Brain Advance Access originally published online on June 25, 2008
Brain 2008 131(7):1845-1853; doi:10.1093/brain/awn107
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PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease
1Turku PET Centre, University of Turku, Turku, 2Department of Neurology, Helsinki University Central Hospital, Helsinki, 3Department of Psychology, Åbo Akademi University, Turku, 4Department of Pathology, University and University Hospital of Helsinki, Helsinki, 5Department of Neurology, Tampere University Central Hospital, Tampere, 6Department of Geriatrics, University of Turku, Turku, 7Department of Pathology, University of Uppsala, Sweden and 8Departments of Pathology and Forensic Medicine, University of Turku, Finland
Correspondence to: Juha O. Rinne, MD, PhD, Turku PET Centre, University of Turku, PO Box 52, 20521 Turku, Finland E-mail: juha.rinne{at}tyks.fi
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Summary |
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Variant Alzheimer's disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1
E9). VarAD is neuropathologically characterized by the presence of unusually large, Aβ42 positive, non-cored ‘cotton wool’ plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [11C]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [11C]PIB binding to the amount and type of Aβ deposits in another group of deceased VarAD patients’ brains. We studied four patients with VarAD and eight healthy controls with PET using [11C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 60–90 min. Group differences in [11C]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [11C]PIB uptake was compared to the immunohistochemically demonstrated deposition of Aβ in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [11C] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [11C]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43% greater than the mean of the control group. The increases in the anterior (28%) and posterior (27%) cingulate gyrus, occipital cortex (21%) and thalamus (14%) were smaller. All VarAD patients showed this similar topographical pattern of increased [11C]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [11C]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to detect amyloid accumulation in vivo in these patients. The pattern of increased [11C]PIB uptake is different from that described in sporadic Alzheimer's disease and resembles that seen in Alzheimer's disease patients with certain presenilin-1 mutations or amyloid precursor protein gene duplication showing predominantly striatal increase in [11C]PIB uptake.
Key Words: variant Alzheimer's disease; PET; PIB
Abbreviations: AβPP, β-amyloid precursor protein; CWPs, cotton wool plaques; FAD, Familial Alzheimer's disease; GP, Globus pallidus; MMSE, Mini-Mental State Examination; PET, positron emission tomography; PS-1, presenilin 1; ROI, region-of-interest; SPM, Parametric Mapping version; VarAD, Variant Alzheimer's disease
Received December 19, 2007. Revised April 14, 2008. Accepted May 9, 2008.
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Introduction |
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TopSummaryIntroductionPatients and MethodsResultsDiscussionReferences |
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Certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1
E9) are associated with a variant Alzheimer's disease (VarAD). PS-1 mutations alter the processing of the β-amyloid precursor protein (AβPP) so that more Aβ42 (and Aβ43) is produced, PS-1E9 being the most effective of the PS-1 mutations to increase Aβ42/43 production (Mehta et al., 1998
; Houlden et al., 2000).
VarAD is an aggressive form of familial Alzheimer's disease (FAD) and is clinically characterized by especially early and prominent memory disturbances together with visuoconstructive difficulties, which in most patients coexist with or are preceded by spastic paraparesis. VarAD has been reported in a number of Finnish, Australian, British, Belgian and Japanese families (Verkkoniemi et al., 2004). The clinical diagnosis of VarAD may be difficult especially in subjects presenting with paraparesis as the first symptom. The diagnosis can be confirmed by genetic analysis, but in vivo biomarkers are needed to detect Alzheimer's disease process. However, there are no published systematic studies on CSF biomarkers (Aβ or phospho-tau) in patients with VarAD.
