Basil H. Ridha

Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study

BACKGROUND Serial MRI scanning of autosomal dominant mutation carriers for Alzheimers disease provides an opportunity to track changes that could predate symptoms or clinical diagnosis of the disease. We used hierarchical modelling to assess how hippocampal and whole-brain volumes change as familial Alzheimers disease progresses from the presymptomatic stage through to diagnosis. METHODS Nine mutation carriers had serial clinical assessments and volumetric MRI scans (41 scans: range 3-8 per patient) at different clinical stages (presymptomatic, mild cognitive impairment, or clinical Alzheimers disease). 25 healthy controls had serial scanning (54 scans: range 2-4 per patient) for comparison. We measured whole brain and total hippocampal volumes using semi-automated techniques, and adjusted for total intracranial volume. Hierarchical models were developed to estimate differences in volume and atrophy rate between mutation carriers and controls in relation to when the disease was clinically diagnosed. FINDINGS Mutation carriers had significantly increased hippocampal and whole-brain atrophy rates compared with controls and these differences increased with time. Differences in hippocampal and whole-brain atrophy rates between controls and mutation carriers were evident 5.5 and 3.5 years, respectively, before diagnosis of Alzheimers disease. At a cross-sectional level, differences in mean hippocampal volume between mutation carriers and controls became significant 3 years before clinical diagnosis, whereas differences in mean brain volumes became significant only 1 year before diagnosis. INTERPRETATION Structural changes can be seen on MRI scans that predate the clinical onset of familial Alzheimers disease. Longitudinal measures of atrophy rates can identify differences between mutation carriers and controls 2-3 years earlier than cross-sectional volumetric measures.

Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease

A significant minority of Alzheimers disease patients present with posterior cortical atrophy (PCA). PCA is characterized by visuospatial and visuoperceptual deficits, and relatively preserved memory, whereas patients with typical Alzheimers disease (tAD) mostly present with early episodic memory deficits. We used two unbiased image analysis techniques to assess atrophy patterns in 48 PCA, 30 tAD, and 50 healthy controls. FreeSurfer was used to measure cortical thickness, and volumetric grey matter differences were assessed using voxel-based morphometry (VBM). Both PCA and tAD showed widespread reductions compared with controls using both techniques. Direct comparison of PCA and tAD revealed thinner cortex predominantly in the right superior parietal lobe in the PCA group compared with tAD, whereas the tAD group showed thinning in the left entorhinal cortex compared with PCA. Similar results were obtained in the VBM analysis. These distinct patterns of atrophy may have diagnostic utility. In a clinical context, a relatively spared medial temporal lobe in the presence of posterior parietal atrophy may imply PCA, and should not discount AD.

The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2

BACKGROUND Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), or Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in two genes encoding subunits of a cell membrane-associated receptor complex: TREM2 and DAP12. The clinical course of PLOSL has not been characterized in a series of patients with TREM2 mutations. METHODS The authors compare neurologic and neuroradiologic follow-up data of six patients carrying TREM2 mutations with PLOSL due to defective DAP12 genes. The authors review the known mutations in these two genes. RESULTS Mutations in DAP12 and TREM2 result in a uniform disease phenotype. In Finnish and Japanese patients with PLOSL, DAP12 mutations predominate, whereas TREM2 is mutated more frequently elsewhere. CONCLUSIONS Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.

Volumetric MRI and cognitive measures in Alzheimer disease : comparison of markers of progression.

BackgroundBoth cognitive tests and MRI-based measures have been suggested as outcomes in trials assessing disease-modifying therapies in Alzheimers disease (AD).ObjectiveTo compare changes in longitudinal MRI measures with changes in performance on cognitive tests routinely used in AD clinical trials.MethodFifty-two subjects from the placebo-arm of a clinical trial in mild-to-moderate AD had volumetric T1-weighted scans and cognitive tests including the Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale, Disability Assessment for Dementia, AD Cooperative Study-Clinical Global Impression of Change and Clinical Dementia Rating at baseline and one-year later. Rates of brain atrophy and ventricular enlargement were measured using the boundary shift integral. Hippocampal (Hc) atrophy was calculated from manual volume measurements. The relationships between MRI and cognitive measures were investigated.ResultsRates of brain atrophy and/or ventricular enlargement were correlated with declining performance on cognitive scales. The strongest association was between brain atrophy rate and MMSE decline (r = 0.59, p < 0.0001). Hc atrophy rate was not significantly correlated with any of the cognitive scales.ConclusionThe lack of correlation between Hc atrophy and cognitive scales may reflect a combination of: the extensive functional damage to the Hc by the time AD is clinically established, the greater influence of ongoing cortical degeneration, and errors in Hc outlining. The strong correlations between brain atrophy and ventricular enlargement, and cognitive scales probably reflect the correspondence between these measures of overall cerebral loss and global cognitive measures in the moderate stages of AD.

