Development of the Dementia Caregiver Positive Feeling Scale 21-item version (DCPFS-21) in Japan to recognise positive feelings about caregiving for people with dementia.

BACKGROUND: This study aimed to develop and validate the Dementia Caregiver Positive Feeling Scale 21-item version (DCPFS-21) in Japan. METHODS: We selected and generated 27 items based on the preliminary 25-item version of the DCPFS. Next, the DCPFS-21 was developed and validated through two phases. In Phase 1, we obtained data from 147 caregivers of people with dementia by using the 27-item version, examined the construct validity and internal consistency of the scale and then selected 21 items (DCPFS-21). In Phase 2, we compared the scores of 30 caregivers of people with dementia on the DCPFS-21 with the standard scales. Four weeks after the first examination, we re-examined the intra-rater reliability. RESULTS: In Phase 1, via factor analysis, we reduced the 27 items to 21 items (DCPFS-21). Moreover, the DCPFS-21 was grouped into four subscales, namely, meaning in caregiving, caregiving mastery, positive emotion on caregiving and support from others. This classification agreed with the following factors extracted from the pilot study. The DCPFS-21 showed good internal consistency (Cronbach's α = 0.92). In Phase 2, the DCPFS-21 correlated with the Caregiving Gratification Scale by 0.54 (P < 0.01). The DCPFS-21 also showed good intra-rater reliability (1.1: ρ = 0.62). CONCLUSION: We developed and validated the DCPFS-21, which measures the positive feelings of family caregivers of people with dementia, in Japan.

Grip force control during object manipulation in cervical myelopathy.

STUDY DESIGN: Cross-sectional research. OBJECTIVES: To objectively evaluate grip force (GF) control while holding a freely movable object in individuals with cervical myelopathy (CM). SETTING: Harunaso Hospital, Takasaki, Japan. METHODS: We studied 52 hands from 26 individuals with CM. Participants performed a grip-and-lift task by pulp pinch using the thumb and index finger before surgery. We monitored individual finger GF (N) during the first 3 s while lifting and holding an object. Correlations between the GF and other clinical tests were evaluated. A multiple stepwise regression analysis was used to examine the contribution of the GF to the severity of clinical symptoms. RESULTS: Thumb GF was negatively correlated with the 10-s test (rs = -0.32), and index finger GF was positively correlated with its cutaneous pressure threshold (rs = 0.34). Multiple regression for the severity of upper extremity symptoms revealed that the model including the GF had a larger adjusted R2 and a lower AIC value than that of conventionally used clinical tests. CONCLUSIONS: These results suggested that the assessment of individual finger GF control could provide an indicator of the clinical severity of upper extremity in individuals with CM.

Increased center of pressure trajectory of the finger during precision grip task in stroke patients.

The aim of this study was to assess the spatial stability of stroke patients while holding a freely movable object. Twenty-two acute stroke patients with mild hand impairment performed a grip and lift task using the thumb and index finger. The displacement of the center of pressure (COP) trajectory, the grip force (GF) and several clinical parameters were monitored. Although the GF was not different between paretic and nonparetic hands, the COP trajectory of the paretic index finger was increased. Moreover, the COP trajectories of the thumb and index finger in hemorrhagic patients were longer than those in ischemic patients. These discrepancies between kinetic parameters suggest that different aspects of grip force control may be considered in patients with mild stroke.

Changes in reaching skill in patients with cervical spondylosis after cervical decompression surgery.

[Purpose] The aim of this study was to evaluate the changes in reaching function during a reaching task in cervical spondylosis (CS) patients before and after surgery. [Participants and Methods] Nine patients participated in the study. Wrist acceleration peaks were monitored pre- and postoperatively using a tri-axial accelerometer, and the Japanese Orthopedic Association (JOA) score was recorded preoperatively. Additional upper extremity function tests were performed pre- and postoperatively. Multiple stepwise regression analysis was used to investigate the contribution of wrist acceleration peak to the severity of clinical symptoms. Moreover, we compared the acceleration peaks produced during the reaching task before and after surgery. [Results] Multiple regression analysis showed that wrist acceleration peak, grip strength and pinch strength were associated with the upper extremity function of the JOA score, explaining 61.0% of the variance. There was a significant improvement in x-axis acceleration peak after surgery. [Conclusion] Our results suggested that quantitative assessments of reaching function are useful to objectively evaluate the changes in reaching function in patients undergoing cervical decompression surgery.