The typical neuropathological feature in VarAD is the presence of large ‘cotton wool’ plaques (CWPs) (Houlden et al., 2000; Verkkoniemi et al., 2004). These unusually large, eosinophilic plaques are positive for Aβ but are non-cored and devoid of dystrophic neurites (Brooks et al., 2003). Aβ42 is the predominant peptide species of CWP (Yokota et al., 2003). However, the exact cause for the neuronal degeneration in VarAD is unclear. One of the hypotheses is that intraneuronal protofibrils of Aβ, rather than extracellular amyloid deposits, may be the primary cause for the neuronal degeneration (Yokota et al., 2003). Large conglomerates of CWPs are present in the interhemispheric precentral cortex corresponding to the motor representation of the lower extremities, while the more lateral motor area is less severely affected (Verkkoniemi et al., 2001). In addition there is clinical evidence of cerebellar involvement in VarAD, such as clumsiness of hands and dysarthria (Verkkoniemi et al., 2001). However, instead of CWPs scattered amyloid plaques with compact cores are present in the cerebellum. Neuropathological analysis showed in addition to CWPs and cerebral involvement, also degeneration of the corticospinal tracts at the level of the medulla oblongata and spinal cord (Verkkoniemi et al., 2001).
The CWPs are different from those plaques typically seen in sporadic Alzheimer's disease. PIB may have different binding properties to different types of plaques. Transgenic mice studies (Maeda et al., 2007) have suggested that N3(pE) isoform of Aβ is an important PIB binding substrate in vivo. This isoform is abundant in Alzheimer's disease (Harigaya et al., 2000), whereas brains in transgenic mice contain little AβN3(pE) (Guntert et al., 2006). Thus, the detectability of amyloid by [11C]PIB positron emission tomography (PET) seems to be dependent on the accumulation of specific Aβ subtypes (Maeda et al., 2007).
Since in post-mortem brain samples CWPs are weakly fluorescent with thioflavin S (Verkkoniemi et al., 2001), we wanted to find out whether [11C]PIB, which is a thioflavin derivative and has increased uptake in Alzheimer's disease (Klunk et al., 2004; Kemppainen et al., 2006; Edison et al., 2007) and in mild cognitive impairment (Forsberg et al., 2007; Kemppainen et al., 2007), would also show increased uptake and serve as an in vivo biomarker of amyloid pathology in VarAD. Therefore we studied four patients with VarAD with PET using [11C]PIB as a ligand and furthermore compared the in vivo binding of [11C]PIB with the site and type of Aβ deposition in the brains of four deceased VarAD patients.
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Patients and Methods |
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Patients
In the PET studies we examined four patients (one woman and three men, mean age ± SD 53.0 ± 5.5 years, ages 59, 56, 50 and 47 years, referred subsequently as patients #1, #2, #3 and #4) with VarAD and eight healthy controls (six women and two men, mean age ± SD 61.0 ± 4.8 years, range 51–69 years). The Mini-Mental State Examination (MMSE) scores in the patients with VarAD were 16 (Patient #1), 27 (Patient #2), 24 (Patient # 3) and 14 (Patient #4). In healthy controls the mean MSSE score was 28 (range 25–30). All controls had a comprehensive neuropsychological examination which was within normal limits. The patients have had neuropsychological testings earlier and at the time of PET scan CERAD-test was performed. The duration of disease of the VarAD patients from the first symptoms was half a year, 1.5, 7 and 9 years. The deletion mutation of a 4555-bp deletion encompassing exon 9 of the PS-1
E9 was confirmed by genetic analysis at diagnostic laboratory (HUSLAB Laboratory of Molecular Genetics) using essentially the same methods that were described in our previous articles (Crook et al., 1998; Prihar et al., 1999). All participants or their caregivers, or both gave informed consent, and the study was approved by the local ethical committee. In addition we analysed deposition of Aβ in the regions corresponding to the present PET findings in the brains of four previously reported, deceased VarAD patients (Verkkoniemi et al., 2001). The degree of dementia ranged from moderate to severe in different patients when measured by the combination of three scales MMSE, CDR and GDS-FAST. However, in the GDS-FAST the walking difficulty grade has been systematically ignored because in contrast with sporadic Alzheimer's disease, spastic paraparesis causing walking difficulties is seen early in the course of this type of Alzheimer's disease.
In addition, extensive neuropsychological examination had been performed to all patients by using the same neuropsychological test battery that has been previously used to study patients carrying this same mutation (Verkkoniemi et al., 2004). All four patients had walking difficulties due to spastic paraparesis, but the severity of spastic paraparesis ranged from mild walking difficulties to the need of electric wheelchair. Two other patients had spastic paraparesis that reduced their functional ability but they were able to walk without aid. The patient with the mildest dementia of these patients had the most severe form of paraparesis. In order to live alone, he needed wheelchair inside and electric wheelchair outside home. Brisk tendon reflexes were found in all patients at the neurological examination. Impaired fine coordination of one or both hands and dysdiadochokinesis was present in 4/4 patients. None of the patients had psychiatric symptoms. Brief clinical descriptions of the patients are given below.
