atrophy than the controls. However, SNCI subjects who progressed to MCI or dementia had increased rates of atrophy compared with those who remained stable. DISCUSSION: Individuals with memory complaints but no objective memory deficits, who progress to MCI or dementia, have increased rates of cerebral atrophy.

An unbiased, staged, multicentre, validation strategy for Alzheimer's disease CSF tau levels.

Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n=99), validated in a large dataset (n=560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323+/-51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n=100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.

The heritability and genetics of frontotemporal lobar degeneration.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. METHODS: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. RESULTS: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). CONCLUSION: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.

Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study.

BACKGROUND: Patients with amnestic mild cognitive impairment (MCI) represent an important clinical group as they are at increased risk of developing Alzheimer disease (AD). (11)C-PIB PET is an in vivo marker of brain amyloid load. OBJECTIVE: To assess the rates of conversion of MCI to AD during a 3-year follow-up period and to compare levels of amyloid deposition between MCI converters and nonconverters. METHODS: Thirty-one subjects with MCI with baseline (11)C-PIB PET, MRI, and neuropsychometry have been clinically followed up for 1 to 3 years (2.68 +/- 0.6 years). Raised cortical (11)C-PIB binding in subjects with MCI was detected with region of interest analysis and statistical parametric mapping. RESULTS: Seventeen of 31 (55%) subjects with MCI had increased (11)C-PIB retention at baseline and 14 of these 17 (82%) clinically converted to AD during follow-up. Only one of the 14 PIB-negative MCI cases converted to AD. Of the PIB-positive subjects with MCI, half (47%) converted to AD within 1 year of baseline PIB PET, these faster converters having higher tracer-retention values than slower converters in the anterior cingulate (p = 0.027) and frontal cortex (p = 0.031). Seven of 17 (41%) subjects with MCI with known APOE status were epsilon4 allele carriers, this genotype being associated with faster conversion rates in PIB-positive subjects with MCI (p = 0.035). CONCLUSIONS: PIB-positive subjects with mild cognitive impairment (MCI) are significantly more likely to convert to AD than PIB-negative patients, faster converters having higher PIB retention levels at baseline than slower converters. In vivo detection of amyloid deposition in MCI with PIB PET provides useful prognostic information.

Patterns of cortical thinning in the language variants of frontotemporal lobar degeneration.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous neurodegenerative disorder. Two subtypes commonly present with a language disorder: semantic dementia (SemD) and progressive nonfluent aphasia (PNFA). METHODS: Patients meeting consensus criteria for PNFA and SemD who had volumetric MRI of sufficient quality to allow cortical thickness analysis were recruited from a tertiary referral clinic: 44 (11 pathologically confirmed) patients with SemD and 32 (4 pathologically confirmed) patients with PNFA and 29 age-matched and gender-matched healthy controls were recruited. Cortical thickness analysis was performed using the Freesurfer software tools. RESULTS: Patients with SemD had significant cortical thinning in the left temporal lobe, particularly temporal pole, entorhinal cortex, and parahippocampal, fusiform, and inferior temporal gyri. A similar but less extensive pattern of loss was seen in the right temporal lobe and (with increasing severity) also in left orbitofrontal, inferior frontal, insular, and cingulate cortices. Patients with PNFA had involvement particularly of the left superior temporal lobe, inferior frontal lobe, and insula, and (with increasing severity) other areas in the left frontal, lateral temporal, and anterior parietal lobes. Similar patterns were seen in the pathologically confirmed cases. Patterns of cortical thinning differed between groups: SemD had significantly more cortical thinning in the temporal lobes bilaterally while PNFA had significantly more thinning in the frontal and parietal lobes. CONCLUSIONS: The language variants of frontotemporal lobar degeneration have distinctive and significantly different patterns of cortical thinning. Increasing disease severity is associated with spread of cortical thinning and the pattern of spread is consistent with progression of clinical deficits.

Microglial activation and amyloid deposition in mild cognitive impairment: a PET study.

BACKGROUND: Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Abeta) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI). OBJECTIVE: To characterize in vivo with (11)C-(R)-PK11195 and (11)C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI. METHODS: Fourteen subjects with MCI had (11)C-(R)-PK11195 and (11)C-PIB PET with psychometric tests. RESULTS: Seven out of 14 (50%) patients with MCI had increased cortical (11)C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased (11)C-(R)-PK11195 uptake. The MCI subgroup with increased (11)C-PIB retention also showed increased cortical (11)C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of (11)C-(R)-PK11195 and (11)C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased (11)C-(R)-PK11195 binding had increased levels of (11)C-PIB retention. CONCLUSIONS: Our findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.

