Cognitive Impairment and Early-onset Cerebral Amyloid Angiopathy in a Middle-aged Man with a History of Childhood Traumatic Brain Injury

Abstract

We herein report the a 42-year-old man with early-onset cerebral amyloid angiopathy (CAA) and a history of traumatic brain injury and neurosurgery in childhood. Computed tomography revealed cognitive impairment and recurrent lobar intracerebral hemorrhaging. Magnetic resonance imaging indicated cerebral microbleeds, and Pittsburgh compound B positron emission tomography detected brain amyloid deposition, mainly in the region of trauma and occipital lobes. Interestingly, the patient had no genetic predispositions or relevant family history. This case suggests that a single traumatic brain injury or neurosurgery in childhood can cause early-onset CAA.

Introduction

Cerebral amyloid angiopathy (CAA) is characterized by β-amyloid (Aβ) deposits within small- to medium-sized blood vessels in the brain and leptomeningeal spaces. It is the main cause of repeated lobar intracerebral hemorrhaging in older adults and is usually diagnosed based on radiological features, such as cortical microbleeds, superficial siderosis, lobar intracerebral hemorrhaging, and pathological findings (1). The major risk factors for CAA onset include Alzheimer's disease and genetic predisposition. Recently, several cases of early-onset CAA with a history of childhood traumatic brain injury (TBI) and/or neurosurgery have been reported (2-13). CAA was confirmed via a brain biopsy or amyloid positron emission tomography (PET) in these cases.

We herein report a 42-year-old man who presented with cognitive impairment and was diagnosed with CAA via Pittsburgh compound B PET (PiB-PET) associated with a history of TBI in his childhood.

Case Report

We encountered a 42-year-old man who had experienced multiple car accidents due to carelessness while driving and had sometimes lost track of work procedures while working as a caregiver over the past year. He reported difficulty clothing himself properly and remembering people's names after a month of repeated vomiting and sought medical help. He was admitted to our hospital because of intracerebral hemorrhaging.

The patient had no relevant family history but did have a history of TBI from a fall accident suffered at three years old, which had been treated via craniotomy. No information was available regarding the use of cadaveric dura mater during neurosurgery. No remarkable neurological deficits were observed during the post-operative follow-up period.

On admission, he was alert with normal vital signs. A neurological examination indicated executive dysfunction, attention deficit, and memory impairment. He had a Mini-Mental Scale Examination score of 29/30 and a Frontal Assessment Battery score of 10/18. Blood tests showed no notable abnormalities, including coagulation function or antibodies associated with vasculitis. A cerebrospinal fluid (CSF) examination revealed a normal cell count (2 cells/μL with 100% lymphocytes) and normal protein levels (30.1 mg/dL). No embolismic abnormalities were observed on electrocardiography or cardiac ultrasonography. Electroencephalography showed continuous semirhythmic regional delta waves in the right frontal area as well as normal background activity. Brain computed tomography (CT) showed lobar intracerebral hemorrhaging in the right parietal lobe (Figure a). Magnetic resonance imaging (MRI) revealed a posttraumatic lesion in the right frontal lobe and lobar intracerebral hemorrhaging (Figure b), and slight atrophy of the bilateral hippocampi (Figure c) Multiple cortical microbleeds. No remarkable cortical atrophy or superficial siderosis is observed. Magnetic resonance angiography did not reveal any abnormalities in cerebrovascular structure. Technetium-99 ethyl cysteinate dimer single-photon emission CT (^99mTc-ECD SPECT) revealed decreased cerebral blood flow in the right frontal lobe, bilateral occipital lobe, and lobar intracerebral hemorrhaging areas. In addition, the CSF showed a decreased level of amyloid β40 (Aβ40) [3,865.9 pg/mL, mean ± standard deviation (SD): 12,793±4,591 pg/mL], decreased level of Aβ42 (128.7 pg/mL, normal ＞490 pg/mL), normal level of total tau protein (275 pg/mL), and normal level of phosphorylated tau (＜25 pg/mL, normal ＜49 pg/mL). PiB-PET showed diffuse amyloid deposits in the cortices, especially in the hemorrhagic and posttraumatic lesions on MRI (Figure d). A genetic analysis showed no mutation in presenilin-1, presenilin-2, or amyloid precursor protein, including Christchurch mutations. The apolipoprotein E (ApoE) was ε3/3.