Hypersialylation is a common feature of neurofibrillary tangles and granulovacuolar degenerations in Alzheimer's disease and tauopathy brains.

Glycosylation is one of the major post-translational modifications of proteins. The status of sialylation of the neuropathological hallmarks of various neurodegenerative disorders was investigated in this study. Here, we report the novel findings that two phosphorylated tau (p-tau)-containing structures associated with Alzheimer's disease (AD), that is, neurofibrillary tangles (NFTs) and granulovacuolar degenerations (GVDs), were hypersialylated. The NFTs, GVDs and dystrophic neurites of senile plaques (SPs) in AD hippocampi were clearly visualized by immunohistochemistry using an anti-sialic acid (SA) antibody. In contrast, the amyloid core of SPs was not sialylated at all. Interestingly, other p-tau-containing structures, that is, globose-type NFTs in progressive supranuclear palsy and Pick bodies and ballooned neurons in frontotemporal lobar degeneration with Pick bodies, were also hypersialylated. Unlike the p-tau-containing structures observed in tauopathies, the hallmarks of other neurodegenerative disorders, such as Lewy bodies in Parkinson's disease, glial cytoplasmic inclusions in multiple system atrophy, Bunina bodies, skein-like inclusions and round inclusions in amyotrophic lateral sclerosis, intranuclear inclusions in neuronal intranuclear inclusion disease and physiological bodies or granules (lipofuscin granules, corpora amylacea and melanin granules), were not immunolabeled by the anti-SA antibody. Because this antibody specifically identified NFTs and GVDs, immunostaining for sialylation represents a useful tool to screen these structures in a diagnostic setting. These results clearly indicate that the pathological hallmarks of various tauopathies are commonly hypersialylated, and that sialylation plays an important role in the process of p-tau accumulation in AD and other tauopathies.

Role of complement activation and disruption of the blood-brain barrier in the pathogenesis of multiple system atrophy.

Multiple system atrophy (MSA) is a progressive and sporadic neurodegenerative disorder characterized by the histological appearance of glial cytoplasmic inclusions primarily composed of α-synuclein. Recently, complement-mediated neuroinflammation has been proposed as a key factor in the pathogenesis of numerous neurodegenerative disorders. We conducted immunohistochemical/immunofluorescent assays targeting a number of complements to explore the role of complements in MSA pathogenesis using brain samples from deceased patients and controls. Complement deposition was notably increased in the cerebral vasculature and myelin sheath in the MSA brains. Furthermore, fibrinogen leakage resulting from the disruption of the blood-brain barrier (BBB) was observed, along with the presence of C1q-positive microglia clusters surrounding the MSA brain vessels. These immunohistochemical/immunofluorescent findings suggest that complement activation and BBB disruption play critical roles in MSA progression.

A randomized controlled trial of the "positive diary" intervention for family caregivers of people with dementia.

PURPOSE: We examined the effectiveness of the "positive diary," in which family caregivers of people with dementia write down three good things that happened with reasons at the end of each day. DESIGN AND METHODS: In this randomized controlled trial, the intervention group used the "positive diary," while the control group kept a record of each meal for 4 weeks. FINDINGS: The intervention group showed improvement on several measures of wellbeing including Neuropsychiatric Inventory Questionnaire and Center for Epidemiologic Studies Depression Scale. PRACTICE IMPLICATIONS: The "positive diary" is a useful self-care tool for caregivers of people with dementia.

Yamaguchi fox-pigeon imitation test (YFPIT) for dementia in clinical practice.