Tracking progression in frontotemporal lobar degeneration: serial MRI in semantic dementia.

BACKGROUND: Semantic dementia is a sporadic neurodegenerative disorder characterized by the progressive erosion of semantic processing and is one of the canonical subtypes of frontotemporal lobar degeneration. This study aimed to characterize the pattern of global and regional longitudinal brain atrophy in semantic dementia and to identify imaging biomarkers that could underpin therapeutic trials. METHODS: Twenty-one patients with semantic dementia (including eight pathologically confirmed cases) underwent whole-brain and region-of-interest analyses on volumetric brain MRI scans at two time points. Sample size estimates for trials were subsequently calculated using these data. RESULTS: Mean (SD) whole-brain atrophy rate was 39.6 (31.9) mL/y [3.2 (12.0) mL/y in controls], with ventricular enlargement of 8.9 (4.4) mL/y [1.0 (1.0) mL/y in controls]. All patients had a smaller left temporal lobe at baseline [left mean 31.9 (6.9) mL, right mean 49.2 (9.5) mL; p < 0.0001]; however, the mean rate of atrophy was significantly greater in the right temporal lobe [right 3.9 (1.7) mL/y, left 2.8 (1.2) mL/y; p = 0.02]. Similarly, whereas the left hippocampus was smaller at baseline, the mean atrophy rate was significantly greater in the right hippocampus. Using the atrophy rates generated, sample size requirements for clinical trials were found to be smallest for temporal lobe measurement. CONCLUSIONS: These findings show that the rate of tissue loss in the right temporal lobe overtakes the left temporal lobe as semantic dementia evolves, consistent with the later development of symptoms attributable to right temporal lobe dysfunction. Furthermore, our findings demonstrate that MRI measures of temporal lobe volume loss could provide a feasible and sensitive index of disease progression in semantic dementia.

Neuropsychological correlates of whole brain atrophy in Alzheimer's disease.

Alzheimer's disease (AD) is associated with excess whole brain volume loss, and progressive cognitive impairment. We aimed to study the extent to which these two potential biomarkers of AD progression are correlated. Forty-six patients with sporadic AD were tested with a neuropsychometric battery including test of verbal and visual memory, vocabulary, arithmetic, naming, visuoperceptual skills and reasoning at two time-points, approximately 1 year apart; annualised rates of change for each test were calculated. Each subject also attended for up to twelve T1-weighted volumetric MRI scans at fixed intervals over a 2-year period. For each individual all possible scan-pairs were positionally registered, and whole brain atrophy rates were calculated using the brain boundary shift integral. Linear mixed models were used to investigate associations between atrophy rate and coincident change in each neuropsychometric score. Each model estimated the effect of a unit change in score, plus the additional effect of a fall to floor, after adjusting for baseline levels. 467 MRI scans were performed, permitting 2199 individual measures of change to be made. The model-derived mean atrophy rate was 2.23% per year with a between-subject SD of 0.99% per year. Increasing atrophy rate was significantly associated with rate of change in a number of non-memory based neuropsychological scores, with the strongest association seen with longitudinal change in matrix reasoning (p=0.004). These results provide further evidence that cerebral atrophy is a clinically relevant marker of AD progression. This methodology whereby data from patients falling to floor on a given test may be included and accounted for, rather than discarded, may find broader application in clinical studies incorporating neuropsychometric outcomes.

The cultural context of visual hallucinations.

Visual hallucinations (VH) are a cardinal neuropsychiatric symptom and often have important diagnostic implications. The interpretation of VH is influenced by the patient's social and cultural milieu, but the impact of socio-cultural factors on the interpretation, presentation and detection of VH has been little studied. When patients exhibit VH and other neuropsychiatric phenomena, appropriate sensitivity to the role of cultural factors is an important determinant of the success of the medical consultation. We discuss this issue using three illustrative cases.

Increased hippocampal atrophy rates in AD over 6 months using serial MR imaging.

