Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch Type Dementia in Joost Haan,
MD; Jan
B. K.
Lanser, PhD; Ingrid Zijderveld; Iris G. F.
\s=b\ Sixteen patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type were examined neuropsychologically. Abnormalities were found in all patients, and dementia was present in 12 of them. Three patients were tested twice at an interval of some years. All three exhibited a progressive intellectual deterioration and memory disturbance; in two of them there was no evidence of intercurrent strokes. Cerebral amyloid angiopathy can lead to dementia because it produces multiple focal cerebral lesions, but a chronic ischemic or metabolic effect on brain parenchyma may play a contributing role. (Arch Neurol. 1990;47:965-967)
XJereditary
cerebral hemorrhage amyloidosis-Dutch type (HCHWA-D) is an autosomal domi¬ nant disease leading to recurrent cere¬ bral hemorrhages caused by extensive deposition of amyloid in cortical arte¬ rioles and small leptomeningeal arteries.'·2 The first hemorrhage usu¬ ally occurs between 45 and 60 years of with
age and is lethal in almost two thirds
of
patients.2 Cerebral amyloid angiopathy is also
constant finding in the brains of pa¬ tients with Alzheimer's disease (AD).3 The amyloid, present in the cere¬ bral blood vessels of patients with HCHWA-D is homologous to the ßamyloid deposits found in patients with AD." Therefore, as with AD, HCHWA-D has been classified as a ce¬ rebral ß-amyloid diseased In some of the hypotheses about the pathogenesis of AD, amyloid angiopathy is regarded as the primary lesion, which causes the development of intraparenchymal (se¬ nile plaques) and intraneuronal (neu¬ rofibrillary tangles) amyloid dea
Accepted for publication February 12, 1990. From the Departments of Neurology (Drs Haan and Roos and Ms van der Does) and Neuropsychology (Dr Lanser and Ms Zijderveld), University Hospital, Leiden, the Netherlands. Reprint requests to the Department of Neurology, University Hospital, PO Box 9600, 2300 RC Leiden, the Netherlands (Dr Haan).
van
der
Does; Raymund A. C. Roos
posits.6·7 Although there
are definite clinical differences between patients with HCHWA-D and patients with AD, a study of the former might pro¬ vide information about the effects of amyloid angiopathy on the brain and thus might be used to study the amy¬ loid hypothesis of AD. Thus far, it has been commonly believed that patients with HCHWA-D did not develop de¬ mentia, simply because they did not survive long enough.89 However, we have encountered some patients with HCHWA-D who did survive several hemorrhages and who later became demented.1011 We reviewed the neu¬ ropsychological examinations per¬ formed in patients with HCHWA-D to determine the frequency, severity, and characteristics of this dementia.
PATIENTS AND METHODS Patients
The neuropsychological examinations of 16 patients with HCHWA-D were reviewed. There were 11 male and 5 female patients, with a mean age of 53.8 years (SD, 6.1; range, 45 to 66 years). The diagnosis was based on clinical and genealogical factors; in 2 patients the diagnosis was confirmed by
biopsy specimen obtained during surgical evacuation of a space-occupying hematoma and in 5 patients the diagnosis was con¬ firmed at autopsy. A stroke was the first manifestation of HCHWA-D in all pa¬ tients. Mean age at onset was 40.4 years (SD, 6.6; range, 45 to 56 years), and the mean time between first manifestation and neuropsychological examination was 3.4 years (SD, 3.6; range, 0.5 to 12 years). The time between the final stroke and the neu¬ ropsychological examination was, in all cases, more than 2 months. Neurological examination undertaken during the neu¬ ropsychological investigation revealed fo¬ cal neurological deficits (hemiparesis, hemisensory signs, and/or hemianopia) in 12 patients, with no abnormalities in the re¬ a
maining 4. Computed tomographic (CT) scans performed at the time of the neu¬ ropsychological examination showed corti¬ cal hypodense residual lesions of previous hemorrhages in 14 patients (number of le¬ sions, 1 to 10), and no cortical lesions in 2 patients. Thirteen patients showed diffuse
Downloaded From: http://archneur.jamanetwork.com/ by a Michigan State University User on 06/09/2015
white matter hypodensity on CT scan (in 2 patients this was the only abnormality). Methods
A single neuropsychological examination was performed in 13 patients, and twice in the remaining 3 patients. It included as¬ sessment of the following: 1. Intelligence: the Dutch version of the Wechsler Adult Intelligence Scale12 or the Wechsler Adult Intelligence ScaleRevised.13 2. Mnestic functions: the Wechsler Mem¬ ory Scale, form I,14 and the Knox Cube Im¬ itation Test for Visual Memory.15 3. Language: comprehension, word find¬ ing, naming (31 pictures of the Object Naming Test16), word fluency (word associ¬ ation test using 4 letters U, N, K, and A with a time limit of 60 seconds; score; the sum of the four subtotals), reading, and writing. 4. Calculation: 4 written sums and 20 presented orally (score, the total number of
good responses).
