4. Eldridge R. Inheritance of torsion dystonia in Jews. Ann Neurol 1981;10:203-204 5. Korczyn AD, Ziber N, Kahana E. Alter M. Inheritance of torsion dystonia. Ann Neurol 1981;10:204-205 (Reply) 6. Rosenberg RN, Grossman A. Molecular genetics of Joseph disease in molecular biology of neurological disease. In: Rosenberg RN, Harding AE, eds. Molecular biology of neurological diseGe. London: Rutterworths, 1988:157-159
The cause of leukoencephalopathy in sporadic [ 1) and hereditary {2 ] amyloid angiopathy remains unclear. W e favor chronic hypoperfusion of the deep white matter due to stenosis of long perforating arterioles by A4 deposits as the most likely cause {Z]. Department of Neurology
Uniuersit> Hospital Leiden The Netbedand.r ’Members of the research-group on HCHWA-D, Leiden.
Alzheimer A4 Peptide, Gamma-Trace, Leukoencephalopathy, and Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type Joost Haan, MD,” and Raymund A. C. Roos, M D X The article by Vinters and colleagues { 11 in Amah of Nruroldescribes the colocalization of Alzheimer A4 peptide and gamma-trace in cerebral microvessel walls of patients with sporadic cerebral amyloid angiopathy and leukoencephalopathy. It is mentioned that ‘‘it is of interest that patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show almost exclusively microvascular deposition of an A4-like molecule, yet show clinical features of dementia that closely mimic those experienced by patients with Alzheimer’s disease (AD) or senile dementia of the Alzheimer type.” W e believe that some additional remarks are justified. First, it is important to mention that besides deposition of A4 in the cerebral arterioles, parenchymal A4 positive amorphous plaques are present in HCHWA-D 121. Second, the dementia in HCHWA-D patients more resembles the pattern of “multi-infarct (hemorrhage) dementia” than that of A D 12). Third, immunostaining of cerebral blood vessels of HCHWA-D patients with gamma-trace was discovered several years ago [3}, making HCHWA-D another disease in which Alzheimer A4 peptide and gamma-trace colocalize. Fourth, almost all HCHWA-D patients show evidence of a severe leukoencephalopathy on computed tomography scans of the brain 121. HCHWA-D is caused by a point-mutation in the Alzheimer A4 peptide precursor gene on chromosome 21 14, 51. Thus, although gamma-trace (and alpha,-antichymotrypsin) certainly can play a role in formation o r maintenance of amyloid, or the causation of cerebral hemorrhages [GI, degradation of the abnormal A4 peptide precursor is the underlying abnormality in HCHWA-D. It is therefore most likely that the deposition of gamma-trace, which is normally present in the blood, occurs secondarily after the deposition of A4 peptide. This is supported by the finding that gamma-trace immunoreactivity was confined to the blood vessels and did not occur in parenchymal amyloid deposits 11, 61.
References 1. Vinters HV, Secor DL, Pardridge WM. Gray FG. Immunohstochemical study of cerebral amyloid angiopathy. 111. Widespread Alzheimer A4 peptide in cerebral microvessel walls colocalizes with gamma trace in patients with leukoencephalopathy. Ann Neurol 1990;28:34-42 2. Haan J, Algra PR, Roos RAC. Hereditary cerebral hemorrhage with amyloidosis-Dutch type. Clinical and computed tomographic analysis of 24 cases. Arch Neurol 1990;47:649-653 3. Jensson 0, Thorsteinsson L, Bots GTAM, et al. Immunohistochemical comparison between the Dutch and the Icelandic form of hereditary central nervous system amyloid angiopathy. Acta Neurol Scand 1986;73:312-313 4. Van Broeckhoven C, Haan J, Bakker E, et al. Amyloid p protein precursor gene and hereditary cerehral hemorrhage with amyloidosis (Dutch). Science 1990;248:1120-I122 5 . Levy E, Carman MD, Fernandez-Madrid IJ, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 1990;248:1124-1126 6. Maruvama K, Ikeda S-I, Ishikara T, et d.Immunolustochernicd characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to p protein -and cystatin C. Stroke 1990;21: 397-403
Reply
H. V. Vinters, MD We thank Drs Haan and Roos for their thoughtful comments on our recent publication. They make several valid and significant points. They are correct in stating that Alzheimer A4 or beta-peptide deposits are seen in the amorphous plaques as well as in the amyloidotic microvessels in cerebral cortex of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). Early articles on this entity, some reporting studies from the era before A4 or beta-peptidc immunohistochemistry was routinely applied to tissue sections, nevertheless emphasized that the cortical microvessel walls in the brains from patients with HCHWA-D are the major, if not the onb, site of amyloid deposition [l, 21. These reports also concluded that Jome patients with HCHWA-D presented with a progressive dementing syndrome clinically similar to A D { 1,2], a finding that the Dutch group has recently reaffirmed [ 3 ] . Haan and Roos accurately emphasize that A4 a i d gamma-trace colocalization was previously discovered in cerebral microvessels from these patients, in essence reinforcing the view that we present, namely, that A4 and gamma-trace forms of cerebral amyloid angiopathy (CAA) are not as biochemically distinctive as had been previously thought. The authors may be correct in claiming that degradation of the abnormal A4 peptide precursor is the primary or underlying abnormality in HCHWA-D,
Annals of Neurology
Vol 29 No 3 March 1991 341
The cause of leukoencephalopathy in sporadic [ 1) and hereditary {2 ] amyloid angiopathy remains unclear. W e favor chronic hypoperfusion of the deep white matter due to stenosis of long perforating arterioles by A4 deposits as the most likely cause {Z]. Department of Neurology
Uniuersit> Hospital Leiden The Netbedand.r ’Members of the research-group on HCHWA-D, Leiden.
