Brain Advance Access originally published online on September 7, 2006
Brain 2006 129(11):2966-2976; doi:10.1093/brain/awl237
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Phenotype associated with APP duplication in five families
1 Department of Neurology, University Hospital IFRMP 2 Inserm U614, Faculty of Medicine IFRMP 3 Department of Genetics, University Hospital Rouen 4 Department of Neuropathology, University Hospital Rouen 5 Department of Neurology, University Hospital Nantes 6 Department of Geriatry CHG Pau 7 Department of Neurology, University Hospital Saint-Etienne 8 Department of Neurology, University Hospital Angers 9 Laboratoire de Biologie Cellulaire, University Hospital Angers 10 Department of Neurology and EA2691, University Hospital Lille 11 Department of Pathology, University Hospital Bordeaux 12 Institut de Pharmacologie Moleculaire et Cellulaire, UMR6097 CNRS/UNSA, Equipe labellisée Fondation pour la Recherche Médicale Valbonne, France
Correspondence to: Didier Hannequin, Department of Neurology, 1 rue de Germont, 76031 Rouen, Cedex, France E-mail: Didier.hannequin{at}chu-rouen.fr
 |
Summary |
|---|
 Top Summary IntroductionPatients and methodsResultsDiscussionReferences |
|---|
Different duplications of the APP locus have been identified in five families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and Aß-related cerebral amyloid angiopathy (CAA). This study describes the phenotype of this new entity. Clinical, neuropsychological, imagery and neuropathological data were reviewed. The phenotype was not dependent on the size of the duplication and there was no clinical feature of Down's syndrome. Dementia was observed in all cases; intracerebral haemorrhage (ICH) was reported in 6 (26%) and seizures occurred in 12 (57%) of 21 patients. Age of onset of dementia ranged from 42 to 59 years, ICH from 53 to 64 years and age at death from 46 to 75 years. The neuropathological findings in five cases demonstrated Alzheimer's disease and severe CAA lesions that were reminiscent from those reported in brains of Down's syndrome patients. A striking feature consisted in intraneuronal Aßx-40 accumulation located in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the Ammon's horn.
Key Words: amyloid angiopathy; Alzheimer's disease; APP duplication; Down's syndrome; intracerebral haemorrhage
Abbreviations: Aß, amyloid ß peptides; ADEOAD, autosomal dominant early onset Alzheimer's disease; BG, basal ganglia; CAA, cerebral amyloid angiopathy; HE, haematoxylin–eosin; ICH, intracerebral haemorrhage; WMC, white matter changes
.
Received July 10, 2006. Revised August 4, 2006. Accepted August 8, 2006.
|
Introduction |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Cerebral amyloid angiopathy (CAA) is a microangiopathy defined by the deposition of amyloid peptides in the media and adventitia of leptomeningeal and cortical arteries and arterioles (Vonsattel et al., 1991
). The most common clinical manifestations of CAA are lobar haemorrhagic stroke and progressive dementia (Greenberg, 1998). In Alzheimer's disease and Down's syndrome, CAA is caused by deposition of amyloid ß peptides (Aß) and associated with pathological hallmarks of Alzheimer's disease (Ellis et al., 1996; Jellinger, 2002; Pfeifer et al., 2002). Autosomal dominant Aß-related CAA had been mainly associated with rare missense mutations of the APP gene located within the Aß coding sequence. In these families, some members had dementia while others had vascular cognitive decline and intracerebral haemorrhage (ICH) or infarcts (Levy et al., 1990; Hendriks et al., 1992; Grabowski et al., 2001; Nilsberth et al., 2001; Bugiani, 2004; Rossi et al., 2004; Obici et al., 2005). Alzheimer's disease and CAA without ICH had also been described with some missense mutations of presenilin-1 (PSEN1) (Verkkoniemi et al., 2000; Mann et al., 2001) and presenilin-2 genes (Nochlin et al., 1998). In the present paper, clinical, neuropsychological, imagery and neuropathological data were collected to describe the phenotype of the five French families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and CAA in which duplications of the APP locus have been recently reported (Rovelet-Lecrux et al., 2006). We compare these features with those found in Down's syndrome patients. |
Patients and methods |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Clinical assessment
Clinical and molecular investigations were performed with the informed consent of participating family members according to a protocol approved by the ethics committees of the CCPPRB Pitié-Salpêtrière and Paris-Necker. The patients were recruited between 1956 and 2005 in six departments of neurology. Patients were considered as affected if they had Alzheimer's disease according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria (American Psychiatric Association, 1994
) or vascular dementia following ICH according to NINDS-AIREN criteria (Roman et al., 1993). Age of onset, bedridden stage and death, neurological signs and vascular risk factors were collected by personal examination, interviews of family members and general practitioners, and medical records. Absence of dysmorphy described in Down's syndrome was evaluated by using a checklist of 25 signs in still alive patients (Jackson et al., 1976).