BACKGROUND: In out-patient clinics, having simple procedures to check for signs of dementia is invaluable. In the present study, we evaluated the imitation of hand gestures to detect visuomotor deficits in dementia in clinical practice. METHODS: In all, 1219 subjects were enrolled in the present study, including 497 with Alzheimer's disease (AD), 98 with dementia with Lewy bodies (DLB), 71 with other types of dementia diseases, 175 with a Clinical Dementia Rating (CDR) of 0.5, and 378 normal controls. All subjects were aged 65 years or older. Subjects were recruited from 10 clinics and two communities. Visuomotor function was evaluated by the Yamaguchi fox-pigeon imitation test (YFPIT), which consists of a simple one-handed sign for 'fox' and a complex two-handed sign for 'pigeon', a rapid, game-like test with low psychological burden. RESULTS: The success rate (successful/total) for imitating the 'pigeon' hand gesture was reduced as the severity of the dementia increased: 85.7% in normal controls, 60.6% in CDR 0.5 (mild cognitive impairment), 39.2% in CDR 1 (mild dementia), 21.2% in CDR 2 (moderate dementia), and 5.7% in CDR 3 (severe dementia). The success rate for imitating the 'pigeon' hand gesture was higher in patients with DLB than AD within the CDR 1 group (51.2% vs 35.4%, respectively), but lower for patients with DLB than AD within the CDR 2 group (12.5% vs 24.4%, respectively). The success of imitating the hand gesture for 'fox' was similar for patients with AD and DLB. Of those subjects who failed to imitate the hand gesture for 'pigeon', 49.5% of those with AD showed the palm-palm pattern (both palms facing outward), suggesting deficits of perspective conversion from the first-person to the third-person. Conversely, 52.8% of patients with DLB showed a dorsum-dorsum pattern (both dorsa facing outwards), suggesting deterioration of visual attention and recognition. CONCLUSION: In conclusion, the YFPIT is a useful test to detect visuomotor deficits in dementia that can differentiate between AD and DLB.

Cerebral Microbleeds, Cerebrospinal Fluid, and Neuroimaging Markers in Clinical Subtypes of Alzheimer's Disease.

Lobar cerebral microbleeds (CMBs) in Alzheimer's disease (AD) are associated with cerebral amyloid angiopathy (CAA) due to vascular amyloid beta (Aß) deposits. However, the relationship between lobar CMBs and clinical subtypes of AD remains unknown. Here, we enrolled patients with early- and late-onset amnestic dominant AD, logopenic variant of primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA) who were compatible with the AD criteria. We then examined the levels of cerebrospinal fluid (CSF) biomarkers [Aß1-42, Aß1-40, Aß1-38, phosphorylated tau 181 (P-Tau), total tau (T-Tau), neurofilament light chain (NFL), and chitinase 3-like 1 protein (YKL-40)], analyzed the number and localization of CMBs, and measured the cerebral blood flow (CBF) volume by 99mTc-ethyl cysteinate dimer single photon emission computerized tomography (99mTc ECD-SPECT), as well as the mean cortical standard uptake value ratio by 11C-labeled Pittsburgh Compound B-positron emission tomography (11C PiB-PET). Lobar CMBs in lvPPA were distributed in the temporal, frontal, and parietal lobes with the left side predominance, while the CBF volume in lvPPA significantly decreased in the left temporal area, where the number of lobar CMBs and the CBF volumes showed a significant inversely correlation. The CSF levels of NFL in lvPPA were significantly higher compared to the other AD subtypes and non-demented subjects. The numbers of lobar CMBs significantly increased the CSF levels of NFL in the total AD patients, additionally, among AD subtypes, the CSF levels of NFL in lvPPA predominantly were higher by increasing number of lobar CMBs. On the other hand, the CSF levels of Aß1-38, Aß1-40, Aß1-42, P-Tau, and T-Tau were lower by increasing number of lobar CMBs in the total AD patients. These findings may suggest that aberrant brain hypoperfusion in lvPPA was derived from the brain atrophy due to neurodegeneration, and possibly may involve the aberrant microcirculation causing by lobar CMBs and cerebrovascular injuries, with the left side dominance, consequently leading to a clinical phenotype of logopenic variant.

Increased Neurofilament Light Chain and YKL-40 CSF Levels in One Japanese IBMPFD Patient With VCP R155C Mutation: A Clinical Case Report With CSF Biomarker Analyses.

Inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (IBMPFD) presents with multiple symptoms and an unknown etiology. Valosin-containing protein (VCP) has been identified as the main causative gene of IBMPFD. However, no studies on neurofilament light chain (NFL) as a cerebrospinal fluid (CSF) marker of axonal neurodegeneration or on YKL-40 as a CSF marker of glial neuroinflammation have been conducted in IBMPFD patients with VCP mutations. A 65-year-old man presented with progressive muscle atrophy and weakness of all limbs, non-fluent aphasia, and changes in personality and behavior. Cerebral MRI revealed bilateral frontal and temporal atrophy. 99mTc-HMDP bone scintigraphy and pelvic CT revealed remodeling changes and active osteoblastic accumulations in the right medial iliac bone. Muscle biopsy demonstrated multiple rimmed vacuoles in muscle cells with myogenic and neurogenic pathological alterations. After the patient was clinically diagnosed with IBMPFD, DNA analysis of the VCP gene revealed a cytosine (C) to thymine (T) (C→ T) mutation, resulting in an amino acid exchange of arginine to cysteine (p.R155C mutation). The CSF levels of NFL at two time points (12 years apart) were higher than those in non-dementia controls (CTR) and Alzheimer's disease (AD); lower than those in frontotemporal dementia with motor neuron disease (FTD-MND); and comparable to those in patients with behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The CSF levels of YKL-40 were comparable at both time points and higher than those in CTR; lower than those in FTD-MND; and comparable to those in bvFTD, PSP, CBS, and AD. The CSF levels of phosphorylated tau 181 (P-Tau) and total tau (T-Tau) were not significantly different from those in CTR and other neurodegenerative diseases, except those in AD, which were significantly elevated. This is the first report that demonstrates increased NFL and YKL-40 CSF levels in an IBMPFD patient with a VCP mutation (p.R155C); NFL and YKL-40 levels were comparable to those in bvFTD, PSP, CBS, and AD and higher than those in CTR. Our results suggest that IBMPFD neuropathology may involve both axonal neurodegeneration and glial neuroinflammation.

Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology.

Initially, trans activation responsive region (TAR)-DNA-binding protein 43 (TDP-43) was considered to be a disease-specific component of ubiquitin-positive and tau-negative inclusions in the brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS); however, it is now widely known that this protein also abnormally accumulates in neurons in other neurodegenerative diseases. On the basis of observation mainly in the medial temporal lobe, TDP-43-immunoreactive neuronal inclusions have been detected in 20-30% of Alzheimer disease (AD) brains. However, it is controversial whether these cases represent a combined disease, that is, mixed AD/FTLD-U. To address this issue, it is necessary to obtain more knowledge on the region-specific distribution of TDP-43 immunoreactivity and also about its relationship to AD common pathology. Here, we describe abnormal TDP-43 immunoreactivity in the medial temporal lobe in 5/16 AD patients (31%). Most of the depositions were cytoplasmic inclusions, mainly located in the subiculum and parahippocampal gyrus and rarely in dentate granular cells of the hippocampus. TDP-43-positive inclusions and senile plaque/neurofibrillary tangle distribution were not always identical, and intracellular colocalizations of TDP-43 and phospho-tau were also infrequent. The cases showing TDP-43-positive inclusions in the medial temporal lobe also showed abnormally highly dense TDP-43 immunoreactivity in the frontal, but not in the parietal and occipital cortices. Intracellularly, TDP-43-positive inclusions were highly ubiquitinated and colocalized with p62 immunoreactivity as well. Our findings suggest that abnormal TDP-43 deposition and AD pathology (formation of senile plaques and neurofibrillary tangles) might occur independently. However, taken together with the results of previous reports, the distribution of TDP-43 immunoreactivity in the hippocampus and frontal cortex in AD appear to be varying. We consider that it is still too early to determine that the TDP-43 accumulation is a part of AD pathology or result from a completely independent pathology.

Association of autophagy with cholesterol-accumulated compartments in Niemann-Pick disease type C cells.

Niemann-Pick disease type C (NPC) is an autosomal recessive disease most commonly caused by a mutation of NPC1, resulting in the accumulation of cholesterol in late endosomes or lysosomes. In this study, we examined whether an abnormality of autophagy is involved in the pathogenesis of NPC and how cholesterol accumulation participates in this process, using both a U18666A-induced NPC model and NPC1-deficient Chinese hamster ovary cells. In these cells, an increase in the level of the microtubule-associated protein 1 light chain 3 (LC3-II) was demonstrated by Western blotting. An increase in the number of granular LC3-positive structures that colocalized with filipin-labeled accumulated cholesterol was also observed in morphological studies. Cholesterol depletion inhibited the formation of granular LC3-positive structures that colocalized with filipin-labeled cholesterol, and instead promoted the formation of ring-shaped LC3-positive filipin-negative structures in U18666A-treated cells. These results demonstrate the close association of the accumulation of LC3 with accumulated cholesterol in NPC cells.

Deep White Matter Lesions Are Associated with Early Recognition of Dementia in Alzheimer's Disease.