Delusions and hallucinations in dementia with Lewy bodies: Worsening with memantine

Three patients with probable dementia with Lewy bodies (DLB) experienced worsening delusions and visual hallucinations as a result of memantine therapy. Significant resolution occurred once treatment was discontinued. Caution is required when prescribing memantine to patients with possible DLB.

Molecular Dissection of Alzheimer'S Disease Neuropathology by Depletion of Serum Amyloid P Component.

New therapeutic approaches in Alzheimers disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimers disease, cerebrovascular and intracerebral Aβ amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. Here, in this unique study in Alzheimers disease of the bis(d-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), we observed depletion of circulating SAP and also remarkable, almost complete, disappearance of SAP from the CSF. We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated τ protein. These results support further clinical study of SAP depletion in Alzheimers disease and potentially other neurodegenerative diseases.

The Different Frameworks Underlying Abstract and Concrete Knowledge: Evidence from a Bilingual Patient with a Semantic Refractory Access Dysphasia

We report the case of a bilingual patient (IRQ) who acquired a semantic refractory access dysphasia following a middle cerebral artery stroke. In a series of spoken word-written word matching tasks, the degree of semantic similarity between target and distractor items was found to affect the accuracy of IRQs identification of concrete but not abstract words. By contrast, the degree of semantic association between target and distractor items was found to affect response accuracy when identifying abstract but not concrete words. These results provide further corroboration for the notion that abstract concepts are supported by an associative representational network whereas concrete concepts are supported by a categorical representational framework. We also demonstrate an equivalent refractory deficit of comprehension in both English and Arabic. In addition, we provide the first documented evidence of a category-specific refractory deficit of knowledge for abstract words. We would like to thank Dr. David Cohen and the therapists on the Harrow Stroke Unit at Northwick Park Hospital who allowed us to study patients under their care. We are grateful to Dr. Jason Warren for his opinion on the neuroimaging data. We are also indebted to Professor Martin Rossor for his continued support of all aspects of our work. This work was supported by an equipment grant from the Alzheimers Research Trust.

Imaging cadavers: cold FLAIR and noninvasive brain thermometry using CSF diffusion

There is increasing interest in imaging cadavers for noninvasive autopsies for research purposes. However, the temperature is well below that of in vivo imaging, and a variety of interesting ‘cold brain’ effects are observed. At lower temperatures conventional FLAIR sequences no longer produce dark cerebrospinal fluid (CSF); T1 is reduced from about 4.0 sec in vivo to 1.7 sec at 1°C. The diffusion coefficient (DC) of CSF is much reduced (from 3.1 10−9 m2s−1 in vivo to 1.1 at 1°C). DC values therefore provide a noninvasive thermometer to measure brain core temperature to within 1.0°C. In three cadavers DC values were 1.1–1.5 10−9 m2s−1, indicating brain core temperatures of 1–10°C, consistent with external thermocouple measurements. An improved inversion time (TI0) can then be found for FLAIR. At 10°C this Cold FLAIR sequence (TI0 = 1.5 sec) gave black CSF. Expressions for CSF DC and T1 as a function of temperature were produced. A measurement of CSF DC could be converted directly to temperature and the required TI0 found. In vitro values of CSF DC were about 1% lower than that of water. Thus, FLAIR imaging can be optimized for cadaveric brains at low and unknown temperatures, thereby improving value for autopsy purposes and facilitating comparisons with in vivo imaging. Magn Reson Med, 2007.

PET Tau and Amyloid-β Burden in Mild Alzheimer’s Disease: Divergent Relationship with Age, Cognition, and Cerebrospinal Fluid Biomarkers

Background: Combining PET amyloid-β (Aβ) and tau imaging may be critical for tracking disease progression in Alzheimer’s disease (AD). Objective: We sought to characterize the relationship between Aβ and tau ligands as well as with other measures of pathology. Methods: We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with Aβ ([18F]AV45) and tau ([18F]AV1451) ligands at baseline. Results: 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical Aβ associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not Aβ. Conclusion: The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker— the CSF total tau/Aβ ratio.

Donepezil enhances understanding of degraded speech in Alzheimer's disease.

Auditory dysfunction under complex, dynamic listening conditions is a clinical hallmark of Alzheimers disease (AD) but challenging to measure and manage. Here, we assessed understanding of sinewave speech (a paradigm of degraded speech perception) and general cognitive abilities in 17 AD patients, before and following a 10 mg dose of donepezil. Relative to healthy older individuals, patients had impaired sinewave speech comprehension that was selectively ameliorated by donepezil. Our findings demonstrate impaired perception of degraded speech in AD but retained perceptual learning capacity that can be harnessed by acetylcholinesterase inhibition, with implications for designing communication interventions and acoustic environments in dementia.