 |
|
Relation of Quantitative Indexes of Concurrent  -Synuclein Abnormalities to Clinical Outcome in Autopsy-Proven Alzheimer Disease
Roee Holtzer, PhD;
Michael C. Irizarry, MD;
Jody Sanders, BA;
Bradley T. Hyman, MD, PhD;
Domonick J. Wegesin, PhD;
Aliza Riba, BA;
Jason Brandt, PhD;
Marilyn Albert, PhD;
Yaakov Stern, PhD
Arch Neurol. 2006;63:226-230.
ABSTRACT
| |
Background Lewy bodies (LBs) and Lewy neurites are frequent concomitant neuropathologic observations in clinical and neuropathologically defined Alzheimer disease (AD), but their relation to clinical features in AD is uncertain. Most studies used semiquantitative measures to determine the presence or absence of LB abnormalities.
Objective To determine the clinical consequences of LB abnormalities in the setting of AD.
Design Prospective study.
Setting Three outpatient research and treatment centers.
Participants Fourteen autopsy cases with a pathologic diagnosis of AD abnormalities and concomitant LBs followed semiannually for up to 8 years (mean age at intake, 72 years; mean age at death, 77 years; mean education, 15 years; 12 women).
Main Outcome Measures The modified Mini-Mental State Examination was used to assess cognitive function. The Unified Parkinson Disease Rating Scale was used to rate extrapyramidal motor signs. Hallucinations were evaluated using the Columbia University Scale for Psychopathology in Alzheimer's Disease. Time from the first evaluation in which diagnostic criteria for probable AD were met to death was used to determine illness duration. Quantitative measures of LB abnormalities were obtained for the frontal cortex, entorhinal cortex, substantia nigra, and hippocampus.
Results Independent-samples t tests were used to assess whether the degree of LB abnormality varied as a function of the presence or absence of hallucinations and extrapyramidal signs. Pearson r correlations were run to examine whether there was a relation among LB abnormalities, cognitive function, and illness duration. There was no relation between quantitative neuropathologic indexes of LB abnormalities and clinical outcome.
Conclusion The variability of clinical features in AD was not related to the presence or degree of LB abnormalities.
INTRODUCTION
Current consensus guidelines1 for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) represent an attempt to synthesize previous studies of dementia associated with LB abnormalities and to develop uniform diagnostic criteria. These guidelines may be relevant to the diagnosis of Alzheimer disease (AD) given that one third to one half of patients with AD have concomitant LB abnormalities when examined at autopsy.2 Previous studies3-17 produced mixed results when examining the relation of LB abnormalities to clinical features such as extrapyramidal signs (EPSs), psychiatric features, changes in cognitive status, and changes in the course or progression of dementia in patients with confirmed AD.
Stern et al2 reported that LB abnormalities were not related to distinct clinical features in 51 autopsy cases with confirmed AD from the Predictors Study cohort.18-19 However, the negative findings might have been due to limitations of the semiquantitative rating method used to determine the presence or absence of LB abnormalities.
The goal of the present study is to extend the previous observations by studying additional brain areas and types of pathologic lesions. The frontal and entorhinal cortices, the hippocampus, and the substantia nigra were examined for LBs and Lewy neurites. Moreover, we used immunostaining to identify these lesions, systematic random sampling to provide quantitative estimates of LB and Lewy neurite numbers, and image analysis approaches to assess amyloid burden, neurofibrillary tangle number, and neuropil thread number. This allowed us to examine the relation of the pathologic lesions to clinical symptoms and to one another.
METHODS
PARTICIPANTS
The Predictors Study consists of 236 patients with probable AD20-21 who were recruited and studied at 3 sites: 91 patients at Columbia Medical Center, 84 at Johns Hopkins School of Medicine, and 61 at Massachusetts General Hospital. The inclusion and exclusion criteria and evaluation procedures of the Predictors Study have been fully described elsewhere.18-19 At entry into the study, patients were required to have mild-to-moderate dementia, which was operationalized as a modified Mini-Mental State Examination (mMMSE) score of 30 or greater (equivalent to  16 on the Folstein MMSE). Patients were evaluated every 6 months.
