John C. Janssen

Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images

BACKGROUND Early diagnosis and monitoring of the progression of Alzheimers disease is important for the development of therapeutic strategies. To detect the earliest structural brain changes, individuals need to be studied before symptom onset. We used an imaging technique known as voxel-compression mapping to localise progressive atrophy in patients with preclinical Alzheimers disease. METHODS Four symptom-free individuals from families with early-onset Alzheimers disease with known autosomal dominant mutations underwent serial magnetic resonance imaging (MRI) over 5-8 years. All four became symptomatic during follow-up. 20 individuals with a clinical diagnosis of probable Alzheimers disease and 20 control participants also underwent serial MR imaging. A non-linear fluid matching algorithm was applied to register repeat scans onto baseline imaging. Jacobian determinants were used to create the voxel-compression maps. FINDINGS Progressive atrophy was revealed in presymptomatic individuals, with posterior cingulate and neocortical temporoparietal cortical losses, and medial temporal-lobe atrophy. In patients with known Alzheimers disease, atrophy was widespread apart from in the primary motor and sensory cortices and cerebellum, reflecting the clinical phenomenology. INTERPRETATION Voxel-compression maps confirmed early involvement of the medial temporal lobes, but also showed posterior cingulate and temporoparietal cortical losses at presymptomatic stage. This technique could be applied diagnostically and used to monitor the effects of therapeutic intervention.

Early onset familial Alzheimer's disease: Mutation frequency in 31 families.

Background: Three causative genes have been identified for autosomal dominant AD. Objective: To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes. Methods: A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years. Results: The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001). Conclusions: Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.

Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study

The extent to which cerebral atrophy in Alzheimers disease changes with time is unknown. We used multiple MRI scans to measure progression of cerebral atrophy in 12 patients with Alzheimers disease who were followed up from a presymptomatic stage through to moderately severe dementia. Analysis with hierarchical regression models with quadratic terms in time provided evidence of increasing yearly percentage losses in brain volume. At the time when patients were judged to have mild dementia (mini-mental state examination score MMSE=23), mean yearly loss of brain volume was 2.8% (95% CI 2.3-3.3), which rose by 0.32% per year (0.15-0.50). Our findings reinforce the need for early diagnosis and therapeutic intervention in Alzheimers disease.

Assessing the onset of structural change in familial Alzheimer's disease.

Regional and global cerebral atrophy are inevitable features of Alzheimers disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3–28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0–7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7–7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms. Ann Neurol 2003;53:000–000

The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases

Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of thetau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series of subjects with progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, idiopathic Parkinson’s disease, and normal controls to (1) confirm this association in a large series and (2) to investigate a possible role for this association in other disorders which involve tau deposition. The results confirm the finding of an overrepresentation of the A0 allele and the A0/A0 genotype in patients with progressive supranuclear palsy, in the largest series reported to date. The A0 allele was found in 91% of patients with progressive supranuclear palsy as opposed to 73% of controls (p<0.001) and the A0/A0 genotype was seen in 84% of patients as compared with 53% of controls (p<0.01). There was no significant difference between patients with Parkinson’s disease, frontotemporal dementia, or corticobasal degeneration, and controls. The A0 allele may have a direct effect on tau isoform expression in progressive supranuclear palsy or it may be in linkage disequilibrium with an adjacent determinant of tau gene expression. The explanation for this difference between a predisposition factor to progressive supranuclear palsy and the other conditions may lie in the molecular pathology of these diseases.

Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation

Objective To describe the clinical features of nine British families with neuropathologically verified frontotemporal dementia (FTD) due to the intronic tau exon 10+16 mutation. MethodsRetrospective chart reviews of family members with FTD belonging to nine tau 10+16 mutation pedigrees in whom neuropathologic examination had been carried out. APOE genotype was determined for those patients for whom DNA was available. ResultsThe median age at onset was 50 years (range 37 to 59 years; n = 30). The median age at death was 61 years (range 42 to 72 years; n = 33). The median duration of the disease was 11 years (range 3 to 22 years; n = 25) for those who have died and is 17 years (range 15 to 23 years; n = 3) for those living. The most common presenting symptom was disinhibition (n = 23). A minority presented with frontal dysexecutive symptoms, apathy, impairment of episodic memory, or depression. All of these patients subsequently developed personality and behavioral change. Memory impairment, language deficits, ritualistic behavior, hyperphagia, and hyperorality were frequent symptoms. Parkinsonism, neuroleptic sensitivity, or primitive reflexes were present in half of the patients, where these data were available. The clinical features of ALS were absent. Neuropathologic examination of 12 patients demonstrated the hallmark tau-positive neuronal and glial inclusions. APOE genotype did not account for the considerable variation in age at onset, age at death, duration of disease, or severity of estimated brain atrophy. Conclusions All cases fulfilled the clinical criteria for a diagnosis of FTD. Despite similar clinical phenotypes, there was considerable variation in age at onset and duration of disease both between and within families, suggesting the presence of an effect due to other genetic or environmental factors.

