Pathological progression of genetic Creutzfeldt–Jakob disease with a PrP V180I mutation

Figures & data

Table 1. Clinicopathological findings of the six patients with V180I genetic Creutzfeldt–Jakob disease.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
Clinical features
Age at onset	87	84	80	78	73	73
Age at death	87	85	82	81	81	81
Sex	Female	Female	Male	Female	Female	Female
Family history	−	−	−	−	−	−
Total disease duration	10 months	20 months	21 months	33 months	101 months	102 months
Initial symptoms	Slow reaction	Numbness, tremor	Right hemiparesis, motor aphasia,	Disorientation	Disorientation	Aphasia
Major symptoms and signs	Dementia, gait disturbance	Dementia	Dementia, tremor	Dementia, abnormal behavior	Dementia	Dementia
Cerebral cortical dysfunction at early disease stage	+	+	+	+	+	+
Visual symptoms at early disease stage	−	−	−	−	−	−
Parkinsonism at early disease stage	−	+	+	+	−	+
Cerebellar symptoms at early disease stage	−	−	−	−	−	−
Myoclonus	−	+	+	+	+	+
Akinetic mutism state (Time to reach)	−	+ (5 months)	+ (9 months)	+ (16 months)	+ (20 months)	+ (22 months)
Cause of death	Respiratory failure	Respiratory failure	Pneumonia	Respiratory failure	Respiratory failure	Respiratory failure
MRI study
MRI study	+ (1 months after the onset)	+ (4 months after the onset)	+ (10 months after the onset)	+ (8 months after the onset)	N.E.	+ (42 months after the onset)
Swelling of the cerebral cortex (T2-weighted image)	+	+	+	+	N.E.	+
DWI hyperintensity (Observed region)	+ (cerebral cortex, basal ganglia)	+ (cerebral cortex, basal ganglia)	N.E.	+ (cerebral cortex, basal ganglia)	N.E.	+ (cerebral cortex)
Cerebral white matter lesion	−	−	−	+	N.E.	−
CSF study
NSE (ng/mL)	N.E.	N.E.	29.9	25	N.E.	17.8
14-3-3 protein (μg/mL)	N.E.	697	N.E.	1435	N.E.	3423
Total tau (pg/mL)	N.E.	> 1200	N.E.	1370	N.E.	5474
EEG study
PSWC	−	−	−	−	−	−
Slowing	+	+	+	+	+	+
PrP gene analysis
Codon 129 polymorphism	Met/Met	Met/Met	Met/Val	Met/Met	Met/Met	Met/Met
Codon 219 polymorphism	Glu/Glu	Glu/Glu	Glu/Glu	Glu/Glu	Glu/Glu	Glu/Glu
Pathological findings
Brain weight (g)	1050	1150	1060	750	600	720
Spongiform degeneration	Widely	Widely	Widely	Widely	Widely	Widely
in the cerebral cortex	observed	observed	observed	observed	observed	observed
PrP immunostaining	Very weak and synaptic	Very weak and synaptic	Very weak and synaptic	Very weak and synaptic	Very weak and synaptic	Very weak and synaptic
Neurofibrillary tangles	Braak stage II	Braak stage I	Braak stage II	Braak Stage II	Braak stage II	Braak stage IV
Senile plaques	CERAD stage C	CERAD stage B	CERAD stage 0	CERAD stage 0	CERAD stage 0	CERAD stage A
Western blot analysis of PrP	Characteristic pattern	Characteristic pattern	Characteristic pattern	Characteristic pattern	Characteristic pattern	Characteristic pattern

DWI, diffusion-weighted image; NE, not examined; NSE, neuron-specific enolase; EEG, electroencephalogram; PSWC, periodic sharp-wave complexes; Met, methionine; Val, valine; Glu, glutamic acid; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PrP, prion protein; CERAD, Consortium to Establish a Registry for Alzheimer's disease

Table 2. Clinicopathological findings of the three patients with MM1 type and two patients with MM2C type sporadic Creutzfeldt–Jakob disease.

	Patient 7	Patient 8	Patient 9	Patient 10	Patient 11
Type of CJD	MM1	MM1	MM1	MM2C	MM2C
Clinical features
Age at onset	88	82	80	68	67
Age at death	88	82	81	68	67
Sex	Female	Male	Female	Male	Male
Family history	−	−	−	−	−
Total disease duration	4 months	5 months	5 months	5 months	5 months
Initial symptoms	Left hemiparesis	Disorientation	Aphasia, right hemiparesis	Dementia	Dementia
Major symptoms and signs	Dementia, dysbasia	Dementia	Right hemiparesis, dementia	Dementia	Dementia
Cerebral cortical dysfunction at early disease stage	+	+	+	+	+
Visual symptoms at early disease stage	−	−	−	−	−
Parkinsonism at early disease stage	−	−	−	−	−
Cerebellar symptoms at early disease stage	−	−	−	−	−
Myoclonus	+	+	+	+	+
Akinetic mutism state (Time to reach)	+ (1 month)	+ (3 month)	+ (2 month)	+ (5 months)	+ (5 months)
Cause of death	Pneumonia	Pneumonia	Respiratory failure	Respiratory failure	Respiratory failure
MRI study
MRI study	+ (2 months after the onset)	+ (1 months after the onset)	+ (3 months after the onset)	+ (5 months after the onset)	+ (2 months after the onset)
DWI hyperintensity (Observed region)	+ (cerebral cortex)	+ (cerebral cortex)	+ (cerebral cortex)	+ (cerebral cortex)	+ (cerebral cortex)
Cerebral white matter lesion	−	−	−	−	−
CSF study
NSE (ng/mL)	29.9	145.4	126.3	N.E.	22.4
14-3-3 protein (μg/mL)	4044	4014	12250	N.E.	N.E.
Tau (pg/mL)	2400	> 1200	27870	N.E.	N.E.
EEG study
PSWC	+	+	+	+	+
Slowing	+	+	+	+	+
PrP gene analysis
Codon 129 polymorphism	Met/Met	Met/Met	Met/Met	Met/Met	Met/Met
Codon 219 polymorphism	Glu/Glu	Glu/Glu	Glu/Glu	Glu/Glu	Glu/Glu
Pathological findings
Brain weight (g)	910	960	940	1300	1385
Spongiform degeneration	Widely	Widely	Widely	Widely	Widely
in the cerebral cortex	observed	observed	observed	observed	observed
PrP immunostaining	synaptic	synaptic	synaptic	perivacuolar and coarse plaques	perivacuolar and coarse plaques
Neurofibrillary tangles	Braak stage II/III	Braak stage II/III	Braak stage II	Braak stage I	Braak stage I
Senile plaques	CERAD C	CERAD 0	CERAD 0	CERAD 0	CERAD 0
Western blot analysis of PrP	Type 1	Type 1	Type 1	Type 2	Type 2

