Patients with early-onset Alzheimer’s disease: high

field MRI findings.

Fidel Núñez*1, Daniel Alcolea2, Esther Granell1, Manel De Juan1, Yolanda Vives3, Albert Lleó2, Beatriz Gómez1.

1 Hospital de la Santa Creu i Sant Pau (Barcelona) Radiology (Neuroradiology Unit).2 Hospital de la Santa Creu i Sant Pau (Barcelona). Neurology.3 Port d’Informació Científica (PIC), Universitat Autònoma de Barcelona (UAB). * fnunez@santpau.cat

Introduction

Although incidence of Alzheimer’s disease (AD) is greater in advanced age, it can begin earlier in life, even before 65 years of age, which is considered early onset Alzheimer’s disease (EAD). Even when it makes for a small percentage of patients with AD, it is still the most frequent cause for early onset dementia1.

Compared to senile or late onset AD (LAD), EAD has more often a genetic cause involved2-4. A faster clinical course of the disease and more severe symptoms have also been described.

Within the multiplicity and heterogeneity of clinical syndromes in AD, a more severe involvement of executive and visuospatial functions has been traditionally described5, with memory impairment being prominent in a later stage of the disease6,7.

Introduction

Structural magnetic resonance imaging (MRI) has allowed to study volume changes in patients with neurodegenerative diseases. Whereas there is wide evidence8-10 in structural MRI findings in patients with LAD/ mild cognitive impairment, studies in EAD are more limited.

Some previous studies have suggested a different pattern of regional volume loss in EAD versus LAD, using voxel based morphometry (VBM)11-15. A relative sparing of medial temporal regions and a more selective volume loss in parietal lobes (focused in precuneus and posterior cingulate) have been described in patients with EAD, according to cognitive differences in these versus LAD patients. Differences in Nuclear Medicine studies have also been found16,17. There is less extent literature in cortical thickness analysis in EAD at present14.

Materials and methods

A total of 30 patients with the diagnosis of AD (18 defined as EAD and 12 as LAD) were recruited in the Memory Disorders Unit of our institution. 12 subjects with no cognitive deficits were also included as controls. Demographics, including age at the onset of symptoms, age at MRI study and evolution time can be seen in the table.

GROUP Age at onset (years) Age at MRI (years) Clinical evolution time at MRI study (years)

average SD average SD average SD

LAD 72.34 3.72 75.87 3.14 3.53 1.61

EAD 55.63 4.30 61.42 4.42 5.78 3.64

CONTROL -- -- 74.16 5.03 -- --

Materials and methods

All the patients were studied with a complete neuropsychological battery. No statistically significant differences were found between EAD and LAD groups.

Structural MRI: Studies were performed in a high field scan (3T Philips, Achieva 2.6.3), including a volumetric 3DT1 sequence (TR=6.7 ms, TE 3.1 ms, voxel size acquisition 1.2x0.0889x0889 mm).

Data processing: MRI studies were prcessed using Freesurfer (version 5.0), with the Dessikan-Killiany atlas for cortical parcellation19. Statistical analysis of obtained data was made with QDEC software. The performed comparisons were EAD versus controls, LAD versus controls and EAD versus LAD.

ResultsEAD vs controls: Figure shows areas of cortical thinning (in blue) in EAD patiens versus controls, all of them statistically significant (p<0,01). Top row shows results in right hemisphere (lateral and medial surface), and bottom row shows results for left hemisphere.

A pattern of manily parietal (including precuneus and posterior cingulate) involvement can be seen, as well as lateral temporal and, in a lesser extent, dorsolateral prefrontal.

Results

EAD vs controls: • Table shows p values in all the clusters with cortical thinning.

RIGHT HEMISPHERE

LEFT HEMISPHERE

CLUSTER p value CLUSTER p value

Inferior parietal 0.00003 Supramarginal 0.000003

Supramarginal 0.0003 Superior parietal 0.00007

Isthmus cingulate 0.0003 Precuneus 0.0001

Rostral middle frontal 0.0003 Caudal middle frontal 0.0002

Caudal middle frontal 0.0004 Post central 0.0004

Inferior temporal 0.0008 Middle temporal 0.0009

Superior frontal 0.0018 Rostral middle frontal 0.0009

Precuneus 0.0019 Inferior parietal 0.0014Middle temporal 0.0032 Isthmus cingulate 0.0014Superior parietal 0.0039 Superior frontal 0.0019

Paracentral 0.0049 Rostral anterior cingulate 0.0056

Pars opercularis 0.0063

Lateral occipital 0.0091

ResultsLAD vs controls: Figure shows areas of cortical thinning (in blue) in LAD patiens versus controls, all of them statistically significant (p<0,01). Top row shows results in right hemisphere (lateral and medial surface), and bottom row shows results for left hemisphere.