Patient #1
A 59-year-old woman with severe dementia (MMSE score 16, CDR 3, GDS-FAST 6d) and severe spastic paraparesis and bilateral spontaneous Babinsky sign. She needs a wheelchair and continuous help from her spouse. She has impaired coordination of the right hand. She cannot move from the wheelchair by herself and she needs help in all personal functions. In addition, she has difficulties in swallowing, her speech is moderately dysartric and she has urinary incontinence but her social ability has preserved and she does not have psychiatric symptoms. Neuropsychological examination is no longer possible, but she had neuropsychological examination done at the beginning of her disease. At that time she had slight problems in memory and visuoconstructional functions. The more detailed results have been described in a previous article where this patient is referred as Patient 2 (Verkkoniemi et al., 2004). Education: 6 years of comprehensive school and 2 years of vocational school. Duration of the disease: she experienced first walking difficulties in the 1997, but at first it was thought to be caused from bilateral hallux valgus. VarAD was diagnosed in August 1999.
Patient #2
A 56-year-old man has mild dementia (MMSE score 27, CDR 1,GDS-FAST 4), but functional decline is mainly due to severe spastic paraparesis. He needs a wheelchair and electric wheelchair to be able to live alone, but he is mentally and socially active in organizations and takes care of all ADL except cleaning. Education: 6 years of comprehensive school and 2 years of vocational school. Duration of the disease: in the spring 2000 the right leg became spastic and gradually walking and balance difficulties progressed. The neurological examination: dysdiadochokinensis of the left hand and clumsiness and impairment of fine coordination of the left hand. Spastic paraparesis and exaggerated knee jerks and clonic ankle jerks were present. Neuropsychological findings: moderate impairment of memory and attention and mild visuoconstructive and executive decline and mild naming problems. No psychiatric symptoms.
Patient #3
A 50-year-old man with mild dementia (MMSE score 24, CDR 1, GDS-FAST 4) and moderate spastic paraparesis. Neuropsychological examination showed remarkable impairment of memory, especially in the episodic memory and decline in the visuoconstructive functions. In addition, he had expressive dysphasia and difficulties in naming. He was able to walk slowly without walking aid, but fell occasionally. Education: 6 years of comprehensive school and 2 years of vocational school. Duration of the disease from the first symptoms: first memory problems and stiffness of the left leg started in 2001. The spastic paraparesis was evident in 2005. VarAD was diagnosed in February 2006. The neurological examination showed abnormal diadochokinesis of both hands, more on the left. Fine coordination of hands was impaired. Bilateral clonus of knee and ankle jerks was present due to spastic paraparesis. He did not have rigidity, or resting tremor but he was slightly hypomimic. No psychiatric symptoms.
Patient #4
A 47-year-old man who has moderate dementia (MMSE score 14, CDR 2, GDS-FAST 5). He had 9 years of basic education in the comprehensive school after which he had been working for 30 years until his disease progressed and disabled him. Neuropsychological examination showed severe impairment in memory, visuoconstructional, spatial and executive functions. In addition, he has diminished speech, and verbal fluency, acalculia, agraphia and dyslexia. He had mental inactivity due to remarkable cognitive decline but psychiatric symptoms were not present. When the PIB-PET was performed his spastic paraparesis became evident only after several hundred meters of walk but he did not need walking aids. His spastic paraparesis has now progressed but he can still manage without walking aid. The neurological examination showed clonus of knee and ankle jerks due to spasticity.
Hypereflexia, clumsiness and abnormal diadochokinesis of the left arm was seen. Finger-to-nose-tests were inaccurate on both sides but the reflexes of the right arm were normal. Rigidity or tremor was not present, but the appearance of his face was slightly hypomimic. Duration of the disease: first cognitive problems in summer 2005, mild walking difficulties from winter 2006. Diagnosis of varAD in January 2007.