Neuropsychological assessment
Mini-Mental State Examination (Folstein et al., 1975) score was available in 10 patients. A similar battery of neuropsychological tests had been used in six patients: Mattis Dementia Rating Scale (Schmidt et al., 1994), oral naming (Deloche and Hannequin, 1997), Grober and Buschke Verbal Learning Test (Grober and Buschke, 1987) or Wechsler Memory Scale (Wechsler, 1970), Frontal Assessment Battery (Dubois et al., 2000), Rey–Osterrieth complex figure copy (Rey, 1970) and 2 min verbal fluency tasks (Cardebat et al., 1990).
Neuroimaging
CT and MRI cans of 12 affected patients have been reviewed to evaluate ICH, white matter (WMC) and basal ganglia (BG) changes and atrophy. The age-related white matter changes scale (Wahlund et al., 2001) with the same criteria applicable to both CT and MRI scans was used to rate the degree and distribution of WMC and BG changes on a 4-point scale. Five regions (frontal, parieto-occipital, temporal, infra-tentorial areas and BG) were rated in both hemispheres except for patient F037/II.3, because of a right ICH. In case of repeated CT or MRI, only the latest images were considered for rating. Six CT scans were used, with a slice thickness varying from 3.75 to 10 mm. MRI equipment used operated at 1.0 or 1.5 T. Six T2-sequences were used with a slice thickness varying from 4 to 9 mm. Additionally, 
-weighted sequences were performed in patients F037/II.5 and F037/II.7. The extent of cortical atrophy was scored individually by three raters on a 4-point rating scale from 0 (no atrophy) to 3 (severe) at three regions (frontal, temporal, parieto-occipital). For each region, the score was the one chosen by 
2 raters/3; otherwise scoring was obtained by consensus reading. Five patients had brain single photon emission computed tomography (SPECT) with 99mTC-ECD (F037/II.5, II.6, II.7; F229/II.4, II.5) and two with 99mTC-HMPAO (F019/II.3; F009/II.3), from 1 to 6 years after onset of dementia.
Neuropathological evaluation
An autopsy restricted to the brain was performed on five patients (F037/II.5, II.6; F028/II.1, II.2; F019/I.4). After extraction of the brain, 1 cm-thick coronal slices obtained from the left hemisphere were stored at –70°C until use. The right hemisphere, and the whole brainstem and cerebellum were fixed in a 10% formaldehyde solution buffer. Tissue samples were taken from representative areas, including middle frontal gyrus, superior temporal gyrus, temporal pole, inferior parietal gyrus, anterior cingulated gyrus, insular and motor cortex, calcarine fissure, hippocampus, nucleus basalis of Meynert, BG, cerebral peduncles, pons, medulla oblongata and cerebellum (vermis, right hemisphere and dentate nucleus). Seven-micrometre sections were cut from paraffin-embedded blocks and stained with haematoxylin–eosin (HE), periodic acid Schiff (PAS), Orcein, Luxol-Phloxine and the modified Bielchowski silver impregnation method. Routine immunohistochemical studies were carried out using antibodies directed against alpha-synuclein (diluted 1/200) (Zymed, Clinisciences, Montrouge, France), the PHF tau (AT8, 1/20) (Innogenetics, Gent, Belgium), glial fibrillary acidic protein (GFAP, 1/300), PrP (1 : 50), ubiquitin (1/100) and the macrophagic marker CD68 (1/300) (Dakopatts, Trappes, France). Vascular and intraparenchymatous amyloid deposits were characterized using ß-amyloid protein (diluted 1/100) and cystatin C (1/500) (Dakopatts, Trappes, France). Further characterization of ß-amyloid deposits was performed using anti-Aß40 and Aß42 antibodies (FCA 3340, 1/400 and FCA 3542, 1/200) (Barelli et al., 1997).
|
Results |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients' characteristics
The familial entity described in this article was characterized by a combination of ADEOAD and ICH. Pedigrees are indicated in Fig. 1. Twenty-one patients were identified (Table 1). Fourteen patients with DNA analysis (Fig. 1) harboured a chromosome 21q21 duplication including the APP gene. Among families, the duplicated segments had different sizes ranging from 0.58 Mb (F028), 0.78 Mb (F037), 1.98 Mb (F009), 3.96 Mb (F019) to 6.37 Mb (F229) and contained 5, 5, 8, 12, 12 annotated genes, respectively (Rovelet-Lecrux et al., 2006
). Age of onset of dementia ranged from 42 to 59 years, ICH from 53 to 64 years and age at death from 46 to 75 years. Dementia was observed in all cases, and results of the neuropsychological assessment in six demented patients with no associated ICH fulfilled criteria for Alzheimer's disease (Table 2). ICH were reported in six patients (26%). In three cases, imagery has been reviewed (Fig. 2); in two cases (F009/II.1, II.3), ICH was mentioned in the medical reports, and for patient F019/I.1, interview of siblings reported that she had been operated for ICH, but the medical record was not available. Vascular risk factors were present in eight cases but only one patient with ICH had previous hypertension (Table 1). One ICH occurred in a patient (F037/II.3) receiving vitamin K antagonist for supraventricular tachycardia (prothrombin time was 45%). Three patients received neuroleptic drugs (F037/II.2; F009/II.1, II.3) before ICH. It could be added that the mothers of two probands (F037/I.1; F229/I.1) died from unspecified stroke at age of 55 and 72, respectively (see Fig. 1).
|
|
|
Seizures were observed in 12 of 21 patients: in four cases, they were associated with or followed ICH, while in the other eight cases seizures occurred from 1 to 9 years after evolution of dementia. Two additional individuals, F229/II.3 and F028/II.6, with unknown genotype could have been possibly affected because they died after status epilepticus at age of 50 and 54, respectively. Nevertheless, interview of their siblings did not find arguments for previous cognitive decline or behavioural impairment and CT scans did not find focal lesion.
