Alzheimer's and related diseases: toward earlier and more accurate diagnosis

Because of population ageing, the prevalence of Alzheimer's disease (AD), the most common cause of dementia, increases progressively. This condition is now considered as a public health priority. New disease modifying therapeutic strategies could be available in the next few years that would necessitate an accurate and early diagnosis of the disease. Recently developed diagnostic tools are being assessed. Development of structural brain imaging allows to measure the hippocampus volume. Metabolic imaging can assess a broad range of functional parameters such as cerebral blood flow and dopaminergic activity with single photon emission computed tomography, cerebral glucose metabolism and cerebral amyloid burden with positron emission tomography. Those imaging methods are under evaluation to appreciate cerebral abnormalities that may occur earlier than structural ones. Cerebrospinal fluid biomarkers, in particular amyloid and tau peptides, allow us to look at in vivo biochemical cerebral changes related to AD, before possible serum biomarkers. Studies are under way to confirm the relevance of these new diagnostic tools. It will help us to improve evaluation of patients with AD or related diseases.     

CSF biomarkers for mild cognitive impairment

A correct clinical diagnosis of Alzheimer's disease (AD) early in the course of the disease is of importance to initiate symptomatic treatment with acetylcholine esterase inhibitors, and will be even more important when disease-arresting drugs, such as beta-sheet breakers or gamma-secretase inhibitors, will reach the clinic. However, there is no clinical method to determine if a patient with mild cognitive impairment (MCI) has incipient AD, i.e. will progress to AD with dementia, or have a benign form of MCI without progression. Thus, there is a great clinical need for diagnostic biomarkers to identify incipient AD in MCI cases. Three cerebrospinal fluid (CSF) biomarkers; total-tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of beta-amyloid (Abeta42) have been evaluated in numerous scientific papers. These CSF markers have high sensitivity to differentiate early and incipient AD from normal ageing, depression, alcohol dementia and Parkinson's disease, but lower specificity against other dementias, such as frontotemporal and Lewy body dementia. However, if the CSF biomarkers are used in the right clinical context, i.e. together with the cumulative information from the clinical examination, standard laboratory tests and brain-imaging techniques [single photon emission tomography (SPECT) and magnetic resonance tomography (MRT) scans], they may have a role in the clinical evaluation of MCI cases.     

Affected siblings with Alzheimer's disease had missense mutation of codon 717 in amyloid precursor protein gene]

Using reverse genetic techniques, the gene responsible for familial Alzheimer's disease (FAD) is one of the clues to identify the pathogenesis of Alzheimer's disease (AD). Recently a missense mutation in the APP (amyloid precursor protein) gene (generally this mutation was called APP717) was detected in 2 Caucasian AD families and the same mutation was found in 3 Japanese AD families. We experienced brother's cases who were diagnosed as AD. Both of them and one normal person of the next generation had APP717. The first symptom of the elder brother (case 1) was forgetfulness at 52 years old, then dementia was advanced. In his clinical course there were characteristic findings such as the mirror sign, pseudodialog and jargon which has been rarely described in the Japanese literature. Finally he died of pneumonia at 57 years old. He was diagnosed as AD pathologically and physical findings of brain CT, SPECT (single photon emission computed tomography) and EEG supported this diagnosis clinically. The first symptom of the younger brother (case 2) was also forgetfulness at 45 years old, then severe dementia was advanced, at last he died of pneumonia at age 53 old. On the other hand the mother of the brothers died of severe dementia, so it was suspected that brothers died of severe dementia, so it was suspected that she had had AD. The clinical courses and pathological findings were thought to be typical of AD, namely there were no significant differences in comparison with other cases of FAD and sporadic AD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biomarkers,mild cognitive impairment and early diagnosis of Alzheimer's disease