Neuroimages of cerebral amyloid-ß (Aß) accumulation and small vessel disease (SVD) were examined in patients with various types of cognitive disorders using 11C-labeled Pittsburgh Compound B-positron emission tomography (PiB-PET) and magnetic resonance imaging (MRI). The mean cortical standardized uptake value ratio (mcSUVR) was applied for a quantitative analysis of PiB-PET data. The severity of white matter lesions (WML) and enlarged perivascular spaces (EPVS) on MRI were assessed to evaluate complicating cerebral SVD using semiquantitative scales. In homozygous apolipoprotein E ɛ3/ɛ3 carriers, the incidence of more severe WML and EPVS was higher in PiB-positive than PiB-negative patients, indicating that WML and EPVS might be associated with enhanced Aß accumulation. An association study between PiB-PET and MRI findings revealed that higher WML grades significantly correlate with lower mcSUVRs, especially in the frontal area, indicating that more severe ischemic MRI findings are associated with milder Aß accumulation among patients with Alzheimer's disease. In these patients SVD may accelerate the occurrence of cognitive decline and facilitate early recognition of dementia.

Nonapoptotic cell death caused by the inhibition of RNA polymerase disrupts organelle distribution.

It is controversial whether the mode of cell death induced by CAG repeat diseases is apoptotic. One technical problem that affects this issue is that the very methods used for DNA injection may induce artificial apoptosis. A recent study demonstrated that the functions of RNA polymerase II are disrupted in spinocerebellar ataxia type 1 (SCA 1) pathology, one of the CAG repeat diseases, and that alpha-amanitin can inhibit the activity of RNA polymerase. To examine the cell death mechanisms involved in CAG repeat diseases, we treated cultured rat neurons with alpha-amanitin to avoid the artifacts caused by DNA transfection. Mature and immature rat neurons were treated with alpha-amanitin for 4-6 days and the effects of the treatment on the elongation of neurites, the distribution or morphology of organelles, and the nature of cell death were assessed by immunocytochemistry and quantitative analysis. Neurons exhibited a disruption of neurite elongation and eventually died by day 15 of the treatment. However, apoptosis was not detected. When the neurons survived well, but showed altered neurites, Golgi complexes and lysosomes exhibited changes in their normal intracellular distribution or morphology, but the endoplasmic reticulum and mitochondria did not. The distribution of phosphorylated Trk receptors was also disrupted in the neurites of treated neurons. The signal intensity of the dynein intermediate chain was markedly decreased in the treated neurons. Thus, organelle transport systems, particularly a minus-end-directed microtubule-dependent pathway, would be disrupted by the inhibition of RNA polymerase, and this change is likely to be an early event involved in SCA 1 pathology.

Immunolocalization of Tom1 in relation to protein degradation systems in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Its pathological hallmarks are senile plaques (SPs), which contain extracellular deposits of amyloid ß (Aß) protein fibrils and dystrophic neurites (DNs), and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau. Impairment of protein-degradation systems, including the ubiquitin-proteasome and the autophagy-lysosome systems, has been proposed as one of the causes of the accumulation of these aberrant proteins in AD brains. Tom1 (target of Myb1) was originally identified by the induction of its expression by the v-Myb oncogene and is a part of two major protein-degradation systems. The present study was conducted by immunohistochemical and immunofluorescent stainings to show that Tom1 was localized in DNs, perisomatic granules (PSGs), and NFTs in AD brains. Moreover, in DNs, Tom1 colocalized with ubiquitin, lysosomal proteins, and Tom1-related proteins (Tollip and myosin VI), which act in both protein-degradation systems via Tom1. These results indicate that Tom1 plays important roles in protein-degradation systems in AD pathogenesis.

Immunolocalization of Smurf1 in Hirano bodies.

The Smad ubiquitination regulatory factor 1 (Smurf1) is one of the E3 ubiquitin ligases and is related to multiple biological processes. Despite the various roles played by this protein, there is no report on the function of Smurf1 in neurodegeneration. Hirano bodies (HBs) are intracellular structures within neuronal processes and were first described in the hippocampus of individuals with amyotrophic lateral sclerosis and the parkinsonism-dementia complex of Guam. In addition, the number of HBs increases in the brains of patients with Alzheimer's disease (AD) compared with age-matched non-demented control individuals. In this study, we immunohistochemically demonstrated that Smurf1 localized in HBs in the brains of patients with AD by using plural anti-Smurf1 antibodies, and Smurf1 co-localized with HBs marker proteins by using confocal microscopy. Moreover, we demonstrated that Smurf1 localized in HB-like F-actin aggregates in a cell culture system via treatment with the actin-stabilizing toxin jasplakinolide (jpk). Smurf1 represents a novel protein component of HBs, to be included in an expanding list of HB-associated proteins.