One patient (F019/II.3) had surgery at 39 years old for one cavernoma of the cervical spinal cord responsible for left hemiparesia 3 years before the dementia onset. For the others, neurological examinations were normal except for focal neurological deficits caused by the location of the haemorrhages. None of the cases had ataxia or cerebellar signs. None of the 21 patients had mental retardation. Retrospective analysis of medical records and personal examination did not reveal any clinical feature suggestive of Down's syndrome.
Neuroimaging
The three available CT scans demonstrated that ICH (Fig. 2) was either small and cortical, or large frontoparietal with an extension involving BG. WMC were found in 6 of 12 patients and were predominant in parieto-occipital regions (Fig. 2). The rating scores of WMC, according to location and side, are presented in Table 1. Among the 115 analysed regions, the three raters agreed unanimously in 76%, and 24% were rated according to the majority. Regarding cortical atrophy, among the 69 analysed regions, the three raters agreed unanimously in 38%, 53% were rated according to the majority and 9% by consensus reading. Eleven affected patients among 12 had symmetric cortical atrophy with parietal location predominance. -weighted sequences performed in two patients did not reveal microbleeds. There were neither cerebral calcifications nor leptomeningeal gadolinium enhancement. SPECT hypoperfusion was diffuse in four patients (F037/II.5, II.7, F019/II.3, F229/II.4), parieto-temporal in F037/II.6, temporal in F229/II.5 and parietal in F009/II.3.
|
Neuropathological findings
Macroscopical examination
Detailed macroscopic data were available in three patients (F019/I.4, F037/II.5, II.6). Brain weight varied from 1200 to 1235 g. External examination revealed a diffuse atrophy, more pronounced in the temporoparietal area. The leptomeninges appeared thick and creamy, particularly around the vessels. The substantia nigra and the locus coeruleus were depigmented. On coronal sections, the cerebral and cerebellar white matter were irregularly discoloured. Caudate nuclei were not atrophic, conversely to temporal, parietal and hippocampal gyri. Cerebral ventricular dilatation was also noted. In patient F019/I.4, ventricular dilatation was severe, and lacunae as well as old and recent haemorrhages in the temporal and hippocampal gyri were macroscopically observed.
Microscopic findings
In all five cases studied, the pigmented nuclei of the brainstem displayed neuronal loss, interstitial pigment deposition and gliosis, but Lewy bodies were never observed. Neuronal loss was also noted in the BG. All cortical structures studied were severely affected. The lesions associated neuronal loss, microvacuolization of layers II and III, as well as vanishing cortical lamination with a relative sparing of the occipital cortex. The cerebellar cortex displayed a marked loss of Purkinje cells, and to a lesser extent, of internal granule cells. Using tau and ubiquitin immunochemistry, numerous fibrillary tangles, senile plaques and neuropil threads were observed in the hippocampal cortex (Fig. 3A), the limbic system and the isocortex (Fig. 3B), the topography and the density of which is consistent with a definite diagnosis of Alzheimer's disease according to CERAD (Consortium to Establish a Registry for Alzheimer's disease) criteria (Mirra et al., 1991) with Braak stage V–VI (Braak and Braak, 1991). Alzheimer's disease lesions were less prominent in the thalamus, the putamen and the caudate nucleus. Alpha-synuclein and PrP antibodies were always negative in all structures studied. In the Ammon's horn, diffuse amyloid deposits were present, as well as amyloid plaques, sometimes arranged in rose petal-like formations (Fig. 3C). Close to the plaques, scarce inflammatory cells could be seen, as evidenced by CD68 immunocytochemistry. Numerous amyloid deposits were observed in all isocortical areas (Fig. 3D), as well as in the pyramidal cell layer and in the dentate gyrus granular cell layer of the hippocampal formation. In the cerebellum, variable amounts of amyloid deposits could be observed in the molecular and granular cell layer, in the vicinity of the Purkinje cells.
|
CAA was diffuse, consisting of an acellular thickening of the leptomeningeal vessels, as well as superficial and deep intraparenchymatous small arteries, capillaries and veinules. The internal elastic lamella was fragmented and the media severely disorganized, as evidenced by Orcein staining. Abundant circumferential deposits invaded the arteriolar walls, extending over the adventitia, with densely packed fibrils radiating from the affected vessels into the surrounding neuropil (Fig. 3E). Around the majority of vessels, pallor of focal areas of demyelination was observed, corresponding to ischaemic changes, and sometimes containing iron-laden macrophages (Fig. 3F). Microaneurysms were present in two patients (F019/I.4 and F037/II.6). In the parietal and occipital lobes, CAA lesions were most often calcified. Numerous microcalcifications were also observed into the surrounding neuropil. PAS stains revealed not only CAA but also small dense deposits corresponding to amyloid pre-plaques. Moreover, several patchy superficial small infarcts were noted in the cerebellum, resulting in the disruption of the cerebellar cortical lamination by a loose fibrillar network containing reactive astrocytes (Fig. 3G). Similar lesions were observed in other cerebral areas such as the brainstem, the frontal (Fig. 3H) and the entorhinal cortex. In the hemispheric white matter, microinfarcts were always located at a short distance from the affected vessels. Old and recent haemorrhages, as well as haemosiderin deposits were noted in patient F019/I.4.