Figure.

a: Brain computed tomography (CT) shows lobar intracerebral hemorrhaging in the right parietal lobe. b: Head magnetic resonance imaging (MRI) shows the posttraumatic lesion in the right frontal lobe with lobar intracerebral hemorrhaging. c: MRI shows slight atrophy in the bilateral hippocampi. d: PiB-PET shows diffuse amyloid deposits in the cortices, especially in the hemorrhagic lesion and posttraumatic lesion on MRI.

The patient was diagnosed with early-onset CAA and received strict blood pressure control therapy and cognitive functional rehabilitation. He was discharged on day 22 of hospitalization.

After five months, he presented with the sudden onset of Gerstmann syndrome, optic ataxia, and disorientation. CT indicated lobar cerebral hemorrhaging in the left parietal lobe.

Discussion

We herein report a patient with early-onset CAA and a history of TBI and neurosurgery in early childhood. He had recurrent lobar intracerebral hemorrhaging and multiple cortical microbleeds based on MRI findings as well as amyloid pathology based on PiB-PET findings. Since CAA generally occurs in older adults, the Boston Criteria for the diagnosis of CAA (14) require that the patient be ＞55 years old in the absence of pathologic evidence. According to the new research framework recommended by the National Institute on Aging and the Alzheimer Association (2018-NIA-AA-RF) (15), this case was defined as falling on the AD continuum [A(+)T(-)N(-)]. Thus, the patient was diagnosed with early-onset CAA, without Alzheimer's disease.

The most significant finding of this case was the development of early-onset CAA without risk factors, a genetic predisposition, or any influence other than a history of TBI and neurosurgery in childhood. To our knowledge, 22 cases of early-onset CAA (onset age ＜55 years old) with a history of TBI or neurosurgery in childhood have been reported previously (2-13) (Table). The majority of patients were men, and the mean age at the onset of intracerebral hemorrhaging was 37.2 (range: 27-51) years old. A history of TBI was found in 12 cases. Furthermore, most cases had a history of neurosurgery or cadaveric dura mater grafting in childhood. Amyloid pathology was confirmed by a brain biopsy or PiB-PET. The present case was diagnosed as CAA based on the MRI and PiB-PET findings. PiB-PET can detect parenchymal amyloid deposition in patients with Alzheimer's disease (AD) and CAA in patients with sporadic CAA but without AD (16). Therefore, brain amyloid deposition may have contributed to the cognitive impairments in this case. However, it should be noted that, with the current technology, it is difficult to strictly distinguish whether a ¹¹C-PiB uptake is due to CAA or scattered small diffuse plaques. It is well known that ApoE ε2 is a risk factor for CAA onset, and ApoE ε4 is a risk factor for a poor prognosis after head trauma and an increased incidence of Alzheimer's disease (17). A few cases have been ApoE heterozygotes (ε2/ε4, ε3/ε4), but most cases, including our case, have been ApoE homozygotes (ε3/ε3).

Table.

Characteristics of Reported Patients with Early Onset Cerebral Amyloid Angiopathy.