Fourteen autopsy cases with adequate blocks for detailed quantitative neuropathologic analysis of LB abnormalities are reported herein. All the participants had cortical neurofibrillary tangles and were Braak stage V or VI; 12 were women and 2 were men. Mean ± SD age at intake was 72 ± 6.6 years and at death was 77 ± 7.7 years. Mean ± SD education was 15 ± 2.4 years. Mean ± SD mMMSE score at entry was 37 ± 7.2, indicating a relatively mild level of dementia. Mean ± SD mMMSE score at the last evaluation was 10.71 ± 10.0. Of the 14 participants, 7 had hallucinations and 10 had EPSs. Mean ± SD illness duration was 10.07 ± 3.91 years. The median ± SD time from the last evaluation to death was 0.61 ± 0.55 year.
MEASURES
Cognition
Cognition was assessed using the mMMSE.22 Modifications to the original MMSE include the addition of digit span forward and backward,23 2 additional calculation items, recall of the current and 4 previous presidents of the United States, confrontation naming of 10 items from the Boston Naming Test,24 1 additional sentence to repeat, and 1 additional figure to copy. The mMMSE has a maximum of 57 points, with lower scores indicating poorer cognitive function.
Extrapyramidal Signs
Selected items from the Unified Parkinson Disease Rating Scale25 were used to rate EPSs. Hypophonia, masked facies, resting tremor, rigidity (neck and each limb), bradykinesia and hypokinesia, and posture and gait abnormalities were rated as absent, slight, mild-moderate, marked, or severe.26 In addition to evaluating individual motor signs, the presence or absence of EPSs in general was considered. Patients who had at least 1 sign rated mild-moderate or worse were considered to have EPSs because ratings of this severity are relatively more reliable and are likely to be noted by most clinicians.26 Our analysis included drug-induced and non–drug-induced EPSs. If, at the visit when EPSs were first detected, the patient was currently taking or had ever taken medications that could induce EPSs, then they were considered to be drug induced; otherwise they were considered to be non–drug induced, even if at subsequent visits the patient received medications that could induce EPSs.
Psychiatric Symptoms
Hallucinations were evaluated using the Columbia University Scale for Psychopathology in Alzheimer's Disease,27 a short, semistructured rating scale that can be administered by clinicians or research technicians. The frame of inquiry is the month before examination.27 Interrater reliability for the major symptom categories was established for concurrent rating of a single interview ( = 0.74-1.00) and for separate interviews ( = 0.53-0.73). The presence or absence of hallucinations at any time during follow-up was used for the present study.
Illness Duration
The time elapsed from the first evaluation in which diagnostic criteria for probable AD were met until death was used to determine the illness duration.
NEUROPATHOLOGIC EVALUATION
Neuropathologic assessments were performed on the substantia nigra, entorhinal cortex, hippocampus, and frontal cortex to survey brainstem, limbic and paralimbic, and neocortical regions with a wide range of susceptibility to LBs, neurofibrillary tangles, and amyloid deposition.8, 28 We selected brain regions representative of lower (hippocampus and frontal cortex), intermediate (entorhinal cortex), and high (substantia nigra) densities of LBs based on studies of Parkinson disease and DLB.3, 8 The availability of pathologic tissue specimens was also considered in selecting the target regions.
Evaluation of LBs
Quantitative neuropathologic studies were conducted in paraffin-embedded sections, 12-µm thick, from the entorhinal cortex, substantia nigra, frontal cortex (middle frontal gyrus), and hippocampus. Sections were stained with antibodies against  -synuclein, which is recognized as a specific immunostain for LB abnormalities.29-30 The LB abnormalities count was performed on adjacent sections for -synuclein using an objective lens (magnification x40) and scanning the whole cortex available for each slide. The total number per volume obtained with each immunostain was compared to further characterize the use of -synuclein in recognizing LBs. The data were recorded using an image analysis system (Bioquant Image Analysis Corp, Nashville, Tenn). This program provides stereologic overlays to assist in estimating the total number of LBs in cortical areas and records the different positions of each of the counted structures using x and y coordinates.