The amyloid-laden vessels were strongly positive for Aß antibodies (Fig. 4A) and cystatin C. Aß immunolabelling was strongly positive on nearly all meningeal vessels, on amyloid deposits, on the cores of plaques and on perivascular deposits, with an antero-posterior gradient of severity. Using FCA 3340, which selectively recognizes Aß-species ending at the 40th residue of the human Aß peptide sequence (Barelli et al., 1997), vascular deposits were strongly positive with a reinforcement in the intimal zone, close to the internal elastic lamella (Fig. 4B). Plaques were also densely positive, particularly around and within the core (Fig. 4C), where some amyloid-laden macrophages could be observed. In contrast, diffuse deposits were exceptionally immunolabelled. On the contrary, FCA 3542, which recognizes Aß species ending at the 42nd amino acid of the human Aß peptide (Barelli et al., 1997), was strongly positive on the dystrophic neuritis of cored plaques (Fig. 4D). It was diffusely positive in intraparenchymatous diffuse deposits (Fig. 4E), particularly in the microvacuolated layers II and III. Sub-pial deposits were also positive. In the majority of the plaques, only the core was positive. Nevertheless, in some plaques, this antibody was also positive in dystrophic neurites, with the presence of spheroids or radiating spicular formations (Fig. 4F). In the vessels, FCA Aßx-42 immunoreactivity was observed in the intima and in the adventitia, creating a double outline pattern. But the most striking feature, in all cases studied, consisted in intracellular Aßx-40 immunoreactivity of numerous neurons, located either in the granular cell layer of the dentate gyrus or in the pyramidal cell layer of the Ammon's horn, and to a lesser extent, in the entorhinal and parahippocampal cortices. The immunostaining had a granular or vesicular pattern, and was concentrated in the perikarya (Fig. 4G and H). Other cortical or sub-cortical structures remained negative. In particular, lipofuscin-laden neurons of associative cortex remained negative in each patient. Furthermore, in none of the cases, intraneuronal Aßx-42 immunoreactivity could be detected.
|
|
Discussion |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
We described five French families with ADEOAD and CAA caused by a novel molecular mechanism of APP gene duplication. A similar clinical, neuropsychological, radiological and neuropathological phenotype was observed in the five families. This phenotype could be compared with the features associated with the rare mutations in the Aß coding sequence of APP. The recently described L705V mutation was exclusively associated with CAA and ICH (Obici et al., 2005
). The E693Q mutation that causes hereditary cerebral haemorrhage with amyloidosis of the Dutch type (HCHWA-D) is associated with severe CAA and diffuse plaques with absent or limited neurofibrillary pathology (Maat-Schieman et al., 2005). Affected individuals suffer primarily from strokes and those who survive develop a progressive dementia (Natte et al., 1998; van den Boom et al., 2005). Exceptionally, cognitive deterioration may develop in the absence of vascular lesion on brain imaging. Roughly 25% of patients with the Flemish A692G APP mutation present ICH and others develop presenile dementia (Roks et al., 2000; Brooks et al., 2004). ICH was also described as recurrent in three Italian families with E693K APP mutation, but prevalence was not provided (Miravalle et al., 2000). On the other hand, to our knowledge, the Arctic E693G APP mutation has been associated with CAA, but ICH has not been reported (Nilsberth et al., 2001). There is also considerable phenotypical variability for the same mutation: ICH were totally absent in the original Iowa pedigree, but were reported in 50% of affected members of a Spanish family (Grabowski et al., 2001) carrying the same D694N APP mutation (Greenberg et al., 2003). The A713T APP mutation was associated with definite Alzheimer's disease and multiple infarcts, and in one case, ICH was secondary to cerebral biopsy (Rossi et al., 2004). In the present study, ICH was found in 6 among 21 patients and was not associated with vascular risk factors (Table 1). It has been proposed that possession of APOE 
2 allele may be a risk factor for ICH due to CAA (Nicoll et al., 1997). None of our patients carried this risk factor (11/14 had an APOE 3/3 genotype, Table 1).
As regards WMC, frequency was 50%, which may be underscored since MRI were performed in only 7/12 patients (Table 1). This result may explain a slightly inferior frequency compared with the 60 to 100% frequency based on MRI studies in patients carrying APP mutations associated with CAA (Roks et al., 2000; Greenberg et al., 2003; Rossi et al., 2004; Panegyres et al., 2005; van den Boom et al., 2005). As in our cases (Fig. 2), distribution of WMC in these patients was symmetrical and preferentially located in periventricular and parieto-occipital regions on T2-weighted and FLAIR (fluid attenuated inversion recovery) images. A similar distribution has also been exceptionally reported in Alzheimer's disease patients carrying PSEN1 mutations (Aoki et al., 1997; O'Riordan et al., 2002). Severity of WMC could be different according to the various APP mutations but also between carriers of the same APP mutation or APP duplication as in the present cases. Again, such intrafamilial diversity could suggest the potential role of additional risk factors. Among six patients with an elevated WMC score, only three had vascular risk factors (Table 1).