Elderly people are concerned about changes in their cognitive functioning. Since cholinergic therapies for Alzheimer's disease have been developed and become widely accepted, elderly people have come to visit clinics to seek medical advice about whether such a subtle change in cognitive ability may represent an early manifestation of Alzheimer's disease (AD). If they are likely to develop dementia or AD, they want to receive immediate medical treatment as soon as possible to prevent further loss of cognitive functioning so that they can live independently as long as possible. The first priority in the clinical application of a biomarker is that biomarker should contribute to early diagnosis of dementia. Among such biomarkers, we believe that cerebrospinal fluid markers and functional brain imaging are clinically the most applicable procedures. Since 1993, we have collected 623 cerebrospinal fluid (CSF) samples at The Tohoku University Hospital for evaluation of dementia (age: 42-93). We found that CSF/phospho-tau measures produced the most adequate sensitivity (85.2%) and specificity (85.0%) in the diagnosis of AD as a sole bio-marker. The CSF levels of A beta 1-42 showed a strong positive correlation with the Mini-mental state examination score and brain glucose metabolism by positron emission tomography. The baseline levels of both total-tau and phospho-tau in CSF increased in approximately 70% of patients with mild cognitive impairment who later developed AD, suggesting that pathological change in the brain might start years before dementia becomes clinically manifested. A combined use of CSF-tau and IMP-SPECT improved the predictability of the transition from mild cognitive impairment into AD.     

Sensitivity of SPECT for the Diagnosis of Alzheimer's Disease

Abstract

The objective of this study was to define the technical and clinical variables which affect the sensitivity of single photon emission computed tomography (SPECT) for the diagnosis of Alzheimer's disease (AD). This was a retrospective analysis of 250 consecutive SPECT studies performed for the diagnostic evaluation of degenerative dementia or memory disorder. The sensitivity of bilateral temporoparie-tal perfusion defects for probable AD cases was not affected by age, education, or technical factors such as the interpreting radiologist, type of radionuclide, and use of a ring detector system. Sensitivity increased with severity of dementia and duration of disease. Sensitivity also increased with male gender due to a higher prevalence of unilateral defects in women with probable AD. This gender effect was absent if unilateral temporoparietal defects were considered diagnostic of AD. Due to the high prevalence of AD, the most common outcome of SPECT in this series was to confirm the clinical diagnosis of AD; however, SPECT may be of greatest value for ruling in a diagnosis of AD in questionable or early dementia cases. For this purpose, the maximum yield of positive diagnosis came from examination of those who had dementia symptoms greater than one year and those who were male.     

The value of positron emission tomography in the clinical evaluation of dementia

Positron emission tomography (PET) has been promoted as a means of improving the diagnosis of Alzheimer's disease (AD), but the evidence to support its incremental value is unclear. To assess the evidence regarding the use of PET in the clinical evaluation of AD, a systematic review of the English-language literature indexed in MEDLINE (1975-January 2001), the Cochrane Library (issue 4, 2000), and health technology assessment (HTA) reports was conducted. Articles identified by this review process were graded for methodological and reporting quality using a standardized grading scheme. Sixteen original articles and seven HTA reports were identified. In general, the articles addressed: using PET to differentiate AD from normal aging or non-Alzheimer's dementias, PET imaging compared with single positron emission computed tomography imaging, using PET to predict the progression of dementia, and agreement and reliability in the interpretation of PET images. Serious problems with study design and methodology in all articles were identified. Previous HTA reports have generally recommended that PET not be used in the clinical evaluation of dementia. In conclusion, there is little evidence to support the addition of PET to the routine clinical evaluation of patients with suspected or established dementia. Suggestions for future research in this area are offered.     

Diagnostic imaging of dementia in the elderly

Dementia is a frequent problem in elderly patients. More than age per se, it may influence the indication for invasive diagnostic and therapeutic procedures to treat other diseases. Here, the role of tomographic imaging methods for differential diagnosis of dementia will be reviewed briefly, with the new possibilities that became available recently. Computed tomography (CT) of the brain is used primarily to detect potentially treatable conditions, such as multiple ischemic infarcts, hematomas, hydrocephalus and brain tumors. It should be performed even at higher age if the general condition of the patient is good enough not to exclude all specific therapeutic measures. Magnetic resonance imaging (MRI) is more sensitive for ischemic white matter lesions and hippocampal atrophy and should therefore used preferentially in mildly affected patients. Functional imaging methods, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET), are necessary only in clinically unclear cases to demonstrate functional impairment of association cortex.     