Evaluation of Lewy Neurites
We examined ubiquitin-immunoreactive neuritic degeneration, which is now accepted as a distinctive part of LB abnormality in patients with DLB. These lesions are preferentially present in the CA2 and CA3 regions of the hippocampus, and their extent usually correlates with the density of cortical LBs. These neurites were studied using -synuclein immunostains. An estimate of the total length of abnormal neurites was derived using the stereologic fractionater procedure. Briefly, a "probe" (a special grid that is anisotopic with respect to the boundaries of the field) was overlaid on the video image, and the number of times a neurite crossed a grid line was recorded using the exclusion lines and the top and bottom exclusion planes of the optical disector approach. This number is proportional to the total length of neuritic staining present in a field.
Evaluation of Amyloid Burden, Neuropil Threads, and Neurofibrillary Tangles
Sections were stained for  -amyloid peptide using the antibody 10D5 (Elan Corp, Dublin, Ireland) with diaminobenzidine visualization.31 The percentage of cortex covered by senile plaques was assessed in a region 700 µm wide x the depth of the cortex. Neuropil threads were assessed using AT8 anti–paired helical filament tau immunostaining and a probe overlaid on the videotape display analogous to that described for Lewy neurite assessments. Neurofibrillary tangles stained with AT8 anti–phospho-tau were counted in a 700-µm-wide region of full cortical thickness using the optical disector technique.31-32
RESULTS
We used t tests for independent samples to assess whether the degree of LB and Lewy neurite abnormalities in each of the 4 locations varied as a function of the presence or absence of hallucinations and EPSs (Table 1). There was no difference in the extent of these pathologic features as a function of hallucinations or EPS status. Although not significant, LB abnormalities in the entorhinal cortex and Lewy neurites in the substantia nigra were greater in individuals with EPSs.
|
|
|
|
Table 1. Relation of Lewy Body and Lewy Neurite Abnormalities to Hallucination and Extrapyramidal Sign Status
|
|
|
Pearson r correlations were calculated to examine whether there was a relation between LB and Lewy neurite abnormalities and 3 continuous measures: mMMSE score from the last examination, rate of cognitive decline (operationalized as the difference between the first and last mMMSE scores), and illness duration (Table 2). There were no significant relationships between LB or Lewy neurite abnormalities and any of the 3 clinical features. Although not significant, Lewy neurites in the entorhinal cortex and substantia nigra tended to be inversely related to cognitive status.
|
|
|
|
Table 2. Simple Bivariate Correlations Between Lewy Body and Lewy Neurite Abnormalities and 3 Clinical Features
|
|
|
We also considered that the relation of LB or Lewy neurite abnormalities and clinical features could be mediated or modified by the relative presence of other AD-related abnormalities. To test this issue, separate regression models were run using 2 separate neuropathologic indexes as predictors. Lewy body abnormalities served as the first predictor (LB or Lewy neurite). The second predictor was an additional neuropathology index (amyloid burden, neuropil threads, or neurofibrillary tangles) from the same brain region. Duration of illness, last mMMSE score, and rate of cognitive decline served as the dependent measures. These regression analyses were not statistically significant, suggesting that the lack of association between LB abnormalities and clinical features was not confounded by the relative presence of other AD abnormalities.
COMMENT
Previous research2 using the Predictors Study cohort did not demonstrate a significant association between LB abnormalities and clinical features in postmortem cases with a confirmed diagnosis of AD, but that study used a semiquantitative rating method as opposed to a detailed quantitative neuropathologic analysis. The present study found no relation between quantitative neuropathologic indexes of LB abnormalities and clinical outcomes, including hallucinations, EPSs, illness duration, cognitive status at the last examination, and rate of cognitive decline.