We checked each patient for additional clinical features that could imply contribution of other genes in the duplicated regions. None had previous mental retardation, and no dysmorphy, cardiological malformation and no haematological disease reminiscent of the Down's syndrome phenotype were observed. A high prevalence of seizures in the five families (12/21 patients and 2 at-risk relatives with unknown genotype) has to be underlined, because it is higher than the none to 33% frequency reported in ADEOAD/CAA cases associated with APP mutations (Roks et al., 2000; Grabowski et al., 2001; Brooks et al., 2004). This high prevalence rate has to be compared with the frequency of seizures in adult patients with Down's syndrome, which ranges from 26% (McDermott et al., 2005) to 46% over the age of 50 years (McVicker et al., 1994) and reaches from 50 to 84% in cases with associated dementia (Van Buggenhout et al., 1999; Menendez, 2005). This suggests that either APP duplication itself, or duplication of other genes in this region, contributes to the occurrence of seizures. One affected patient (F019/II.3) had a particular association with one unique cervical cavernoma. We are presently considering this association as fortuitous because this cavernoma was unique, and no linkage data have been reported between the APP locus and cavernoma.
Our results would suggest a high prevalence of dementia and ICH due to CAA in Down's syndrome patients over 50 years of age. Prevalence of Alzheimer's disease in Down's syndrome patients is age-related, ranging from 11% between ages 40 and 49 (Visser et al., 1997) to 55% between 50 and 59 (Lai and Williams, 1989), 77% between 60 and 69 and 100% over 70 years old (Visser et al., 1997). Moreover, CAA is detected in Down's syndrome brains, even in young patients in their 30s, but tended to be more abundant in older patients (Vonsattel et al., 1991; Iwatsubo et al., 1995; Lemere et al., 1996). Prevalence of cerebrovascular as the main cause of death was found to be more frequent in the Down's syndrome population than expected in general population according to age and sex (Day et al., 2005). Nevertheless, we did not find large cohort studies of aged Down's syndrome patients reporting either MRI WMC or stroke prevalence, and there have been only occasional reports of ICH (Belza and Urich, 1986; Donahue et al., 1998; McCarron and Nicoll, 1998). This discrepancy between the ICH phenotype of our cases occurring in their 50s and the rare ICH in Down's syndrome patients could be partly explained by shorter life expectancy (Strauss and Shavelle, 1998; Glasson et al., 2002; Yang et al., 2002). Alternatively, for some genuine reason, the present cases may have more severe clinical expression of CAA than equally old patients with Down's syndrome.
Exhaustive neuropathological examination established definite Alzheimer's disease in all cases (Braak and Braak, 1991; Mirra et al., 1991). Nevertheless, one of the major features consisted of CAA, whose location, extent and intensity were different from those observed in classical Alzheimer's disease, with an anteroposterior gradient of severity (although CAA lesions remained significant in the frontal areas), as well as a relative sparing of infra-tentorial structures. Vascular lesions were similar in all cases studied, consisting of severe CAA (Vonsattel et al., 1991), and were characterized by a severe disruption of the vascular architecture, with a ‘double outline’ barrelling and microaneurysm formation, associated with multiple perivascular leakage of blood, and with white matter hypoxic–ischaemic chronic changes related to stenoses observed in most vessels. In classical Alzheimer's disease, CAA affects as a rule cortical and leptomeningeal arterioles and capillaries, whereas white matter is usually spared (Revesz et al., 2002), in opposition to our cases where multiple areas of myelin pallor, mainly perivascular and closely related to amyloid-laden small vessels, could be observed. In our cases the CAA was similar to that reported in middle aged patients with Down's syndrome, with deposition of both Aßx-40 and Aßx-42 in the cerebral vessel walls, with a predominance of Aßx-40 (Iwatsubo et al., 1995). As regards parenchymal lesions, some particularities were observed, that is, the presence of huge petal rose-like amyloid plaques in the hippocampal formation, associated with a macrophagic resorption, with no immunohistochemically proven microglial activation differing from Mori et al.'s (2002) report, and with no prominent astrocytosis or amyloid-laden astrocytes, in contrast to the findings of Gyure et al. (2001). But the most striking feature, in all cases studied, consisted in intraneuronal Aßx-40 accumulation located in the granular cell layer of the dentate gyrus, in the pyramidal cell layer of the Ammon's horn, and to a lesser extent, in the entorhinal and parahippocampal cortices. Transient intraneuronal accumulation of Aß42 peptide in the pyramidal neurons of the hippocampus and entorhinal cortex of patients with early Alzheimer's disease pathology has been reported, but intraneuronal immunoreactivity was less noticeable with disease progression, when the number of extracellular plaques was high, suggesting an inverse relationship between intraneuronal Aß42 content and extracellular