5. Constructional abilities: in addition to
performance subtests of the Wechsler Adult Intelligence Scale, copying of per¬ spective and geometric figures and draw¬ ings. 6. Gnosis and praxis (for schedule see Strub and Black17). The criteria of the Diagnostic and Statis¬ tical Manual of Mental Disorders, ed 3,18 were used to establish the diagnosis of de¬ mentia. The grade of intellectual and mem¬ ory impairment was determined as the dis¬ crepancy between the estimated premorbid IQ, based on education, profession, and in¬ tact abilities," and the current IQ and memory quotient. Impairment was divided into none (discrepancy, 25 points). In addition, two independent observers made a qualitative judgment concerning impairment of spe¬ cific disorders in the areas of calculation, language, constructional abilities, gnosis, and praxis, which was done on the basis of the scores achieved or performance levels in the tests.
Statistics
The Mann-Whitney U test and 2 test with Yates' correction were used for com¬ parison of demented and nondemented pa¬ tients. RESULTS
Results of the neuropsychological examination are listed in Tables 1 and
Table 1.—Clinical,
Radiological, and Neuropsychological Characteristics of
16 Patients With HCHWA-D*
Focal
No. of
WAIS
Age at Onset, y
Neurological
Lesions
,-·-
2/M/55
52
+
5/F/46
45 45
No./Sex/
Age, yt
Deficits
on
CT
WMH
Verbal
Performance
WMS
Dementia
Mild Moderate No No
99
83
91
105
89
79
84
73
112
101 110
106
107
3-93
100
95
103
NP
62
62
4 -
2 -
Diagnosis
Full
+
116
Based
Severe
-
Severe
7/F/53
46
+
10
+
66
9/M/53
52 56 45 54 62 45
+
8
+
105
70
89
99
0
+
69
63
65
74
Moderate Severe
-
+
6
+
98
74
87
89
Mild
+
3
+
54
59
51
MD; Jan
B. K.
Lanser, PhD; Ingrid Zijderveld; Iris G. F.
\s=b\ Sixteen patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type were examined neuropsychologically. Abnormalities were found in all patients, and dementia was present in 12 of them. Three patients were tested twice at an interval of some years. All three exhibited a progressive intellectual deterioration and memory disturbance; in two of them there was no evidence of intercurrent strokes. Cerebral amyloid angiopathy can lead to dementia because it produces multiple focal cerebral lesions, but a chronic ischemic or metabolic effect on brain parenchyma may play a contributing role. (Arch Neurol. 1990;47:965-967)
XJereditary
cerebral hemorrhage amyloidosis-Dutch type (HCHWA-D) is an autosomal domi¬ nant disease leading to recurrent cere¬ bral hemorrhages caused by extensive deposition of amyloid in cortical arte¬ rioles and small leptomeningeal arteries.'·2 The first hemorrhage usu¬ ally occurs between 45 and 60 years of with
age and is lethal in almost two thirds
of
patients.2 Cerebral amyloid angiopathy is also
constant finding in the brains of pa¬ tients with Alzheimer's disease (AD).3 The amyloid, present in the cere¬ bral blood vessels of patients with HCHWA-D is homologous to the ßamyloid deposits found in patients with AD." Therefore, as with AD, HCHWA-D has been classified as a ce¬ rebral ß-amyloid diseased In some of the hypotheses about the pathogenesis of AD, amyloid angiopathy is regarded as the primary lesion, which causes the development of intraparenchymal (se¬ nile plaques) and intraneuronal (neu¬ rofibrillary tangles) amyloid dea
Accepted for publication February 12, 1990. From the Departments of Neurology (Drs Haan and Roos and Ms van der Does) and Neuropsychology (Dr Lanser and Ms Zijderveld), University Hospital, Leiden, the Netherlands. Reprint requests to the Department of Neurology, University Hospital, PO Box 9600, 2300 RC Leiden, the Netherlands (Dr Haan).
van
der
Does; Raymund A. C. Roos
posits.6·7 Although there
are definite clinical differences between patients with HCHWA-D and patients with AD, a study of the former might pro¬ vide information about the effects of amyloid angiopathy on the brain and thus might be used to study the amy¬ loid hypothesis of AD. Thus far, it has been commonly believed that patients with HCHWA-D did not develop de¬ mentia, simply because they did not survive long enough.89 However, we have encountered some patients with HCHWA-D who did survive several hemorrhages and who later became demented.1011 We reviewed the neu¬ ropsychological examinations per¬ formed in patients with HCHWA-D to determine the frequency, severity, and characteristics of this dementia.