Regional cerebral blood flow patterns in extremely elderly patients with Alzheimer's disease

AIM: Clinical and pathologic features in Alzheimer's disease (AD) patients differ depending on the age of onset. The aim of our study was to compare the regional cerebral blood flow (rCBF) patterns of younger, elderly, and extremely elderly patients with AD with that of controls to characterize the rCBF patterns in extremely elderly patients with AD. METHODS: Single photon emission CT (SPECT) was performed in 113 patients with probable AD, including 34 younger (<70 years), 41 elderly (70-84 years), and 38 extremely elderly (>or=85 years) patients divided according to age at examination. The SPECT data were analyzed using three-dimensional stereotactic surface projection (3D-SSP). RESULTS: No significant differences regarding gender, duration of disease, education, and Mini-Mental State Examination score were found among the groups. As compared with controls, younger and elderly AD demonstrated significant reduction of rCBF in the temporo-parietal areas, posterior cingulate cortices and precunei, which is considered to be a characteristic rCBF pattern in AD. On the other hand, the extremely elderly AD group demonstrated significant reduction of rCBF in the frontal and medial temporal areas, in addition to the temporo-parietal areas, posterior cingulate cortices and precunei, but the reductions were milder than in those in younger and elderly AD groups. CONCLUSION: The extremely elderly patients with AD showed atypical rCBF patterns in AD compared to younger and elderly patients with AD. Our data suggest that pathological features in extremely elderly AD may be different from those in younger and elderly AD and that diseases different from AD, such as senile dementia of the neurofibrillary tangle type may be clinically diagnosed as extremely elderly AD.     

老年期痴呆74例脑CT径线测量与神经心理测评观察

目的观察老年期痴呆患者头颅CT与神经心理测评的特点。方法通过Hackinski缺血指数表区分血管性痴呆（VD）及阿尔茨海默病（AD）,将有关的头颅CT径线和神经心理测评量表进行对比。结果①AD组和VD组头颅CT扫描各径线比较,差异具有统计学意义（P〈0.05）。②AD组和VD组简易智力状态检查表（MMSE）总分比较有统计学意义（P〈0.05）。AD和VD组与对照组比较,部分MMSE因子分差异有统计学意义（P〈0.05或P〈0.01）。③AD组和VD组小脑沟条数差异具有统计学意义（P〈0.05）。结论 AD组大脑萎缩及痴呆程度重于VD组,而小脑萎缩则不尽然。结合CT检查和神经心理测评仍是鉴别VD及AD的有效方法 。     

胰腺癌影像诊断新进展

目前,胰腺癌的早期诊断受到关注.传统影像诊断技术有CT、MR和超声.新的技术已经发展起来,比如PET/CT融合和MRS,尤其是分子影像的实验研究,为今后胰腺癌的早期诊断提供新的技术手段.     

Advances in neuroimaging for HIV-1 associated neurological dysfunction: clues to the diagnosis, pathogenesis and therapeutic monitoring

Persons with advanced human immunodeficiency virus type one (HIV-1) infection seek medical advice for a wide range of neurological disorders including, but not limited to, peripheral neuropathy, toxoplasmosis, cryptococcal meningitis, cytomegalovirus retinitis progressive multifocal leukoencephalopathy, lymphoma and dementia. The diagnosis of HIV-1-associated dementia (HAD) induced as a direct consequence of HIV infection of the brain comes commonly by exclusion. Diagnostic decisions can often be clouded by concomitant depression, motor impairments, and lethargy that follow debilitating immune suppression and weight loss. Indeed, cognitive, motor and behavior abnormalities underlie a variety of neurological dysfunctions associated with advanced HIV-1 infection. Thus, even combinations of clinical, laboratory and neuroimaging tests [for example, magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET)] often fail to provide conclusive diagnostic information. Nonetheless, the recent development of quantitative MR spectroscopic imaging has improved diagnostic possibilities for HAD. We are pleased to discuss these developments as well as taking a forward look into what will soon be made available to improve neuroimaging diagnostic precision. New MR and SPECT testing are being developed in our laboratories and elsewhere both for animal model systems and in humans with HIV-1 disease. Such tests can facilitate dynamic measures of HIV-1 neuropathogenesis providing information for disease events that even 2 years ago were unattainable.     

Orthostatic hypotension in Alzheimer's disease: result or cause of brain dysfunction?