Aß42 deposition (Gouras et al., 2000). Subcellular intraneuronal localization of Aß peptide has been studied in Alzheimer's disease brains (Takahashi et al., 2002; Cataldo et al., 2004) as well as in the neurons of APPxPSEN1 transgenic mice, in which both Aß40 and Aß42 species accumulate intracellularly (Langui et al., 2004). It was found that Aß immunoreactivity was concentrated (Takahashi et al., 2002; Langui et al., 2004) in multivesicular bodies that are vesicles carrying cargo from neuronal terminals to the cell body for degradation in lysosomes or in early endosomes (Cataldo et al., 2004). On the other hand, studies performed on Down's syndrome brains have consistently demonstrated intraneuronal deposition of Aß peptides, with a similar vesicular pattern of accumulation in the perikarya (Gyure et al., 2001; Mori et al., 2002; Cataldo et al., 2004). Nevertheless, the nature of amyloid varied among studies, demonstrating either an accumulation of Aß42 peptide (Mori et al., 2002) predominance of Aß40 (Gyure et al., 2001) or accumulation of both peptides (Cataldo et al., 2004). The study of Mori et al. (2002) was limited to the temporal cortex, but the two other studies (Gouras et al., 2000; Gyure et al., 2001; Takahashi et al., 2002; Cataldo et al., 2004) examined more extended cortical regions and demonstrated the presence of intraneuronal Aß peptide in associative cortices, in particular in the frontal cortex, in contrast to our cases where the intraneuronal Aßx-40 remained restricted to the limbic structures. The cause of these discrepancies remains unclear, but could be related to inclusion of patients at different stages of the disease process, or to binding of Aß to chaperone proteins preventing antibodies from detecting some epitopes (Mori et al., 2002). We conclude that, although minor discrepancies exist, lesions in patients with APP gene duplication are reminiscent of those found in Down's syndrome.
In autosomal dominant Aß-related CAA associated with mutations of the APP gene, peculiar neuropathological features are, in a large part, due to the specific fibrillogenic properties of the mutant peptides (Fraser et al., 1992; De Jonghe et al., 1998; Watson et al., 1999; Nilsberth et al., 2001; Walsh et al., 2001 Maat-Schieman et al., 2005). In Down's syndrome and the present ADEOAD/CAA cases, alteration of gene dosage is the only variable to be considered. How this alteration in gene dosage affects gene expression and protein amount is insufficiently known. However, in brains of aged patients with Down's syndrome or in human foetal cells from pregnancies affected by trisomy 21, levels of APP mRNA are elevated 
1.5-fold as compared with those of controls (Oyama et al., 1994; Fitzpatrick et al., 2002). An immunohistochemical study has revealed overexpression of APP protein in adult Down's syndrome brain (Griffin et al., 1998). It has also been reported that APP levels are elevated in the hippocampus of segmental trisomy 16 mouse model of Down's syndrome (Ts25Dn) compared with their littermates at 12 months of age (Seo and Isacson, 2005). Although the exact ratio at which Aß40 and Aß42 are produced in the brain of subjects carrying three doses of the APP gene is not known, both peptides are deposited in vascular and parenchymal lesions. In Down's syndrome, it is well established that the initial species initially deposited as diffuse plaques in the 30s is Aß42; Aß40 only appears a decade later (Iwatsubo et al., 1995; Lemere et al., 1996). Aß42 is essential to seed both parenchymal and vascular deposits (McGowan et al., 2005) but a high Aß40/Aß42 ratio influences the extent of vascular versus parenchymal deposition (Herzig et al., 2004). Altering the ratio of Aß40/Aß42 has influence on time to onset of deposition, type of deposit and extent of CAA. It could be speculated that in subjects expressing three doses of the APP gene, both an overproduction of the Aß peptide and a possible shift toward a high Aß40/Aß42 ratio account for the pathological hallmarks of the disease.
|
Footnotes |
|---|
*These authors have contributed equally to this work.
|
Acknowledgements |
|---|
We thank Drs P. Ahtoy, T. Edouard, J. Godard, P. Lainé, A. Libert, J. P. Mary, F. Mounier-Vehier and A. Verrier for having provided information on the history of some patients. This work was supported by the Fondation pour la Recherche Médicale (F.C.).
|
References |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Aoki M, Abe K, Oda N, Ikeda M, Tsuda T, Kanai M, et al. (1997) A presenilin-1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI. Neurology 48:1118–20.[Abstract]
American Psychiatric Association. (1994) AP. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). (DC: APA, Washington).
Barelli H, Lebeau A, Vizzavona J, Delaere P, Chevallier N, Drouot C, et al. (1997) Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases. Mol Med 3:695–707.[ISI][Medline]
Belza MG and Urich H. (1986) Cerebral amyloid angiopathy in Down's syndrome. Clin Neuropathol 5:257–60.[ISI][Medline]
Braak H and Braak E. (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–59.[CrossRef][Medline]
Brooks WS, Kwok JB, Halliday GM, Godbolt AK, Rossor MN, Creasey H, et al. (2004) Hemorrhage is uncommon in new Alzheimer family with Flemish amyloid precursor protein mutation. Neurology 63:1613–7.