A major contribution of the present study lies in the detailed neuropathologic analyses used to determine the presence and degree of LB abnormalities in 4 brain regions: the entorhinal cortex, substantia nigra, frontal cortex, and hippocampus. Both LB and Lewy neurite abnormalities were assessed using sections that were stained with antibodies to -synuclein, which is increasingly recognized as a more specific immunostain for LB-related neuropathologic disorders.29-30 Furthermore, we evaluated the possibility that statistical suppression may underlie the lack of association between LB abnormalities and clinical outcome. However, consistent with previous findings,2 the association between LB abnormalities and 5 selected clinical features remained statistically nonsignificant.
We originally predicted that the presence or absence, quantity, and distribution of LB abnormalities might represent a major underlying cause of observed differences in the disease course of patients with the clinical diagnosis of probable AD. Although there had been some early reports of a relationship between LB abnormalities counts in several cortical areas and dementia severity,13, 33-35 other researchers did not find such relationships.8, 36-37 Furthermore, the neuropathologic basis of dementia is unclear even in pure DLB because neuronal loss and synaptophysin levels do not correlate with clinical symptoms.38 In the present study, using quantitative evaluation of LB abnormalities, we found no evidence that the variability of clinical features in AD is related to the presence or degree of LB abnormalities, suggesting that "incidental" LBs in AD may be truly incidental. On the other hand, the clinically significant moiety may not be -synuclein aggregated as LBs, per se, but rather as soluble or oligomerized forms of -synuclein, which were not quantitated in this study.39-41
The present sample did not include patients encompassing the full clinical spectrum of DLB. Instead, patients in this study received a clinical diagnosis of AD and were determined to have mild-to-moderate impairments. Moreover, initially, patients were evaluated for complaints about cognitive but not motor function. Hence, the clinicopathologic relations reported herein are relevant to the question of whether clinical outcome in patients with AD varies as a function of the presence and the degree of LB abnormalities in this patient population.
The strict selection criteria limited the number of autopsy cases and, consequently, our power to see effects of even a moderate size. In light of these circumstances, liberal statistical criteria were used to determine whether the relation of LB abnormalities to distinct clinical features was significant. The actual noted effect size for any relationship was very small. Thus, it is not clear whether increasing the number of participants would have yielded an association between LB abnormalities and the selected clinical outcomes. It is possible that LB abnormalities in other brain regions (eg, the amygdala and the cingulate cortex) may be more critical. However, the detailed quantitative evaluation of LB abnormalities, careful prospective clinical follow-up, and consistency with previous findings that relied on a much larger sample size2 suggest that the variability of clinical features in AD is not related to the presence or degree of LB abnormalities.
AUTHOR INFORMATION
Correspondence: Yaakov Stern, PhD, Sergievsky Center, Columbia University College of Physicians and Surgeons, 630 W 168th St, P & S Box 16, New York, NY 10032 (ys11{at}columbia.edu).
Accepted for Publication: September 22, 2005.
Author Contributions: Study concept and design: Holtzer, Hyman, Albert, and Stern. Acquisition of data: Irizarry, Sanders, Hyman, Riba, Albert, and Stern. Analysis and interpretation of data: Holtzer, Irizarry, Hyman, Wegesin, Brandt, and Stern. Drafting of the manuscript: Holtzer, Irizarry, and Sanders. Critical revision of the manuscript for important intellectual content: Holtzer, Irizarry, Hyman, Wegesin, Riba, Brandt, Albert, and Stern. Statistical analysis: Holtzer and Stern. Obtained funding: Hyman, Albert, and Stern. Administrative, technical, and material support: Irizarry, Sanders, Hyman, Wegesin, Riba, and Brandt. Study supervision: Irizarry, Hyman, Albert, and Stern.
Author Affiliations: Sergievsky Center (Drs Holtzer, Wegesin, and Stern and Ms Riba) and Departments of Neurology and Psychiatry (Dr Stern), Columbia University College of Physicians and Surgeons, New York, NY; Ferkauf Graduate School of Psychology and Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, New York (Dr Holtzer); Departments of Psychiatry and Neurology, Massachusetts General Hospital, Harvard Medical Center, Boston (Drs Irizzary, Hyman, and Albert and Ms Sanders); and Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Md (Dr Brandt).
REFERENCES
| |
1. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47:1113-1124.