In Alzheimer's disease (AD), an association was found between autonomic dysfunction and frontal hypoperfusion in brain during orthostatic testing. To ascertain whether frontal hypoperfusion is dependent on longitudinal effects of hemodynamic disturbances, or contributes to them, we studied the relationship between the presence of orthostatic hypotension (OH) and resting cerebral blood flow (CBF) in late stages of AD. Twelve women with senile dementia of Alzheimer type (SDAT), and 15 non-demented women (mean age 82.6 years, SD 3.8 vs 81.8 years, SD 3.5) were examined with the orthostatic test. Four of 12 patients with SDAT, and 9 controls had OH (defined as systolic blood pressure fall > or = 20 mmHg). CBF was determined under resting conditions using 600 Mbq 99mTc HMPAO single photon emission computerized tomography (SPECT), and quantified in cortical areas in relation to cerebellum. In patients with SDAT and OH, CBF was lower in frontal and parieto-frontal cortical areas than in SDAT patients without OH. The former group was younger and had a shorter dementia duration. No significant differences in CBF were observed between controls with vs without OH. No differences in SDAT patients with or without OH were observed in the Berger dementia scale or Katz' ADL index. No difference in incidence of symptoms related to autonomic disturbances (diarrhea, obstipation, dysphagia, vertigo) was observed in either the SDAT or control group with regard to OH presence. We conclude that during the course of AD, OH can contribute to frontal brain changes and may exacerbate the disease. The further involvement of frontal dysfunction in aggravating blood pressure dysregulation in the elderly is discussed.     

Brain accumulation of amyloid β protein visualized by positron emission tomography and BF‐227 in Alzheimer's disease patients with or without diabetes mellitus

Aim: Although diabetes mellitus (DM) is considered to be one of the most consistent risks for developing dementia, it is not known if the pathology in dementia patients with DM is similar to or distinct from typical pathological features of Alzheimer's disease (AD). To discover the mechanism of developing dementia in AD patients with DM in a living state, we studied the distribution of amyloid β (Αβ) protein of diabetic AD patients. Methods: To evaluate the accumulation of Aβ, we examined 14 normal controls, four diabetic patients with AD and 11 non‐diabetic patients with AD by positron emission tomography (PET) using BF‐227, a currently developed Aβ tracer. Results: The analysis of PET images among the three groups showed an abundant aggregated Aβ accumulation in the cerebral cortex of both AD patients with and without DM. The extent and distributions of BF‐227 accumulation in diabetic AD patients were not significantly different from these of non‐diabetic AD patients. Conclusion: These results suggest that the degree and extent of Aβ deposition is not significantly different between AD with DM and AD alone. Geriatr Gerontol Int 2013; 13: 215–221.     

脑血流储备的临床意义和测定方法

脑血流储备是评价脑血管病的一项重要参数,临床意义重大。脑血流储备的检测方法较多,如正电子发射体层摄影、单光子发射计算机体层摄影、氙吸入技术、氙-CT、灌注CT、MRI、经颅多普勒、经颅超声波谐振灌流成像、近红外线光谱、激光多普勒,但迄今尚无统一的标准。使脑血流增加的激发试验包括CO_2吸入试验、屏气试验、乙酰唑胺试验等。文章重点阐述了各种检测方法的优缺点。     

Iofetamine I 123 single photon emission computed tomography is accurate in the diagnosis of Alzheimer's disease

To determine the diagnostic accuracy of iofetamine hydrochloride I 123 (IMP) with single photon emission computed tomography in Alzheimer's disease, we studied 58 patients with AD and 15 age-matched healthy control subjects. We used a qualitative method to assess regional IMP uptake in the entire brain and to rate image data sets as normal or abnormal without knowledge of subjects'clinical classification. The sensitivity and specificity of IMP with single photon emission computed tomography in AD were 88% and 87%, respectively. In 15 patients with mild cognitive deficits (Blessed Dementia Scale score, less than or equal to 10), sensitivity was 80%. With the use of a semiquantitative measure of regional cortical IMP uptake, the parietal lobes were the most functionally impaired in AD and the most strongly associated with the patients' Blessed Dementia Scale scores. These results indicated that IMP with single photon emission computed tomography may be a useful adjunct in the clinical diagnosis of AD in early, mild disease.     