Bugiani OA. (2004) Beta-related cerebral amyloid angiopathy. Neurol Sci 25:Suppl 1, S1–S2.
Cardebat D, Doyon B, Puel M, Goulet P, Joanette Y. (1990) [Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level]. Acta Neurol Belg 90:207–17.[ISI][Medline]
Cataldo AM, Petanceska S, Terio NB, Peterhoff CM, Durham R, Mercken M, et al. (2004) Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome. Neurobiol Aging 25:1263–72.[CrossRef][ISI][Medline]
Day SM, Strauss DJ, Shavelle RM, Reynolds RJ. (2005) Mortality and causes of death in persons with Down syndrome in California. Dev Med Child Neurol 47:171–6.[CrossRef][ISI][Medline]
De Jonghe C, Zehr C, Yager D, Prada CM, Younkin S, Hendriks L, et al. (1998) Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion. Neurobiol Dis 5:281–6.[CrossRef][ISI][Medline]
Deloche G and Hannequin D. (1997) DO80. Paris: Edition du Centre de Psychologie Appliquée.
Donahue JE, Khurana JS, Adelman LS. (1998) Intracerebral hemorrhage in two patients with Down's syndrome and cerebral amyloid angiopathy. Acta Neuropathol (Berl) 95:213–6.[CrossRef][Medline]
Dubois B, Slachevsky A, Litvan I, Pillon B. (2000) The FAB: a frontal assessment battery at bedside. Neurology 55:1621–6.
Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, Beekly D, et al. (1996) Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, part XV. Neurology 46:1592–6.
Fitzpatrick JL, Mize AL, Wade CB, Harris JA, Shapiro RA, Dorsa DM. (2002) Estrogen-mediated neuroprotection against beta-amyloid toxicity requires expression of estrogen receptor alpha or beta and activation of the MAPK pathway. J Neurochem 82:674–82.[CrossRef][ISI][Medline]
Folstein MF, Folstein SE, McHugh PR. (1975) ‘Mini-Mental State’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–98.[CrossRef][ISI][Medline]
Fraser PE, Nguyen JT, Inouye H, Surewicz WK, Selkoe DJ, Podlisny MB, et al. (1992) Fibril formation by primate, rodent, and Dutch-hemorrhagic analogues of Alzheimer amyloid beta-protein. Biochemistry 31:10716–23.[CrossRef][Medline]
Glasson EJ, Sullivan SG, Hussain R, Petterson BA, Montgomery PD, Bittles AH. (2002) The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clin Genet 62:390–3.[CrossRef][ISI][Medline]
Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, et al. (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20.
Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM. (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49:697–705.[CrossRef][ISI][Medline]
Greenberg SM. (1998) Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology 51:690–4.
Greenberg SM, Shin Y, Grabowski TJ, Cooper GE, Rebeck GW, Iglesias S, et al. (2003) Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. Neurology 60:1020–2.
Griffin WS, Sheng JG, McKenzie JE, Royston MC, Gentleman SM, Brumback RA, et al. (1998) Life-long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis. Neurobiol Aging 19:401–5.[CrossRef][ISI][Medline]
Grober E and Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol 1987:13–36.
Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC. (2001) Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med 125:489–92.[ISI][Medline]
Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F, et al. (1992) Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet 1:218–21.[CrossRef][ISI][Medline]
Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, et al. (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7:954–60.[CrossRef][ISI][Medline]
Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y. (1995) Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome. Ann Neurol 37:294–9.[CrossRef][ISI][Medline]
Jackson JF, North ER III, Thomas JG. (1976) Clinical diagnosis of Down's syndrome. Clin Genet 9:483–7.[ISI][Medline]
Jellinger KA. (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–36.[CrossRef][ISI][Medline]
Lai F and Williams RS. (1989) A prospective study of Alzheimer disease in Down syndrome. Arch Neurol 46:849–53.[Abstract]
Langui D, Girardot N, El Hachimi KH, Allinquant B, Blanchard V, Pradier L, et al. (2004) Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165:1465–77.
Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32.[Medline]
Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, et al. (1990) Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–6.
Maat-Schieman M, Roos R, van Duinen S. (2005) Hereditary cerebral hemorrhage with amyloidosis-Dutch type. Neuropathology 25:288–97.[CrossRef][ISI][Medline]
Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T. (2001) Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease. Am J Pathol 158:2165–75.
McCarron MO and Nicoll JA. (1998) High frequency of apolipoprotein E epsilon 2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett 247:45–8.[CrossRef][ISI][Medline]
McDermott S, Moran R, Platt T, Wood H, Isaac T, Dasari S. (2005) Prevalence of epilepsy in adults with mental retardation and related disabilities in primary care. Am J Ment Retard 110:48–56.[CrossRef][ISI][Medline]
McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, et al. (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47:191–9.[CrossRef][ISI][Medline]
McVicker RW, Shanks OE, McClelland RJ. (1994) Prevalence and associated features of epilepsy in adults with Down's syndrome. Br J Psychiatry 164:528–32.
Menendez M. (2005) Down syndrome, Alzheimer's disease and seizures. Brain Dev 27:246–52.[CrossRef][ISI][Medline]
Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, et al. (2000) Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem 275:27110–6.