PET imaging
All subjects underwent a 90 min dynamic PET imaging with GE Advance PET scanner (General Electric Medical Systems, Milwaukee, Wisconsin, USA) in the 3D scanning mode. Dynamic images were computed into quantitative parametric images using either cerebellum or pons as a reference area. Parametric images representing [11C]PIB uptake in each pixel were calculated as a region-to-cerebellum ratio or as a region-to-pons ratio of the radioactivity concentration over 60–90 min. Since patients with VarAD have also cerebellar plaques (Verkkoniemi et al., 2001), this may render cerebellum vulnerable as a reference area. Therefore, we also calculated the results by using pons as a reference area as demonstrated in a previous publication with PS-1 gene mutation patients (Klunk et al., 2007).
To obtain quantitative regional values, [11C]PIB uptake was analysed with automated region-of-interest (ROI) method as described in detail previously (Kemppainen et al., 2006). Briefly, voxel-based statistical analysis was performed using Statistical Parametric Mapping version 99 (SPM99) and MATLAB 6.5 for Windows (Math Works, Natick, MA). Spatial normalization of individual parametric images was performed using a ligand-specific [11C]PIB template. The preparation of the template and the procedure has been described in detail earlier (Kemppainen et al., 2006). The ROIs for automated ROI analysis were defined using Imadeus software (version 1.50, Forima Inc., Turku, Finland) on a spatially normalized MRI template image representing the same spatial space (MNI template space) as spatially normalized individual [11C]PIB ratio images. ROIs were drawn on the anterior and posterior cingulate gyrus, lateral frontal cortex, caudatus, pons, putamen, thalamus, lateral temporal cortex, parietal cortex, medial temporal lobe, cerebellar cortex and white matter (large bilateral ROIs in six consecutive planes in the periventricular white matter at level of the lateral venricles). The mean regional values of [11C]PIB uptake were calculated in patients with VarAD and healthy controls and the between-group comparison was made using two-sample t-test. In addition, the supplemental between-group SPM analysis comparison was made using two-sample t-test to test the difference in ratio values at voxel-level. The analysis was performed as an explorative analysis covering the whole brain. Atrophy correction was not utilized in image analysis.
Histopathology
The specimens for histopathological analyses were not from the same patients that were scanned with [11C]PIB. Specimens from the caudate, putamen, pallidum, thalamus, cingulate gyrus, cerebellum and pons were collected from the brains of four previously deceased VarAD patients (Verkkoniemi et al., 2001), were used for a comparison between the present in vivo [11C]PIB uptake results and post-mortem Aβ deposition. The brains had been routinely fixed in 4% buffered formaldehyde and selected samples had been embedded in paraffin. Microscopic sections were stained with hematoxylin and eosin, alkaline Congo as well as with modified Bielschowsky and Gallyas silver stains. For immunostaining antibodies to Aβ (mouse monoclonal NCL-B-amyloid, clone 6F3D, Novocastra, Newcastle, U.K., mouse monoclonal to Aβ17–24, clone 4G8, Biodesign, Memphis, TN, USA and rabbit polyclonal to Aβ1–40 and Aβ1–42, Biosource-QCB, Camarillo, CA, USA) were applied after pre-treatment with formic acid. The bound antibodies were visualized using an appropriate peroxidase-labelled secondary antibody ABC kit (Vector Laboratories, Burlingame, CA, USA) with diaminobenzidine or aminoethylcarbazole as the chromogen.
Radioautography
Paraffin sections were deparaffinized in xylene and taken through ethanol to water. Then sections were placed in 0.25% potassium permanganate solution for 10 min, washed with water, treated with solution of 2% potassium metabisulfite and 1% oxalic acid and washed with water again.
Pre-treated sections were preincubated in 2% human serum albumin in phosphate buffer for 10 min, which followed 30 min incubation in 10 nM (0.4 MBq/ml) [11C]PIB in the same buffered albumin solution. After incubation sections were taken through two 2 min washes in the buffered albumin solution and two 2 min washes in phosphate buffer. Finally sections were briefly rinsed in water and rapidly air dried (Klunk et al., 2004).