Repeated encephalopathy and hemicerebral atrophy in a patient with familial hemiplegic migraine type 1.

We herein describe a case of a 38-year-old man with familial hemiplegic migraine with a T666M mutation in the electrical potential-dependent calcium ion channel (CACNA1A) gene. His migraine was accompanied by hemiparesis and impaired consciousness. Brain magnetic resonance imaging revealed abnormalities in the right cortical hemisphere. Single-photon emission computed tomography demonstrated a decrease in iomazenil uptake and an increase in (99m)Tc-ethyl cysteinate dimer uptake at the ipsilateral site. Positron emission tomography showed a decrease in 18F-fluorodeoxyglucose uptake in the same area, which later showed atrophic changes. The patient's brain atrophy ceased after treatment with sodium valproate. This case suggests that the progression of brain atrophy can be prevented with adequate prophylaxis.

CSF levels of Aß1-38/Aß1-40/Aß1-42 and (11)C PiB-PET studies in three clinical variants of primary progressive aphasia and Alzheimer's disease.

Primary progressive aphasia (PPA) is a cognitive syndrome characterized by progressive and isolated language impairments due to neurodegenerative diseases. Recently, an international group of experts published a Consensus Classification of the three PPA clinical variants (naPPA, svPPA and lvPPA). We analyzed 24 patients with PPA by cognitive functions, neuroimaging (MRI, (99 m)Tc ECD-SPECT, (11)C PiB-PET and FDG-PET) and cerebrospinal fluid (CSF) analysis (ptau-181, Aß1-42, Aß1-40 and Aß1-38), to elucidate relationships between neuroimaging studies and biochemical findings in the three PPA clinical variants. Cognitive and speech functions were measured by mini-mental state examination and standard language test of aphasia. The patients with lvPPA showed significant decreases in CSF Aß1-42 and ratios of Aß1-42/Aß1-40 and Aß1-42/Aß1-38, and significant increases in CSF ptau-181 and ratios of ptau-181/Aß1-42 and ptau-181/Aß1-38; these findings were similar to those of patients with Alzheimer's disease (AD). We observed a higher frequency of the ApoE ε4 allele in the lvPPA patients relative to the two other PPA variants. In (11)C PiB-PET of lvPPA patients, PiB positive findings were detected in cortices of frontal, temporal and parietal lobes and the posterior cingulate, where massive Aß may accumulate due to AD. Our results of AD-CSF markers including Aß1-38 and (11)C PiB-PET in the lvPPA patients demonstrate a common pathological mechanism with the occurrence of AD.

Cerebrospinal fluid levels of phosphorylated tau and Aß1-38/Aß1-40/Aß1-42 in Alzheimer's disease with PS1 mutations.

We studied seven cases of Alzheimer's disease (AD). Six of the patients had presenilin 1 (PS1) mutations (PS1AD). Three novel PS1 mutations (T99A, H131R and L219R) and three other missense mutations (M233L, H163R and V272A) were found in the PS1AD group. We measured the levels of phosphorylated tau (ptau-181, ptau-199) and Aß (Aß1-42, Aß1-40 and Aß1-38) in the cerebrospinal fluid (CSF) of PS1AD patients, early-onset sporadic AD (EOSAD), late-onset sporadic AD (LOSAD) and non-demented subjects (ND). The CSF levels of Aß1-42 in the three AD groups were significantly lower than those of the ND group (p < 0.0001). CSF levels of Aß1-42 in the PS1AD group were significantly lower than those in the two sporadic AD groups. The Aß1-40 and Aß1-38 levels in the CSF of the PS1AD group were significantly lower than those of the three other groups (p < 0.0001, respectively). The levels of Aß1-40, Aß1-38 and Aß1-42 in the CSF of the PS1AD group remained lower than those of the ND group for 4 years. Not only CSF Aß1-42, but also Aß1-40 and Aß1-38 decreased in the advanced stages of PS1AD.