Upbeat nystagmus: clinicoanatomical correlation

A patient is reported on with isolated upbeating nystagmus with a linear slow phase in whom a solitary lesion, probably inflammatory, was detected radiologically in the dorsal paramedian caudal medulla, encompassing the most caudal of the perihypoglossal nuclei, the nucleus intercalatus of Staderini. The conjunction of a vestibular pattern of nystagmus with this focal lesion runs contrary to a previous suggestion that the nucleus intercalatus may act as a neural integrator for vertical conjugate eye movements.

Neuropathologic variation in frontotemporal dementia due to the intronic tau 10+16 mutation

BackgroundAn increasing number of recently described tau mutations show considerable clinical heterogeneity. The assessment of this phenotypic variation is of vital importance in the differential diagnosis of neurodegenerative diseases. Objective To assess the neuropathologic heterogeneity in a comprehensive study of 12 brains with a tau mutation at exon 10+16 (C-to-T) splice site from 9 families. MethodsA comprehensive neuropathologic examination has been carried out, using a wide range of tau antibodies. ResultsAll brains showed frontotemporal atrophy of varying severity and pallor of the pigmented nuclei of the brainstem. The histologic changes were more extensive to include other cortical areas, the deep gray matter, and the white matter. The hallmark histologic lesions were the tau-positive neuronal and glial inclusions. In neurons, these ranged from typical neurofibrillary tangles through well-circumscribed inclusions to diffuse cytoplasmic staining. This tau pathology was complemented by the presence of large, abnormal achromatic neurons, neuronal loss, astrocytosis, and superficial status spongiosus. Conclusion The distribution, type, and severity of these histologic abnormalities varied not only from case to case but also within the same brain. These brains with a common tau mutation raise important differential diagnostic problems: cases in the past might have been misdiagnosed as corticobasal degeneration or even atypical Pick disease, disorders with similar, if not identical, phenotypic manifestations.

Analysis of tau haplotypes in Pick's disease

Abstract—Pick’s disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.

Mapping the onset and progression of atrophy in familial frontotemporal lobar degeneration

Background: Frontotemporal lobar degeneration (FTLD) may be inherited as an autosomal dominant disease. Studying patients “at risk” for developing FTLD can provide insights into the earliest onset and evolution of the disease. Method: We carried out approximately annual clinical, MRI, and neuropsychological assessments on an asymptomatic 51 year old “at risk” family member from a family with FTLD associated with ubiquitin-positive and tau-negative inclusion bodies. We used non-linear (fluid) registration of serial MRI to determine areas undergoing significant regional atrophy at different stages of the disease. Results: Over the first 26 months of the study, the patient remained asymptomatic, but subsequently developed progressive speech production difficulties, and latterly severe orofacial dyspraxia, dyscalculia, frontal executive impairment, and limb dyspraxia. Regional atrophy was present prior to the onset of symptoms, and was initially centred on the left dorsolateral prefrontal cortex and the left middle frontal gyrus. Latterly, there was increasing asymmetric left frontal and parietal atrophy. Imaging revealed excess and increasing global atrophy throughout the study. Neuropsychological evaluation revealed mild intellectual impairment prior to the onset of these clinical symptoms; frontal executive and left parietal impairment subsequently emerged, culminating in widespread cognitive impairment. Fluid registered MRI allowed the emerging atrophy patterns to be delineated. Conclusion: We have demonstrated the onset and progressive pattern of in vivo atrophy in familial FTLD using fluid registered MRI and correlated this with the clinical features. Fluid registered MRI may be a useful technique in assessing patterns of focal atrophy in vivo and demonstrating the progression of degenerative diseases.