We measured hippocampi on baseline-, 6- and 12-month scans in a group of AD (n=36) and control subjects (n=20). We found that mean annualised atrophy rates using 6-month intervals were comparable at a group level to those generated from a 12-month interval. Higher variance was seen using shorter intervals, although this was only significant in the control group. This has implications where shorter inter-scan intervals may be advantageous, such as rapid diagnosis, and tracking of disease progression including in a clinical trial.

A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer's disease.

We report the case of a 40 year-old woman who, at 38 years of age, developed insidious memory loss and, subsequently, progressive dementia satisfying criteria for probable Alzheimer's disease (AD) (NINCDS-ADRDA) [Neurology 1984; 34: 939]. Analysis of the presenilin 1 gene (PSEN1) revealed a 496_498delCTT mutation at codon 166. The amnestic presentation and absence of other features contrasts with the majority of other documented deletions which have been associated with spastic paraparesis. They are, however, consistent with the reported clinical phenotype in the majority of PSEN1 exon 6 mutations so far reported.

A systematic review and meta-analysis of CSF neurofilament protein levels as biomarkers in dementia.

BACKGROUND: Loss of cortical neurons is a key pathological feature in neurodegenerative dementias. Cerebrospinal fluid (CSF) neurofilaments (Nf) are a biomarker for neuronal death and axonal loss. OBJECTIVE: To perform a meta-analysis to investigate the value of CSF Nf levels for the laboratory-supported differential diagnosis of neurodegenerative dementias. METHODS: A systematic review and meta-analysis of studies on CSF Nf heavy (NfH) and light (NfL) levels in patients with dementia. The dementia subgroups analysed were Alzheimer (AD), frontotemporal lobe dementia (FTLD), vascular dementia (SVD), minimal cognitive deficit (MCI). RESULTS: We identified 12 studies on CSF NfH and NfL levels which met the inclusion criteria and 11 were of a quality good enough to be used in this meta-analysis. CSF data was available on 818 patients (306 AD, 106 SVD, 98 FTLD, 25 MCI, 283 controls). Overall CSF NfH and NfL levels were higher in patients with AD, FTLD and SVD when compared to controls. The size of the effect ranged from 0.71 to 1.38. The strongest effect was observed for the comparison of FTLD patients with controls, both for NfL (1.38) and NfH (0.74). CSF NfL were also able to separate patients with FTLD from those with AD. CONCLUSION: At present we cannot recommend CSF NfH and NfL levels for use as a screening test in the diagnosis of dementia because of the rather small effect size. However, both neurofilament proteins may be of value for targeted investigation of some patients with FTLD, SVD and AD.

Magnetization transfer ratio in Alzheimer disease: comparison with volumetric measurements.

BACKGROUND AND PURPOSE: Alzheimer disease (AD) is accompanied by macroscopic atrophy on volumetric MR imaging. A few studies have also demonstrated reduction in magnetization transfer ratio (MTR), suggesting microstructural changes in remaining brain tissue. This study assessed the value of measuring MTR in addition to volumetric MR in differentiating patients with AD from control subjects. MATERIALS AND METHODS: Volumetric T1-weighted images and 3D MTR maps were obtained from 18 patients with AD and 18 age-matched control subjects. Whole-brain (WB) and total hippocampal (Hc) volumes were measured using semiautomated techniques and adjusted for total intracranial volume. Mean MTR was obtained for WB and in the Hc region. Histogram analysis was performed for WB MTR. Among patients, associations between volumetric and MTR parameters and the Mini-Mental State Examination (MMSE) were explored. RESULTS: Patients with AD had significantly reduced WB volume (P<.0001) and mean WB MTR (P=.002) and Hc volume (P<.0001) and Hc mean MTR (P<.0001) compared with control subjects. Histogram analysis of WB MTR revealed significant reduction in the 25th percentile point in patients with AD (P=.03). Both WB volume and mean MTR were independently associated with case-control status after adjusting for the other using linear regression models. However, measuring Hc mean MTR added no statistically significant discriminatory value over and above Hc volume measurement alone. Of all MR imaging parameters, only WB volume was significantly correlated with MMSE (r=0.47, P=.048). CONCLUSIONS: This study demonstrates the independent reduction of WB volume and mean MTR in AD. This suggests that the 2 parameters reflect complementary aspects of the AD pathologic lesion at macrostructural and microstructural levels.