The sections were apposed to imaging plates (Fuji Imaging Plate BAS-TR2025, Fuji Photo Film Co., Tokyo, Japan) for 2 h. The plates were scanned with a Fuji FLA-5100 laser scanner (Fuji Photo Film Co.). The digital autoradiography images were analysed using the image analysis software AIDA, version 4.06 (Raytest, Straubenhardt, Germany).
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Results |
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PET studies
In both the region-to-cerebellum and region-to-pons ratios the patients with VarAD had at group level significantly higher [11C]PIB uptake than the controls in the caudate nucleus and putamen (striatum) and neocortical brain regions (Table 1).
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In the region-to-cerebellum ratios the most prominent differences were seen in the caudate and putamen where a 43% increase from mean control value was seen. The [11C]PIB uptake in the anterior and posterior cingulate gyrus was also higher in VarAD patients than in the controls (Table 1). However, in the lateral frontal cortex, parietal cortex or lateral temporal cortex there was no significant difference in [11C]PIB uptake between VarAD patients and controls (Table 1). Remarkably, in two areas typically affected in sporadic Alzheimer's disease, i.e. lateral frontal cortex and parietal cortex, the mean [11C]PIB uptake was increased by only 17 and 7%, respectively.
The mean region-to-pons ratios of the VarAD patients and controls were essentially similar as the region-to-cerebellum ratios (Table 1). The most prominent increases in [11C]PIB uptake were seen in the caudate (mean 45%, range 29–71%) and putamen (mean 41%, range 36–49%). The increase of [11C]PIB uptake was also significant in the anterior (mean increase 29%) and posterior (27%) cingulate gyrus. Figure 2 shows increased areas of [11C]PIB uptake in VarAD patients as compared to controls using SPM.
Individually all VarAD patients showed similar pattern of increased [11C]PIB uptake with most prominent differences in comparison to controls in the striatum and posterior and anterior cingulate gyrus (Table 2). However, the percentual increase in region-to-cerebellum ratios varied from 80 to 13% in the caudate and from 58 to 27% in the putamen and in region-to-pons ratios from 71 to 29% in the caudate and from 49 to 36% in the putamen. In region-to-cerebellum ratio the patient having the smallest increase in [11C]PIB uptake as compared to controls (Table 2) had [11C]PIB uptake over 2 SD greater than the control mean in the putamen and occipital cortex. The patient with lowest MMSE score (14) had the highest increase in [11C]PIB uptake as compared to controls.
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Histopathology
The deposition of Aβ in the caudate nucleus, putamen and thalamus had similar pattern (Fig. 1). Widely distributed patchy deposits were immunopositive with both the Aβ1-42 and general Aβ antibody (6F/3E clone), whereas with Aβ1–40 antibody only very few irregular deposits were seen. Most of the deposits corresponded to small diffuse type of plaques, i.e. plaques with irregular contours, devoid of cores and dystrophic neurites. These plaques were different from the larger, sharply outlined CWPs (Fig. 1C and D). No Congo positivity or birefringence was detectable. Remarkably in the pallidum no diffuse type Aβ1–42 deposits were observed, instead small irregular deposits staining strongly with all Aβ antibodies, many of these deposits representing amyloid angiopathy of small arterioles.
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In all cerebral cortices the results were as described earlier (Verkkoniemi et al., 2001
), i.e. a great majority of the plaques were of the cotton wool type (Fig. 2 in Verkkoniemi et al., 2001), strongly immunopositive for Aβ1–42 but only weakly positive for Aβ1–40. In the cingulate cortex, the findings of which have not been previously described, the plaques were similar as elsewhere in the cerebral cortex, though the relative proportion of conglomerate immunopositivity was similarly increased as in the interhemispheric motor cortex (cf. Fig. 2A in Verkkoniemi et al., 2001). In the cerebellum the findings were as described previously, i.e. no CWPs, but scattered cored plaques in the molecular layer and some diffuse plaques in all three layers (Verkkoniemi et al., 2001). Cored and diffuse plaques in approximately similar numbers as in the cerebellum were present in the grey matter of the pons in the post-mortem samples, in concordance with the similar in vivo PIB binding in these two reference regions.