Reference	sex	TBI (age)	Surgery (age)	Cadaveric dura	Hemorrhage (age)	Diagnosis	ApoE
(2)	M	Childhood	Childhood	No data	38 y.o.	Biopsy	ɛ3/ ɛ3
(3)	M	Childhood	No data	No data	37 y.o.	Biopsy	No data
(3)	M	2 y.o.	No data	No data	42 y.o.	Biopsy	No data
(4)	M	1 y.o.	1 y.o.	No data	32 y.o.	Biopsy	ɛ3/ ɛ3
(5)	F	2 y.o.	2 y.o.	(+)	46 y.o.	Biopsy	ɛ2/ ɛ3
(6)	F	1 y.o.	1 y.o.	(-)	33 y.o.	Biopsy	ɛ3/ ɛ4
(6)	M	(-)	1 y.o.	No data	31 y.o.	Biopsy	ɛ2/ ɛ3
(6)	F	(-)	1 y.o.	No data	36 y.o.	Biopsy	ɛ3/ ɛ4
(7)	M	(-)	11 y.o.	(+)	48 y.o.	Biopsy	ɛ3/ ɛ3
(7)	M	(-)	2 y.o.	(+)	27 y.o.	Biopsy PET	ɛ2/ ɛ3
(7)	F	4 w	3 m	(+)	34 y.o.	PET	ɛ3/ ɛ3
(8)	M	1 y.o.	1 y.o.	(-)	29 y.o.	Biopsy	ɛ3/ ɛ3
(9)	M	(-)	7 m	No data	30 y.o.	Biopsy	ɛ3/ ɛ3
(9)	M	3 m	16 m	No data	30 y.o.	Biopsy	ɛ3/ ɛ3
(10)	M	(-)	4 y.o.	No data	44 y.o.	Biopsy	No data
(10)	M	(-)	3 y.o.	(+)	39 y.o.	Biopsy	ɛ2/ ɛ3
(10)	F	(-)	6 y.o.	(+)	45 y.o.	Biopsy	ɛ3/ ɛ3
(11)	M	5 m	5 m	(+)	34 y.o.	Biopsy	ɛ3/ ɛ3
(12)	M	19 y.o.	10 y.o.	(-)	39 y.o.	No data	No data
(12)	M	4 y.o.	4 y.o.	(+)	37 y.o.	Biopsy	ɛ3/ ɛ3
(12)	M	(-)	2 y.o.	(+)	36 y.o.	Biopsy PET	No data
(13)	F	(-)	2 y.o.	(+)	51 y.o.	Biopsy	ɛ2/ ɛ3
Our case	M	3 y.o.	3 y.o.	No data	42 y.o.	PET	ɛ3/ ɛ3

ApoE: apolipoprotein E, F: Female, M: Male, PET: positron emission tomography, TBI: traumatic brain injury

CAA cases without TBI commonly present with microbleeds mainly in the occipital lobe, whereas the present case had microbleeds mainly in the region of trauma and occipital lobes. Furthermore, PiB-PET revealed Aβ deposition near the site of trauma and intracerebral hemorrhaging.

Potential mechanisms underlying CAA after childhood neurosurgery or TBI have been proposed in previous reports (18). Neuropathological studies of autopsied brains have reported that increased Aβ deposition was detected in iatrogenic Creutzfeldt-Jakob disease via injection of cadaver-derived growth hormone and cadaveric dura mater grafting (19-21). Furthermore, transgenic AD mouse models with intracerebral injection of brain homogenates from AD patients have shown increased Aβ deposition (22). These findings suggest that CAA can be transmitted between individuals through cadaveric dura mater grafts or neurosurgical instruments that contain Aβ aggregates (18). Our patient had a history of neurosurgery; however, the use of a cadaveric dura mater graft during neurosurgery could not be excluded. Another potential mechanism is the disturbance of the Aβ clearance systems due to neurosurgery. According to previous studies on Alzheimer's disease, the glymphatic system and intramural periarterial drainage pathway have been proposed to be involved in the clearance of Aβ (23). Animal experiments have reported that a single TBI increases the production of amyloid precursor protein and decreases the clearance of Aβ in the brain in the short term (24). We speculate that neurosurgery or a single TBI may have contributed to the development of CAA in this patient. However, the effects of TBI on the long-term accumulation of Aβ in the brain and vessel walls need to be investigated.

This case highlights three important clinical issues. First, it is important to consider the potential for CAA onset and assess the cognitive function in patients with a history of TBI or neurosurgery during childhood. Second, PiB-PET can facilitate the diagnosis of early-onset CAA. Third, this case supports the findings of previous studies suggesting that Aβ may be transmitted by neurosurgical procedures or cadaveric dura mater grafting.

The authors state that they have no Conflict of Interest (COI).