PATIENTS AND METHODS Patients
The neuropsychological examinations of 16 patients with HCHWA-D were reviewed. There were 11 male and 5 female patients, with a mean age of 53.8 years (SD, 6.1; range, 45 to 66 years). The diagnosis was based on clinical and genealogical factors; in 2 patients the diagnosis was confirmed by
biopsy specimen obtained during surgical evacuation of a space-occupying hematoma and in 5 patients the diagnosis was con¬ firmed at autopsy. A stroke was the first manifestation of HCHWA-D in all pa¬ tients. Mean age at onset was 40.4 years (SD, 6.6; range, 45 to 56 years), and the mean time between first manifestation and neuropsychological examination was 3.4 years (SD, 3.6; range, 0.5 to 12 years). The time between the final stroke and the neu¬ ropsychological examination was, in all cases, more than 2 months. Neurological examination undertaken during the neu¬ ropsychological investigation revealed fo¬ cal neurological deficits (hemiparesis, hemisensory signs, and/or hemianopia) in 12 patients, with no abnormalities in the re¬ a
maining 4. Computed tomographic (CT) scans performed at the time of the neu¬ ropsychological examination showed corti¬ cal hypodense residual lesions of previous hemorrhages in 14 patients (number of le¬ sions, 1 to 10), and no cortical lesions in 2 patients. Thirteen patients showed diffuse
Downloaded From: http://archneur.jamanetwork.com/ by a Michigan State University User on 06/09/2015
white matter hypodensity on CT scan (in 2 patients this was the only abnormality). Methods
A single neuropsychological examination was performed in 13 patients, and twice in the remaining 3 patients. It included as¬ sessment of the following: 1. Intelligence: the Dutch version of the Wechsler Adult Intelligence Scale12 or the Wechsler Adult Intelligence ScaleRevised.13 2. Mnestic functions: the Wechsler Mem¬ ory Scale, form I,14 and the Knox Cube Im¬ itation Test for Visual Memory.15 3. Language: comprehension, word find¬ ing, naming (31 pictures of the Object Naming Test16), word fluency (word associ¬ ation test using 4 letters U, N, K, and A with a time limit of 60 seconds; score; the sum of the four subtotals), reading, and writing. 4. Calculation: 4 written sums and 20 presented orally (score, the total number of
good responses).
5. Constructional abilities: in addition to
performance subtests of the Wechsler Adult Intelligence Scale, copying of per¬ spective and geometric figures and draw¬ ings. 6. Gnosis and praxis (for schedule see Strub and Black17). The criteria of the Diagnostic and Statis¬ tical Manual of Mental Disorders, ed 3,18 were used to establish the diagnosis of de¬ mentia. The grade of intellectual and mem¬ ory impairment was determined as the dis¬ crepancy between the estimated premorbid IQ, based on education, profession, and in¬ tact abilities," and the current IQ and memory quotient. Impairment was divided into none (discrepancy, 25 points). In addition, two independent observers made a qualitative judgment concerning impairment of spe¬ cific disorders in the areas of calculation, language, constructional abilities, gnosis, and praxis, which was done on the basis of the scores achieved or performance levels in the tests.
Statistics
The Mann-Whitney U test and 2 test with Yates' correction were used for com¬ parison of demented and nondemented pa¬ tients. RESULTS
Results of the neuropsychological examination are listed in Tables 1 and
Table 1.—Clinical,
Radiological, and Neuropsychological Characteristics of
16 Patients With HCHWA-D*
Focal
No. of
WAIS
Age at Onset, y
Neurological
Lesions
,-·-
2/M/55
52
+
5/F/46
45 45
No./Sex/
Age, yt
Deficits
on
CT
WMH
Verbal
Performance
WMS
Dementia
Mild Moderate No No
99
83
91
105
89
79
84
73
112
101 110
106
107
3-93
100
95
103
NP
62
62
4 -
2 -
Diagnosis
Full
+
116
Based
Severe
-
Severe
7/F/53
46
+
10
+
66
9/M/53
52 56 45 54 62 45
+
8
+
105
70
89
99
0
+
69
63
65
74
Moderate Severe
-
+
6
+
98
74
87
89
Mild
+
3
+
54
59
51