DWI, diffusion-weighted image; NE, not examined; NSE, neuron-specific enolase; EEG, electroencephalogram; PSWC, periodic sharp-wave complexes; Met, methionine; Val, valine; Glu, glutamic acid; CJD, Creutzfeldt–Jakob disease; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PrP, prion protein; CERAD, Consortium to Establish a Registry for Alzheimer's disease

Figure 1. Macroscopic findings in patient 5. (A) the lateral aspect of the left cerebral hemisphere. The arrowhead indicates the central sulcus. (B) the left coronal section of the frontotemporal lobe through the anterior commissure from the posterior side. (C) the horizontal cut surface of the brainstem, from the left to the midbrain, pons, and medulla oblongata. (D) the sagittal division plane of the cerebellar vermis.

Figure 2. Microscopic findings of frontal lobe HE staining in patients with V180I genetic Creutzfeldt–Jakob disease (CJD) (A: patient 1, B: patient 2, C: patient 3, D: patient 4, E: patient 5, F: patient 6). Spongiform change is noted. However, neuronal loss and gliosis are mild compared to in sporadic CJD (MM1-type, MM2C-type). Even in patients 5 and 6, neurons remain. Scale bars: 100 μm HE, hematoxylin and eosin.

Table 3. The approximate degree of neocortical pathological findings in the six patients with V180I gCJD.

	Spongiform change	Gliosis	Neuropil rarefaction	Neuronal loss
Patient 1	Severe	Moderate	Mild	Mild
Patient 2	Severe	Moderate	Mild	Mild
Patient 3	Severe	Moderate	Mild	Moderate
Patient 4	Severe	Moderate	Mild	Moderate
Patient 5	Moderate	Severe	Moderate	Severe
Patient 6	Moderate	Severe	Severe	Severe

gCJD, genetic Creutzfeldt–Jakob disease.

Figure 3. Microscopic findings of HE staining of the hippocampus (CA1) (A) and cerebellum (B) in patient 5. Mild neuronal loss, gliosis, and spongiform change are shown. Scale bars: 100 μm HE, hematoxylin and eosin.

Figure 4. Microscopic findings of frontal lobe HE staining in patients 7–11 (A: patient 7, B: patient 8, C: patient 9, D: patient 10, E: patient 11). Fine vacuoles are observed in MM1-type sporadic Creutzfeldt–Jakob disease (sCJD) (A–C). Large confluent vacuoles are observed in MM2C-type sCJD (D, E). Scale bars: 100 μm HE, hematoxylin and eosin.

Table 4. The total number of vacuoles, mean vacuolar major diameter, and the coefficient of variation in all patients.

	Type of CJD	disease duration (months)	Total number of vacuoles	Vacuolar major diameter, Mean ± SD (μm) (range)	Coefficient of variation
Patient 1	V180I gCJD	10	1202	9.92 ± 4.11 (3.12–34.37)	0.41
Patient 2	V180I gCJD	20	1347	9.94 ± 5.26 (3.12–37.50)	0.53
Patient 3	V180I gCJD	21	1250	9.97 ± 4.46 (3.12–34.37)	0.45
Patient 4	V180I gCJD	33	1088	9.74 ± 4.46 (3.12–29.69)	0.46
Patient 5	V180I gCJD	101	726	9.77 ± 3.842 (3.12–26.56)	0.39
Patient 6	V180I gCJD	102	1166	9.75 ± 4.22 (3.12–29.68)	0.43
Patient 7	sCJD (MM1)	4	947	5.99 ± 1.93 (1.56–15.62)	0.32
Patient 8	sCJD (MM1)	5	965	6.16 ± 1.93 (3.12–17.19)	0.31
Patient 9	sCJD (MM1)	5	1142	5.63 ± 2.00 (1.56–15.62)	0.36
Patient 10	sCJD (MM2C)	5	452	13.06 ± 12.76 (3.12–85.94)	0.97
Patient 11	sCJD (MM2C)	5	505	12.68 ± 9.57 (3.12–93.75)	0.76

CJD, Creutzfeldt–Jakob disease; g, genetic; s, sporadic.

Coefficient of variation signifies the evaluation of dispersion of vacuole size.

Figure 5. Comparison of vacuolar diameters in all patients with V180I genetic Creutzfeldt–Jakob disease (gCJD), and MM1-type and MM2C-type sporadic CJD by box-and-whisker plots of vacuole major diameter. The horizontal line inside each box indicates the median value, and the length of the box is the interquartile range (25th–75th percentile). The extremes of the whiskers contain 95% values. Open circles indicate outliers.