Alzheimer A4 Peptide, Gamma-Trace, Leukoencephalopathy, and Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type Joost Haan, MD,” and Raymund A. C. Roos, M D X The article by Vinters and colleagues { 11 in Amah of Nruroldescribes the colocalization of Alzheimer A4 peptide and gamma-trace in cerebral microvessel walls of patients with sporadic cerebral amyloid angiopathy and leukoencephalopathy. It is mentioned that ‘‘it is of interest that patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show almost exclusively microvascular deposition of an A4-like molecule, yet show clinical features of dementia that closely mimic those experienced by patients with Alzheimer’s disease (AD) or senile dementia of the Alzheimer type.” W e believe that some additional remarks are justified. First, it is important to mention that besides deposition of A4 in the cerebral arterioles, parenchymal A4 positive amorphous plaques are present in HCHWA-D 121. Second, the dementia in HCHWA-D patients more resembles the pattern of “multi-infarct (hemorrhage) dementia” than that of A D 12). Third, immunostaining of cerebral blood vessels of HCHWA-D patients with gamma-trace was discovered several years ago [3}, making HCHWA-D another disease in which Alzheimer A4 peptide and gamma-trace colocalize. Fourth, almost all HCHWA-D patients show evidence of a severe leukoencephalopathy on computed tomography scans of the brain 121. HCHWA-D is caused by a point-mutation in the Alzheimer A4 peptide precursor gene on chromosome 21 14, 51. Thus, although gamma-trace (and alpha,-antichymotrypsin) certainly can play a role in formation o r maintenance of amyloid, or the causation of cerebral hemorrhages [GI, degradation of the abnormal A4 peptide precursor is the underlying abnormality in HCHWA-D. It is therefore most likely that the deposition of gamma-trace, which is normally present in the blood, occurs secondarily after the deposition of A4 peptide. This is supported by the finding that gamma-trace immunoreactivity was confined to the blood vessels and did not occur in parenchymal amyloid deposits 11, 61.
References 1. Vinters HV, Secor DL, Pardridge WM. Gray FG. Immunohstochemical study of cerebral amyloid angiopathy. 111. Widespread Alzheimer A4 peptide in cerebral microvessel walls colocalizes with gamma trace in patients with leukoencephalopathy. Ann Neurol 1990;28:34-42 2. Haan J, Algra PR, Roos RAC. Hereditary cerebral hemorrhage with amyloidosis-Dutch type. Clinical and computed tomographic analysis of 24 cases. Arch Neurol 1990;47:649-653 3. Jensson 0, Thorsteinsson L, Bots GTAM, et al. Immunohistochemical comparison between the Dutch and the Icelandic form of hereditary central nervous system amyloid angiopathy. Acta Neurol Scand 1986;73:312-313 4. Van Broeckhoven C, Haan J, Bakker E, et al. Amyloid p protein precursor gene and hereditary cerehral hemorrhage with amyloidosis (Dutch). Science 1990;248:1120-I122 5 . Levy E, Carman MD, Fernandez-Madrid IJ, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 1990;248:1124-1126 6. Maruvama K, Ikeda S-I, Ishikara T, et d.Immunolustochernicd characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to p protein -and cystatin C. Stroke 1990;21: 397-403
Reply
H. V. Vinters, MD We thank Drs Haan and Roos for their thoughtful comments on our recent publication. They make several valid and significant points. They are correct in stating that Alzheimer A4 or beta-peptide deposits are seen in the amorphous plaques as well as in the amyloidotic microvessels in cerebral cortex of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). Early articles on this entity, some reporting studies from the era before A4 or beta-peptidc immunohistochemistry was routinely applied to tissue sections, nevertheless emphasized that the cortical microvessel walls in the brains from patients with HCHWA-D are the major, if not the onb, site of amyloid deposition [l, 21. These reports also concluded that Jome patients with HCHWA-D presented with a progressive dementing syndrome clinically similar to A D { 1,2], a finding that the Dutch group has recently reaffirmed [ 3 ] . Haan and Roos accurately emphasize that A4 a i d gamma-trace colocalization was previously discovered in cerebral microvessels from these patients, in essence reinforcing the view that we present, namely, that A4 and gamma-trace forms of cerebral amyloid angiopathy (CAA) are not as biochemically distinctive as had been previously thought. The authors may be correct in claiming that degradation of the abnormal A4 peptide precursor is the primary or underlying abnormality in HCHWA-D,
Annals of Neurology
Vol 29 No 3 March 1991 341