FREE FULL TEXT
2. Stern Y, Jacobs D, Goldman J, et al. An investigation of clinical correlates of Lewy bodies in autopsy-proven Alzheimer disease. Arch Neurol. 2001;58:460-465.
FREE FULL TEXT
3. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease–related pathology. Cell Tissue Res. 2004;318:121-134.
FULL TEXT
|
ISI
| PUBMED
4. Ballard CG, Jacoby R, Del Ser T, et al. Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with Lewy bodies. Am J Psychiatry. 2004;161:843-849.
FREE FULL TEXT
5. Serby M, Brickman AM, Haroutunian V, et al. Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease. Am J Geriatr Psychiatry. 2003;11:371-374.
FREE FULL TEXT
6. Del Ser T, Hachinski V, Merskey H, Munoz DG. Clinical and pathologic features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer-type lesion load. Alzheimer Dis Assoc Disord. 2001;15:31-44.
FULL TEXT
|
ISI
| PUBMED
7. Lopez O, Wisniewski S, Hamilton RL, Becker JT, Kaufer DI, DeKosky ST. Predictors of progression in patients with AD and Lewy bodies. Neurology. 2000;54:1774-1779.
FREE FULL TEXT
8. Gomez-Tortosa E, Newell K, Irizarry MC, Sanders JL, Hyman BT. -Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining. Acta Neuropathol (Berl). 2000;99:352-357.
FULL TEXT
| PUBMED
9. Haroutunian V, Serby M, Purohit DP, et al. Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer disease neuropathological conditions. Arch Neurol. 2000;57:1145-1151.
FREE FULL TEXT
10. Heyman A, Fillenbaum G, Gearing M, et al. Comparison of Lewy body variant of Alzheimer's disease with pure Alzheimer's disease. Neurology. 1999;52:1839-1844.
FREE FULL TEXT
11. Connor DJ, Salmon DP, Sandy TJ, Galasko D, Hansen LA, Thal LJ. Cognitive profiles of autopsy-confirmed Lewy body variant vs pure Alzheimer's disease. Arch Neurol. 1998;55:994-1000.
FREE FULL TEXT
12. Olichney JM, Galasko D, Salmon DP, et al. Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology. 1998;51:351-357.
FREE FULL TEXT
13. Samuel W, Alford M, Hofstetter CR, Hansen L. Dementia with Lewy bodies versus pure Alzheimer's disease: differences in cognition, neuropathology, cholinergic dysfunction, and synaptic density. J Neuropathol Exp Neurol. 1997;56:499-508.
ISI
| PUBMED
14. Galasko D, Katzman R, Salmon DP, Hansen L. Clinical and neuropathological findings in Lewy body dementias. Brain Cogn. 1996;31:166-175.
FULL TEXT
|
ISI
| PUBMED
15. McKeith IG, Perry RH, Fairbairn AF, et al. Operational criteria for senile dementia of Lewy body type (SDLT). Psychol Med. 1992;22:911-922.
ISI
| PUBMED
16. Forstl H, Burns A, Luthert PJ, Cairns N, Levy R. The Lewy-body variant of Alzheimer's disease: clinical and pathological findings. Br J Psychiatry. 1993;162:385-392.
FREE FULL TEXT
17. Hansen L, Salmon D, Galasko D, et al. The Lewy body variant of Alzheimer's disease: a clinical and pathological entity. Neurology. 1990;40:1-7.
FREE FULL TEXT
18. Stern Y, Albert SM, Sano M, et al. Assessing patient dependence in Alzheimer's disease. J Gerontol. 1994;49:M216-M222.
ISI
| PUBMED
19. Richards M, Folstein M, Albert M, et al. Multicenter study of predictors of disease course in Alzheimer disease (the "Predictors Study"), II: neurological, psychiatric, and demographic influences on baseline measures of disease severity. Alzheimer Dis Assoc Disord. 1993;7:22-32.
ISI
| PUBMED
20. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939-944.
FREE FULL TEXT
21. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Washington, DC: American Psychiatric Press Inc; 1987.22. Stern Y, Sano M, Paulson J, Mayeux R. Modified Mini-Mental State Examination: validity and reliability [abstract]. Neurology. 1987;37(suppl 1):179.