Quantitative electroencephalography, with serial subtraction and odour detection in the differentiation of Alzheimer's disease and vascular dementia

The diagnosis of dementia can be difficult, yet diagnostic accuracy has important prognostic and therapeutic implications. Nevertheless, conventional electroencephalography (EEG) has always played a secondary role in dementia investigation. More recently quantitative EEG (qEEG) has allowed more detailed and objective analysis of EEG data, but there is still no clearly defined clinical role for qEEG. We have used relative power qEEG measures made during resting and active brain conditions (serial subtraction and odour detection tasks) to differentiate between demented and non-demented subjects, and between subjects with different forms of dementia. Electroencephalograms were obtained from 15 subjects with clinically diagnosed Alzheimer's disease (AD), 16 with a clinical diagnosis of vascular dementia (VaD), and 16 non-demented control subjects. Discriminate function analyses were used to differentiate groups according to task, electrode site, and frequency bandwidth. Correct classification, as demented or non-demented, was made for 93% of cases using qEEG comparisons of resting states with eyes closed and eyes opened. Almost all subjects with AD and VaD were correctly classified with qEEG recorded during odour detection (95%). qEEG for serial subtraction correctly classified AD and VaD in 91% of the dementia group. These results have important implications for future qEEG research, and may be pertinent to the precision of diagnosis in patients with dementia.     

Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) epsilon4 gene dose (i.e., the number of epsilon4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE epsilon4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47-68 years of age, including 36 epsilon4 homozygotes, 46 heterozygotes, and 78 epsilon4 noncarriers who were individually matched for their gender, age, and educational level, we now find that epsilon4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.     

Vascular dementia: Different forms of vessel disorders contribute to the development of dementia in the elderly brain

The diagnosis of vascular dementia (VaD) describes a group of various vessel disorders with different types of vascular lesions that finally contribute to the development of dementia. Most common forms of VaD in the elderly brain are subcortical vascular encephalopathy, strategic infarct dementia, and the multi infarct encephalopathy. Hereditary forms of VaD are rare. Most common is the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Sporadic forms of VaD are caused by degenerative vessel disorders such as atherosclerosis, small vessel disease (SVD) including small vessel arteriosclerosis, arteriolosclerosis, and lipohyalinosis, and cerebral amyloid angiopathy (CAA). Less frequently inflammatory vessel disorders and tumor-associated vessel lesions (e.g. angiocentric T-cell or angiotropic large cell lymphoma) can cause symptoms of dementia. Here, we review and discuss the impact of vessel disorders to distinct vascular brain tissue lesions and to the development of dementia in elderly individuals. The impact of coexisting neurodegenerative pathology in the elderly brain to VaD as well as the correlation between SVD and CAA expansion in the brain parenchyma with that of Alzheimer's disease (AD)-related pathology is highlighted. We conclude that “pure” VaD is rare and most frequently caused by infarctions. However, there is a significant contribution of vascular lesions and vessel pathology to the development of dementia that may go beyond tissue damage due to vascular lesions. Insufficient blood blow and alterations of the perivascular drainage mechanisms of the brain may also lead to a reduced protein clearance from extracellular space and subsequent increase of proteins in the brain parenchyma, such as the amyloid β-protein, and foster, thereby, the development of AD-related neurodegeneration. As such, it seems to be important for clinical practice to consider treatment of potentially coexisting AD pathology in cognitively impaired patients with vascular lesions.     

Dementia with Lewy bodies: a review

The dementia with Lewy bodies (DLB) is the second major type of senile, degenerative dementia, after the Alzheimer disease (AD). It is characterized by the presence of cytoplasmic inclusions of alpha-synuclein in the cerebral cortex and in the nuclei of the brain stem. DLB patients frequently have complex visual hallucinations, depressive symptoms, Parkinsonian manifestations and cognitive deficits, showing important associations with the Parkinson disease and the AD. The DLB should be differentiated from atypical Parkinsonisms, but the differential diagnosis often remains difficult and unsafe. Clinical and neuropathological findings, as well as neuroimaging are valuable tools in establishing specific diagnosis of DLB. Acetylcholinesterase inhibitors, dopamine-agonists, benzodiazepines of short or medium half-life, and antidepressants may be useful in the treatment of DLB, depending on the dominant symptoms of the given patients.