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Figure 3 demonstrates that in sporadic Alzheimer's disease there are diffuse plaques in the nucleus caudatus and putamen, but in lesser degree than in VarAD (cf. Fig. 1A and B). Figure 4 shows as an example radioautographs of [11C]PIB binding to post-mortem tissue sections from the striatum and gyrus cinguli in a previously deceased VarAD patient and a sporadic Alzheimer's disease patient depicting the more abundant binding to the putamen in the VarAD patient compared to that in the sporadic Alzheimer's disease patient.
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Discussion |
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This VarAD caused by a 4555-bp deletion encompassing exon 9 of the PS1 gene was the first mutation that was, in addition to classical Alzheimer's disease findings, shown to be associated with spastic paraparesis and neuropathological CWPs. In this study, we found that patients with VarAD had increased [11C]PIB uptake especially in the striatum and in the anterior and posterior cingulate gyrus, in which locations abundant accumulation of Aβ could be also verified in the brains of deceased VarAD patients. The pattern of increased [11C]PIB uptake is different from that seen in sporadic Alzheimer's disease where most prominent increases are seen in the frontal, parietal and temporal cortices and in the posterior cingulate gyrus. This kind of pattern has been observed by other investigators (Klunk et al. 2004
; Rowe et al., 2007) and also in our previously published series of sporadic Alzheimer's disease patients (Kemppainen et al., 2006), who had been scanned and analysed in an identical way as the current VarAD patients. The findings indicate that [11C]PIB can be used as an in vivo marker to detect amyloid pathology in VarAD.
Previous study of PIB PET of two pedigrees with PS1 missense mutations (C410Y or A426P) carriers has documented that the initial amyloid deposition in these mutation carriers begins in the striatum (Klunk et al., 2007). Interestingly, despite of the fully florid disease and totally different PS1 mutation the PIB PET of deletion mutation patients shows astonishingly similar findings of amyloid deposition in the striatum. VarAD patients have early memory disturbances together with visuoconstructive difficulties and spastic paraparesis or brisk stretch reflexes of lower extremities. Some of our VarAD patients have hypomimia, but do not have overt parkinsonian features despite the clear amyloid deposition in the striatum. Similarly, in sporadic Alzheimer's disease and in early-onset FAD due to PS-1 C410Y or A426P mutations increased striatal amyloid did not lead to clinical extrapyramidal symptoms (Klunk et al., 2007). The reason for the lack of parkinsonian symptoms remains unclear. Revealing factors that protect the striatum from amyloid toxicity in spite of increased accumulation could help in understanding the mechanism of amyloid toxicity and in developing treatments to protect neurons from this effect.
On the other hand, in VarAD clumsiness of hands is a typical sign, which was originally thought to be associated with cerebellar dysfunction, but could as well be due to parkinsonism. Possible rigidity of lower extremities could easily be hidden under the strong spastic paraparesis. Both spastic paralysis and rigidity due to deletion of exon 9 of PS-1 gene have been reported in a Japanese family (Sato et al., 1998). In another Japanese family point mutation G217D in exon 8 of the PS-1 gene caused presenile dementia and parkinsonism with stooped posture, rigidity and bradykinesia (Takao et al., 2002).
Pathologically VarAD is characterized by CWPs. These eosinophilic plaques that are Aβ-positive but non-cored and display no dystrophic neurites are weakly fluorescent with thioflavin S and emerge from the background, but in contrast with neuritic plaques they do not show congophilia/red–green dichroism or bright fluorescent cores. Another previously reported neuropathological feature of VarAD, distinct from classic Alzheimer's disease, is the degeneration of corticospinal tracts, which may be due to the abundance of CWPs particularly in the interhemispheric motor cortex representing the lower extremities. The degeneration of the corticospinal tracts is observed both at the level of the medulla oblongata and in the spinal cord. Furthermore, VarAD differs from classic Alzheimer's disease also because of the presence of many cored amyloid plaques in the cerebellum.