A pattern of mainly inferior and medial temporal (including fusiform gyrus) involvement can be seen. There is no selective involvement of precuneus, or dorsolateral prefrontal cortex.

Results

LAD vs controls: • Table shows p values in all the clusters with cortical thinning.

RIGHT HEMISPHERE

LEFT HEMISPHERE

CLUSTER p value CLUSTER p value

inferior temporal 0.0002 superior temporal 0.0001

inferior parietal 0.0002 inferior temporal 0.0003

superior temporal 0.0005 middle temporal 0.0003

fusiform 0.0010 superior frontal 0.0004

supramarginal 0.0010 paracentral 0.0007

rostral middle frontal 0.0012 fusiform 0.0012

isthmus cingulate 0.0011 pars opercularis 0.0014

pars orbitalis 0.0013 lateral orbitofrontal 0.0034

middle temporal 0.0013 pars orbitalis 0.0057

pars opercularis 0.0014

superior frontal 0.0025

medial orbito-frontal 0.0035

caudal anterior cingulate 0.0083

ResultsEAD vs LAD: Figure shows areas of

cortical thinning (in blue) in

EAD patients. Areas of

cortical thinning in LAD are

shown in red. All of them are

statistically significant

(p<0,01). Top row shows

results for right hemisphere

(lateral and medial surface),

and bottom row shows

results for left hemisphere.

The most imortant loss of

cortical thickness in EAD

patients can be seen in

precuneus. Opposite, in

LAD patients a more

selective inferior temporal

(fusiform gyrus) and

inferior frontal cortical

thinning can be seen.

Results

EAD vs LAD: • Table shows p values in all the clusters with cortical thinning in EAD patients versus

LAD patients.

• Table shows p values in all the clusters with cortical thinning in LAD patients versus EAD patients.

RIGHT HEMISPHERE LEFT HEMISPHERE CLUSTER p value CLUSTER p valueCuneus 0.0015 Precuneus 0.0002Supramarginal 0.0018 Inferior parietal 0.0034Inferior parietal 0.0019 Superior temporal 0.0052Precuneus 0.0057 Caudal middle-frontal 0.0079Rostral middle frontal 0.0057 Superior parietal 0.0079 Pericalcarine 0.0085 Supramarginal 0.0091

RIGHT HEMISPHERE LEFT HEMISPHERE

CLUSTER p value CLUSTER p valueFusiform 0.0004 Superior temporal 0.0012Enthorinal 0.0004 Pars triangularis 0.0015Pars orbitalis 0.0028 Lateral orbitofrontal 0.0025Insula 0.0035 Enthorinal 0.0029Superior temporal 0.0046 Post-central 0.0045Precentral 0.0050 Temporal pole 0.0046Temporal pole 0.0078 Pars opercularis 0.0079

Discussion

EAD patients show cortical thinning predominating in parietal, temporal lateral and dorsolateral prefrontal regions of both hemispheres, with a pattern which is similar in comparison with LAD patients and controls. Precuneus and posterior cingulate cortex (the latter more evident versus control group) involvement is remarkable, and is in line with volumetry (VBM) studies available, which have also related it to the different clinical features in these patients11-15 (more visuospatial and executive impairment). Taking into account the lower ages of EAD group (age was not included as a covariable in analysis) makes results more noticeable.

Patients of the LAD group show a different pattern of cortical thinning (being compared to controls of similar age) with involvement of inferior and medial temporal regions (and parietal to a lesser extent). These findings are in line with expected changes in AD patients which have been widely shown in volumetry and cortical thickness studies. The absence of precuneus involvement in this group versus controls is also remarkable.

Discussion

Neuropsychological tests did not show statistically significant results (especially those focused on executive and visuospatial functions) between groups. The different evolution time of the disease at the time of the study (longer in EAD group) might be an explanation. The clinical differences between EAD and LAD have been described in literature predominantly in early stages of the disease, and a faster clinical course of EAD has been suggested as a cause for normalization of differences in neuropsychological tests in later stages of both EAD and LAD18.

Conclusions

• EAD patients show a pattern of cortical thinning which is different to LAD patients.

• EAD patients show selective involvement of medial parietal regions (precuneus, posterior cingulate) compared to LAD patients and controls.

• These findings are in line with current literature.

• Studies in earlier stages of the disease and focused in neuropsychological differences might be required.

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