FREE FULL TEXT
23. Wechsler D. Wechsler Adult Intelligence Scale–Revised. New York, NY: Psychological Corp; 1981.24. Kaplan E, Goodglass H, Weintraub S. Boston Naming Test. Philadelphia, Pa: Lea & Febiger; 1983.25. Stern MB, Hurting HI. The clinical characteristics of Parkinson's disease and parkinsonian syndromes: diagnosis and assessment. In: The Comprehensive Management of Parkinson's Disease. New York, NY: PMA Corp; 1978:3-50.26. Richards M, Marder K, Bell K, Dooneief G, Mayeux R, Stern Y. Interrater reliability of extrapyramidal signs in a group assessed for dementia. Arch Neurol. 1991;48:1147-1149.
ABSTRACT
27. Devanand DP, Miller L, Richards M, et al. The Columbia University Scale for Psychopathology in Alzheimer's Disease. Arch Neurol. 1992;49:371-376.
ABSTRACT
28. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb Cortex. 1991;1:103-116.
FREE FULL TEXT
29. Irizarry M, Growden M, Gomez-Isla T, et al. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain -synuclein immunoreactivity. J Neuropathol Exp Neurol. 1998;57:334-337.
ISI
| PUBMED
30. Spillantini MG, Schmidt ML, Lee VM, Jakes R, Trojanowski JQ, Goedert M. Alpha-synuclein in Lewy bodies [letter]. Nature. 1997;388:839-840.
FULL TEXT
| PUBMED
31. Gomez-Isla T, Wasco W, Pettingell WP, et al. A novel presenilin-1 mutation: increased -amyloid and neurofibrillary changes. Ann Neurol. 1997;41:809-813.
FULL TEXT
|
ISI
| PUBMED
32. Ingelsson M, Fukumoto H, Newell KL, et al. Early A accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925-931.
FREE FULL TEXT
33. Lennox G, Lowe J, Landon M, et al. Diffuse Lewy body disease: correlative neuropathology using anti-ubiquitin immunocytochemistry. J Neurol Neurosurg Psychiatry. 1989;52:1236-1247.
ABSTRACT
34. Lennox G, Lowe J, Morrell K, Landon M, Mayer R. Antiubiquitin immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease. J Neurol Neurosurg Psychiatry. 1989;52:67-71.
ABSTRACT
35. Samuel W, Galasko D, Masliah E, Hansen LA. Neocortical Lewy body counts correlate with dementia in the Lewy body variant of Alzheimer's disease. J Neuropathol Exp Neurol. 1996;55:44-52.
ISI
| PUBMED
36. Perry R, Jaros EB, Irving D. et al. What is the neuropathological basis of dementia associated with Lewy bodies? In: Perry RMIPE, ed. Dementia With Lewy Bodies: Clinical, Pathological and Treatment Issues. New York, NY: Cambridge University Press; 1996:212-223.37. Gomez-Tortosa E, Newell K, Irizarry MC, Albert M, Growdon JH, Hyman BT. Clinical and quantitative pathologic correlates of dementia with Lewy bodies. Neurology. 1999;53:1284-1291.
FREE FULL TEXT
38. Hansen LA, Daniel SE, Wilcock GK, Love S. Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia. J Neurol Neurosurg Psychiatry. 1998;64:653-656.
FREE FULL TEXT
39. Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant -synuclein linked to early-onset Parkinson disease. Nat Med. 1998;4:1318-1320.
FULL TEXT
|
ISI
| PUBMED
40. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT Jr. Acceleration of oligomerization, not fibrillization, is a shared property of both -synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci U S A. 2000;97:571-576.
FREE FULL TEXT
41. Bodles AM, Guthrie DJ, Greer B, Irvine GB. Identification of the region of non-A component (NAC) of Alzheimer's disease amyloid responsible for its aggregation and toxicity. J Neurochem. 2001;78:384-395.
FULL TEXT
|
ISI
| PUBMED
|