Aβ deposits in the deceased VarAD patients’ caudate, putamen and thalamus were of diffuse type, whereas they were mainly CWPs in the upper layers of the cingulate cortex similarly as in cerebral cortex, but of conglomerate diffuse type in deeper layers. The total burden of Aβ in VarAD patients is heavier in the interhemispheric cortex than in the lateral cerebral cortex (Verkkoniemi et al., 2001). The pattern in the striatum and thalamus differs from that in the above mentioned Japanese patients (Sato et al., 1998; Takao et al., 2002) in whom CWPs were present throughout the cerebral cortex as well as in the caudate nucleus, putamen, claustrum, thalamus, substantia innominata and colliculi. The pattern of striatal and thalamic Aβ deposits in our VarAD patients also differs from that in our sporadic Alzheimer's disease patients, in whom there were clearly fewer diffuse plaques (Fig. 3A and B) and lesser [11C]PIB binding (Fig. 4A and C) relative to the Aβ burden in their cerebral cortex. It is not known, whether the structure of Aβ plaques (diffuse versus CWP) could influence the [11C]PIB uptake, since the histopathological specimens were not from the same individuals that had [11C]PIB PET. In our living patients the highest [11C]PIB uptake was observed in the regions where plaques in the post-mortem brains appeared to be of diffuse type, whereas the uptake was lower in those regions where CWPs predominated. Nonetheless, we believe that CWP also bind [11C]PIB in vivo, since in tissue sections we observed marked in vitro uptake in insular cortex (Fig. 4A), where the great majority of plaques are CWPs. However, CWPs are cut open in tissue sections as opposed to being rounded and compact in vivo. In any case, [11C]PIB uptake is not a specific marker for CWPs but probably binds to several types of plaques. A more detailed analysis is needed and is in progress in our laboratory.
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In addition to the parenchymal deposits, cerebrovascular amyloid could contribute to increased [11C]PIB signal, as suggested in a case report of a patient with post-mortem confirmed dementia with Lewy bodies (Bacskai et al., 2007
). In VarAD amyloid angiopathy is present in leptomeningeal and cortical penetrating blood vessels and is particularly extensive in the precentral cortex and cerebellum. It is seen also in thioflavin S preparations. However, amyloid angiopathy in VarAD is not particularly prominent in the striatum and thus it is unlikely that amyloid angiopathy would have major contribution to the present findings.
In general PS-1 mutations alter AβPP processing so that more Aβ42(43) is produced resulting in a faster disease process and exceptionally severe Alzheimer's disease pathology. Several cultured cells and transgenic animal studies have shown that the over-production of Aβ42(43) is most pronounced in cells expressing a PS-1E9 mutation. In addition to classic neuropathological amyloid plaques, VarAD is associated with CWPs. The abundance of Aβ42 in the putamen, globus pallidus and claustrum indicates disease activity in these brain areas that may correlate with the unusual pattern of [11C]PIB uptake. Interestingly, also in families with other presenilin-1 mutations (C410Y or A426P; Klunk et al., 2007) or amyloid precursor protein gene duplication (Remes et al., 2007) there is a predominant striatal increase of [11C]PIB uptake.
CWP is the predominat type of plaques in VarAD, but classic neuropathological findings are also present. Variable numbers of diffuse and cored plaques appeared in the cerebral cortex and occasional amyloid plaques with compact cores were identified in the cerebellum and pons. However, it is not known at what stage of the disease cerebellar or pontine plaques appear in VarAD, since the deceased patients naturally have died at the late, severe stage of the disease with long duration of illness. Since the presence of cored plaques could lead [11C]PIB binding in the cerebellum and thus bias the uptake ratio, we also calculated the uptake ratio using pons as a reference area, as been demonstrated earlier (Klunk et al., 2007). In our VarAD patients the results were virtually identical regardless whether using cerebellum or pons as a reference area. Moreover, the possible presence of Aβ positive plaques in the cerebellum or pons of our VarAD patients would reduce the absolute region-to-cerebellum or region-to-pons ratios. This could, if anything, make it less likely to see differences between VarAD patients and controls. In spite of this, we saw clearly increased [11C]PIB uptake in VarAD patients. In addition, the possible presence of cerebellar or pontine plaques would not influence the relative differences in [11C]PIB uptake between various brain areas.
In VarAD increased [11C]PIB uptake is seen especially in the striatum being different from the pattern described in sporadic Alzheimer's disease. The reason for particular increase in [11C]PIB uptake in the striatum in VarAD, and in cases with presenilin mutations (Klunk et al., 2007) and AβPP duplication (Remes et al., 2007) deserves further studies.
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References |
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