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. (1991) The consortium to establish a registry for Alzheimer's disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41:479–86.
Mori C, Spooner ET, Wisniewsk KE, Wisniewski TM, Yamaguch H, Saido TC, et al. (2002) Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid 9:88–102.[ISI][Medline]
Natte R, Vinters HV, Maat-Schieman ML, Bornebroek M, Haan J, Roos RA, et al. (1998) Microvasculopathy is associated with the number of cerebrovascular lesions in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Stroke 29:1588–94.
Nicoll JA, Burnett C, Love S, Graham DI, Dewar D, Ironside JW, et al. (1997) High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol 41:716–21.[CrossRef][ISI][Medline]
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci 4:887–93.[CrossRef][ISI][Medline]
Nochlin D, Bird TD, Nemens EJ, Ball MJ, Sumi SM. (1998) Amyloid angiopathy in a Volga German family with Alzheimer's disease and a presenilin-2 mutation (N141I). Ann Neurol 43:131–5.[CrossRef][ISI][Medline]
O'Riordan S, McMonagle P, Janssen JC, Fox NC, Farrell M, Collinge J, et al. (2002) Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities. Neurology 59:1108–10.
Obici L, Demarchi A, de Rosa G, Bellotti V, Marciano S, Donadei S, et al. (2005) A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol 58:639–44.[CrossRef][ISI][Medline]
Oyama F, Cairns NJ, Shimada H, Oyama R, Titani K, Ihara Y. (1994) Down's syndrome: up-regulation of beta-amyloid protein precursor and tau mRNAs and their defective coordination. J Neurochem 62:1062–6.[ISI][Medline]
Panegyres PK, Kwok JB, Schofield PR, Blumbergs PC. (2005) A Western Australian kindred with Dutch cerebral amyloid angiopathy. J Neurol Sci 239:75–80.[CrossRef][ISI][Medline]
Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. (2002) Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 58:1629–34.
Revesz T, Holton JL, Lashley T, Plant G, Rostagno A, Ghiso J, et al. (2002) Sporadic and familial cerebral amyloid angiopathies. Brain Pathol 12:343–57.[ISI][Medline]
Rey A. (1970) Test de copie et de reproduction de mémoire de figures géométriques complexes. (Edition du Centre de Psychologie Appliquée, Paris).
Roks G, Van Harskamp F, De Koning I, Cruts M, De Jonghe C, Kumar-Singh S, et al. (2000) Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain 123:2130–40.
Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. (1993) Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43:250–60.
Rossi G, Giaccone G, Maletta R, Morbin M, Capobianco R, Mangieri M, et al. (2004) A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology 63:910–2.
Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, et al. (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–6.[ISI][Medline]
Schmidt R, Freidl W, Fazekas F, Reinhart B, Grieshofer P, Koch M, et al. (1994) The Mattis Dementia Rating Scale: normative data from 1,001 healthy volunteers. Neurology 44:964–6.
Seo H and Isacson O. (2005) Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice. Exp Neurol 193:469–80.[CrossRef][ISI][Medline]
Strauss D and Shavelle R. (1998) Life expectancy of persons with chronic disabilities. J Insur Med 30:96–108.[Medline]
Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, et al. (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–79.
Van Buggenhout GJ, Trommelen JC, Schoenmaker A, De Bal C, Verbeek JJ, Smeets DF, et al. (1999) Down syndrome in a population of elderly mentally retarded patients: genetic-diagnostic survey and implications for medical care. Am J Med Genet 85:376–84.[CrossRef][ISI][Medline]
van den Boom R, Bornebroek M, Behloul F, van den Berg-Huysmans AA, Haan J, van Buchem MA. (2005) Microbleeds in hereditary cerebral hemorrhage with amyloidosis-Dutch type. Neurology 64:1288–9.
Verkkoniemi A, Somer M, Rinne JO, Myllykangas L, Crook R, Hardy J, et al. (2000) Variant Alzheimer's disease with spastic paraparesis: clinical characterization. Neurology 54:1103–9.
Visser FE, Aldenkamp AP, van Huffelen AC, Kuilman M, Overweg J, van Wijk J. (1997) Prospective study of the prevalence of Alzheimer-type dementia in institutionalized individuals with Down syndrome. Am J Ment Retard 101:400–12.[ISI][Medline]
Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr. (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30:637–49.[CrossRef][ISI][Medline]
Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, et al. (2001) A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 32:1318–22.
Walsh DM, Hartley DM, Condron MM, Selkoe DJ, Teplow DB. (2001) In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692
Gly) Alzheimer's disease. Biochem J 355:869–77.[ISI][Medline]
Watson DJ, Selkoe DJ, Teplow DB. (1999) Effects of the amyloid precursor protein Glu693Gln ‘Dutch’ mutation on the production and stability of amyloid beta-protein. Biochem J 340:703–9.
Wechsler D. (1970) Echelle clinique de mémoire. Forme 1. (Edition du Centre de Psychologie Appliquée, Paris).
Yang Q, Rasmussen SA, Friedman JM. (2002) Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet 359:1019–25.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |