Multiple brain pathologies in dementia are common

Multiple pathological processes are common in those with dementia and can affect clinical presentations. This study defined the extent of multiple pathological processes at autopsy in a well-characterized dementia clinic population and determined their impact on cognitive deficits. Forty-five cases from the Canadian Collaborative Cohort of Related Dementia (ACCORD) were prospectively assigned one primary clinical diagnosis and up to one secondary clinical diagnosis. Neuropathological examination followed a uniform protocol including mandatory semiquantitative assessment of a wide range of pathological changes. Multiple significant pathologies were identified in 21 cases (46.7%) including 19 cases with two cases with three pathological diagnoses. The pathological diagnoses in these mixed cases included Alzheimer disease (AD) (n = 18), dementia with Lewy Bodies (DLB) (n = 9, eight also with AD), frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) (n = 10, eight with coexisting AD), cerebrovascular disease (CVD) (n = 5, three cases with coexisting AD) and progressive supranuclear palsy (PSP) (n = 1, also with CVD and FTLD-TDP). Only two cases with multiple pathological diagnoses were all recognized in the clinical diagnoses. Additional pathology of uncertain significance in 24 cases included vascular lesions, argyrophilic grains and hippocampal sclerosis. Patients with multiple pathologies were older and their baseline MMSE score higher at presentation.     

Prevalence of dementia subtypes: a 30-year retrospective survey of neuropathological reports

We investigated the distribution of neuropathologically defined dementia subtypes among individuals with dementia disorder. The neuropathological reports were studied on all patients (n=524; 55.3% females; median age 80, range 39-102 years) with clinically diagnosed dementia disorder who underwent complete autopsy including neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1974-2004. The neuropathological diagnosis was Alzheimer's disease (AD) in 42.0% of the cases, vascular dementia (VaD) in 23.7%, dementia of combined Alzheimer and vascular pathology in 21.6%, and frontotemporal dementia in 4.0% of the patients. The remaining 8.8% of the patients had other dementia disorders, including combinations other than combined Alzheimer and vascular pathology. The registered prevalence of dementia subtypes depends on many variables, including referral habits, clinical and neuropathological judgments and diagnostic traditions, all of these variables potentially changing over time. This, however, does not seem to obscure the delineation of the major dementia subgroups. In this material of 30 years from Lund in the south of Sweden, AD by far dominated among dementia subtypes, while cerebrovascular pathology corresponded with the dementia disorder, either entirely or partly, in almost half of the demented patients.     

Neuroimaging in the Clinical Diagnosis of Dementia: Observations from a Memory Disorders Clinic

OBJECTIVES: To determine how often neuroimaging confirms, clarifies, or contradicts initial diagnoses of late‐life cognitive disorders. DESIGN: Retrospective case review. SETTING: Outpatient clinic specializing in memory disorders. PARTICIPANTS: One hundred ninety‐three consecutively referred cognitively impaired patients. MEASUREMENTS: Diagnoses using research criteria were developed for each patient at the first visit and ranged from cognitive impairment without dementia to dementias of single, complex, or indeterminate etiology. Structural (noncontrast magnetic resonance imaging) and perfusion (technetium‐99m ethyl cysteine dimer single photon emission computed tomography) images were categorized together as normal, suggestive of specific diseases, or abnormal/not diagnostic. RESULTS: When a single neurodegenerative disease was suspected clinically (n=94), imaging confirmed the diagnosis in 50, contradicted the diagnosis in 32, and was abnormal/not diagnostic in 12. When more than one neurodegenerative etiology was clinically suspected (n=21), imaging assigned a single diagnosis in 13 and only cerebrovascular disease in one and was abnormal/not diagnostic in seven. In dementia not otherwise specified (NOS) (n=33), imaging suggested a specific etiology in 23 and was abnormal/not diagnostic in 10. Abnormal/not diagnostic images were more common in cognitive disorder NOS (n=25, 68%) than in other clinical groups (22%, chi‐square=22.8 P<.001). Neuroimaging indicators of cerebrovascular disease were common (60% prevalence) but not predicted by the presence of vascular risk factors alone. CONCLUSION: Overall, neuroimaging confirmed, clarified, or contradicted the initial clinical diagnosis in more than 80% of patients, whereas fewer than 20% had abnormal/not diagnostic patterns. Imaging suggested a complex dementia etiology in 21% of cases clinically thought to be caused by a single process, whereas 46% of complex clinical differential diagnoses appeared to reflect a single causal pattern. Further work is needed to determine whether refinement of clinical diagnoses using specialized neuroimaging improves clinical decision‐making and patient outcomes.     

Demenz

Dementia is a clinical syndrome characterized by progressive memory loss. Alzheimer’s disease, a neurodegenerative disorder, accounts for the majority of clinical cases. The differential diagnosis comprises other neurodegenerative disease entities and vascular dementia, but also secondary and potentially reversible disturbances of cognitive function such as delirium or depression. Diagnostic work-up consists of standardized cognitive testing, neuroimaging, and a basic laboratory test battery. Pharmacological treatment of cognitive symptoms is accompanied by pharmacological and nonpharmacological treatment of psychiatric and behavioral symptoms, establishment of a supportive social network, as well as prevention and treatment of medical complications of dementia. This article summarizes current clinical knowledge on dementia and has a special interest in treatment and prophylaxis of complications in the field of internal medicine.     

阿尔茨海默病各种临床记忆检测方法的评价

目的评价各种临床记忆检测方法对阿尔茨海默病(Alzheimer’s disease,AD)诊断的临床效度,从而组合出最适宜AD患者的一套记忆力检测量表。方法以北京市十五攻关项目中研究的患者为背景,对正常老年人1 584例(常模组),AD患者351例(AD组),应用各种记忆力检测量表进行临床分析。结果各种记忆力检测量表对AD的记忆力检测均有较好的临床效度。结合记忆力检测量表的敏感性、特异性、临床可行性及不同的记忆模式,以常模组记忆总得分的第5百分位为分界值,联合各量表的记忆检测,轻度AD患者敏感性为82.57%,特异性为93.29%;检测中度AD患者的敏感性为85.46%,特异性为91.63%。结论联合各量表的记忆检查对AD患者的记忆力检测,敏感性及特异性高,对AD的轻、中度分界有辅助作用。     

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.     

Clinical impact of 11C-Pittsburgh compound-B positron emission tomography in addition to magnetic resonance imaging and single-photon emission computed tomography on diagnosis of mild cognitive impairment to Alzheimer's disease

This study aimed to evaluated the clinical impact of adding [¹¹C] Pittsburgh compound-B (¹¹C-PiB) PET for clinical diagnosis of mild cognitive impairment (MCI) to Alzheimer''s disease (AD) dementia.Twenty six (mean age 78.5 ± 5.18 years, 21 females) AD (n = 7), amnestic MCI (n = 12), non-amnestic MCI (n = 3), vascular dementia, progressive supranuclear palsy (PSP) with frontotemporal dementia (FTD), FTD (n = 1 each), and normal (n = 1) patients underwent ¹¹C-PiB-PET, MRI, and SPECT scanning. ¹¹C-PiB-PET was compared with MRI and SPECT for clinical impact.¹¹C-PiB-PET showed positivity in 6, 9, and 0 of the AD, amnestic MCI, and non-amnestic MCI patients, respectively, and 0 of those with another disease. Parahippocampal atrophy at VSASD was observed in 5 AD patients, 6 amnestic and PiB-positive MCI patients, 1 amnestic and PiB-negative MCI patient, and 1 vascular dementia patient. Parietal lobe hypoperfusion in SPECT findings was observed in 6, 4, and 2 of those, respectively, as well as 1 each of non-amnestic MCI, vascular dementia, and normal cases. Sensitivity/specificity/accuracy for selecting PiB-positive patients among the 15 MCI patients for ¹¹C-PiB-PET were 100% (9/9)/100% (6/6)/100% (15/15), for VSRAD were 66.7% (6/9)/83.3% (5/6)/73.3% (11/15), and for SPECT were 44.4% (4/9)/50.0% (3/6)/46.7% (7/15), while those were 88.9% (8/9)/33.3% (2/6)/66.7% (10/15)/for combined VSRAD and SPECT. ¹¹C-PiB-PET accuracy was significantly higher than that of SPECT.¹¹PiB-PET alone may be useful for selecting patients who will progress from MCI to AD in the future, although follow-up study is necessary to clarify the outcome of MCI patients.     

Diagnostic criteria for vascular dementia.

The term vascular dementia implies the presence of a clinical syndrome (dementia) caused by, or at least assumed to be caused by, a specific disorder (cerebrovascular disease). In this review, the various sets of criteria used to define vascular dementia are outlined. The various sets of criteria are judged whether they contain criteria for both dementia and vascular disease as well as for the relationship between the two. We conclude that only the criteria of the State of California Alzheimer's Disease Diagnostic and Treatment Centers and of NINDS-AIREN provide sufficient operational criteria for dementia suitable for use in patients with vascular disease as well as for the diagnosis of cerebrovascular disease and for the establishment of a relationship between dementia and vascular disease. The latter criteria include also specific recommendations to the use of CT and MRI. However, the interpretation of the neuroimaging findings in the context of mixed vascular and degenerative dementia demands further study. Given the heterogeneous pathophysiology and pathology of vascular dementia and the modest reliability of the criteria, it seems plausible that the diagnosis of vascular dementia will become more reliable when specific diagnostic tests for the various degenerative diseases, from which vascular dementia has to be differentiated, become available.     

How do patients with parkinsonism present? A clinicopathological study

Background:  The early clinical features of neurodegenerative parkinsonism can be subtle and often coexist with autonomic, sensory and psychic symptoms, making accurate early diagnosis challenging.
Methods:  We retrospectively assessed the initial, clinical presentation and referral patterns of 494 patients with a pathological diagnosis of parkinsonism (344 with Parkinson's disease (PD), 89 with progressive supranuclear palsy (PSP) and 61 with multiple system atrophy (MSA)) archived at the Queen Square Brain Bank, London.
Results:  Forty-four per cent of all patients were initially referred to a neurologist. Of those with PD, 28% were referred to a general physician, and approximately 5% each to orthopaedic surgeons, urologists, psychiatrists and rheumatologists. Pain was common in those not initially referred to neurologists and most lacked early tremor, rigidity and bradykinesia. More PSP patients were initially referred to ophthalmologists than in PD (9 vs 1%, χ² P  < 0.001) and more MSA patients were referred to a urologist or gynaecologist than in PD (21 vs 5%, χ² P  < 0.001). In PD a frozen shoulder, degenerative spine disease and benign prostatic hypertrophy were the most common early diagnoses. In PSP, the most common misdiagnosis was PD, followed by vascular parkinsonism and degenerative spinal disease. This was similar in MSA, but bladder outlet obstruction and idiopathic vocal cord palsy were other initial diagnoses.
Conclusion:  The early clinical manifestations of PD, PSP and MSA are protean and often non-specific, leading to diverse specialist referrals. When diagnoses, such as frozen shoulder and cervical spondylosis, benign prostatic hypertrophy or unstable bladder and depression are made, specialists should consider the possibility of early parkinsonism and look carefully for additional subtle motor abnormalities.     

MRI, CT, SPECT, PET: their use in diagnosing dementia

The differential diagnosis of the dementia syndrome may pose a difficult clinical problem, since the most common dementia, Alzheimer's disease (AD), is marked by normal laboratory tests. Neuroimaging has played an important role in evaluating the demented patient, and its uses are growing. Computed tomography (CT) is useful for excluding reversible and treatable causes of dementia, such as subdural hematoma and tumor. More recently, magnetic resonance imaging (MRI) has improved our ability to diagnose vascular disease and may show the presence of cerebral infarcts and white matter disease not visible on CT. Single photon emission computed tomography (SPECT) and positron emission tomography (PET), techniques that visualize such cerebral functions as glucose metabolism and blood flow, may provide positive evidence supportive of the diagnosis of AD.     

进行性核上性麻痹的临床表现和神经影像学特点

目的探讨进行性核上性麻痹(progressive supranuclear palsy,PSP)的临床特点及头颅MRI、正电子发射体层扫描(PET)检查在本病中的诊断价值。方法回顾性分析19例PSP患者临床特点、神经影像学特征。结果19例PSP患者中,12例患者以走路不稳、反复向后跌倒为首发.17例患音出现垂直性核上性眼肌麻痹,假性球麻痹出现较早,还伴有轴性肌张力障碍、轻度痴呆等症状。19例患者均行头颅MRI检查,10例患者正中矢状位可见中脑上端萎缩,呈"蜂鸟征",水平位可见中脑前后径变小,呈"鼠耳征",1例患者中脑被盖和顶盖部T_2加权像显示弥散性高信号,中脑萎缩随病程加重。13例患者PET检查,均可见中脑葡萄糖代谢降低,双侧额叶葡萄糖代谢降低比较明显,部分合并顶叶或顶枕联合区葡萄糖代谢降低。结论 PSP临床表现变异较大,但通过头颅MRI、PET等辅助检查的特征性表现,可为诊断及鉴别诊断提供依据。     

脑膜血管型神经梅毒的诊治(附4例报道及文献复习)

目的分析脑膜血管型神经梅毒的临床表现、实验室检查和神经影像学检查特点及其治疗和预后,提高对该病的诊治水平。方法对我院收治的4例脑膜血管型神经梅毒患者的临床资料、实验室检查、神经影像学检查结果及诊治经过进行回顾性分析。结果 4例患者中3例男性,1例女性,均以脑卒中样表现起病,脑血管病危险因素较少,影像学检查无特异性,血清及脑脊液血梅毒螺旋体明胶凝集试验(TPPA)和快速血浆反应素试验(RPR)阳性以确诊,大剂量青霉素治疗预后较好。结论脑膜血管型神经梅毒临床表现及神经影像学检查无特异性,容易误诊,对没有明确病因或病因较少的脑梗死患者,及早进行梅毒血清学实验和脑脊液检查,大剂量青霉素治疗有效。     

Is there any role for computed tomography measurements of medial temporal lobe atrophy in dementia? A review of the literature and case series from a memory clinic

Neuroimaging in dementia has focused on documenting any burden of vascular disease or excluding any reversible intracranial pathology. We review the use of computed tomography to examine for medial temporal lobe atrophy in dementia and compare this with a case series of such measurements from our memory clinic. Measures of medial temporal lobe atrophy were used to separate patients with Alzheimer's disease from those with normal cognition, mood disorders or other forms of early dementia.     

Systematic review of clinical prediction rules for neuroimaging in the evaluation of dementia

BACKGROUND: Clinical practice guidelines for dementia do not recommend routine neuroimaging but vary in their recommended clinical prediction rules to identify patients who should undergo neuroimaging for potentially reversible causes of dementia. METHODS: Using a MEDLINE search supplemented by other strategies, we identified studies from January 1, 1983, through December 31, 1998, that evaluated the diagnostic performance of a clinical prediction rule. We calculated the sensitivity and specificity of each rule, then evaluated their diagnostic performance in a hypothetical cohort of 1000 patients with dementia, varying the prevalence of potentially reversible dementia from 1% to 15%. RESULTS: We identified 7 studies that evaluated at least 1 of 6 different clinical prediction rules. Only one rule consistently had high sensitivity (>85%) across all studies; none consistently had high specificity (>85%). Six of the 7 studies included less than 15 cases of potentially reversible dementia; thus the sensitivity and specificity for each rule had relatively wide confidence intervals. At a 5% prevalence of potentially reversible dementia, all rules had low positive predictive value (<15%) in our hypothetical cohort. Depending on the rule, our analysis predicts 6 to 44 of the 50 patients with potentially reversible dementia (5% prevalence in cohort of 1000 patients) would not undergo imaging. CONCLUSIONS: There is considerable uncertainty in the evidence underlying clinical prediction rules to identify which patients with dementia should undergo neuroimaging. Application of these rules may miss patients with potentially reversible causes of dementia.     

肿瘤病理诊断与临床诊断不一致成因分析

目的研究肿瘤患者病理诊断与临床诊断之间不一致的发生率、成因及对患者的影响。方法收集安徽医科大学第二附属医院肿瘤中心1275例住院患者的临床资料,通过病理会诊及临床随访判断病理诊断与临床诊断的一致性。分析不一致的成因和对患者的影响。结果 65例(5.3%)病理诊断与临床诊断不一致。病理诊断与临床诊断不一致原因:取材不当36例(55.4%)、病变复杂22例(33.9%)、病理医生的经验6例(9.2%)和提供病史不完整1例(1.5%)。分别对比不同级别医院获得的病理诊断与临床诊断一致性的差异(P0.05)、不同病变部位病理诊断与临床诊断一致性的差异(P0.05),均有统计学意义。结论病理诊断与临床诊断之间不一致真实存在。临床医生应正确看待病理诊断,并且将病理诊断结果与临床特点、影像学结果综合分析,以得到最为准确的诊断。     

Exploration of functional brain networks in neurodegenerative disease

Neurodegenerative diseases target specific anatomical and functional brain networks. A number of intrinsic functional brain networks can be identified in individuals at rest, that correspond to networks found in task-based functional MRI studies. However, the impact of pathological changes and relation to disease severity remains unclear.We examined three networks of interest in patients with progressive supranuclear palsy (PSP) and the neurodegenerative corticobasal syndrome (CBS). These two diseases share features of cognitive decline and a movement disorder, although they have important phenotypic differences. They are both associated with accumulation of tau protein in neuronal and glial cells. We examined the default mode network, which is deactivated during tasks and has been consistently implicated in Alzheimer's disease; the salience network, often activated during tasks and affected in frontotemporal dementia; and the basal ganglia network, since both PSP and CBS pathology affects the basal ganglia.Using resting state functional MRI scanning, we applied independent component analysis and template matching to identify networks of interest. Spatiotemporal group differences in network architecture were identified with dual regression to extract spatial maps for each network in individuals and perform group-wise t tests. In addition, clinical test scores were added as covariates to group comparisons.Increased functional connectivity was seen within all three networks in disease groups. Decreased connectivity was seen between the basal ganglia network and cortical regions in PSP. Network changes correlated with worse scores on clinical measures of disease.Increased connectivity in relevant functional brain networks identify neurodegenerative diseases and mirror clinical disease features.FundingUK Medical Research Council.     

Blood-based biomarkers of microvascular pathology in Alzheimer’s disease

Sporadic Alzheimer’s disease (AD) is a genetically complex and chronically progressive neurodegenerative disorder with molecular mechanisms and neuropathologies centering around the amyloidogenic pathway, hyperphosphorylation and aggregation of tau protein, and neurofibrillary degeneration. While cerebrovascular changes have not been traditionally considered to be a central part of AD pathology, a growing body of evidence demonstrates that they may, in fact, be a characteristic feature of the AD brain as well. In particular, microvascular abnormalities within the brain have been associated with pathological AD hallmarks and may precede neurodegeneration. In vivo assessment of microvascular pathology provides a promising approach to develop useful biological markers for early detection and pathological characterization of AD. This review focuses on established blood-based biological marker candidates of microvascular pathology in AD. These candidates include plasma concentration of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) that are increased in AD. Measures of endothelial vasodilatory function including endothelin (ET-1), adrenomedullin (ADM), and atrial natriuretic peptide (ANP), as well as sphingolipids are significantly altered in mild AD or during the predementia stage of mild cognitive impairment (MCI), suggesting sensitivity of these biomarkers for early detection and diagnosis. In conclusion, the emerging clinical diagnostic evidence for the value of blood-based microvascular biomarkers in AD is promising, however, still requires validation in phase II and III diagnostic trials. Moreover, it is still unclear whether the described protein dysbalances are early or downstream pathological events and how the detected systemic microvascular alterations relate to cerebrovascular and neuronal pathologies in the AD brain.     

Frontal lobe degeneration of non-Alzheimer type. II. Clinical picture and differential diagnosis

In a longitudinal prospective study of dementia, 158 patients were investigated post mortem. Sixteen patients were classified as frontal lobe dementia (FLD) of non-Alzheimer type and four cases as Pick's disease. Positive heredity for dementia was reported in 50% of these cases compared to 30% in a reference group of patients with Alzheimer's disease (AD). The typical clinical picture in FLD and Pick's disease was that of a slowly progressive dementia, at an early stage dominated by personality change, lack of insight, disinhibition, and later on stereotypy and increased apathy. There was also a progressive dynamic aphasia ending in mutism and amimia. Memory and spatial functions were comparatively spared. Disinhibition, oral/dietary hyperactivity, and echolalia were more consistently found in Pick's disease compared to FLD. The differential diagnosis against AD, cerebrovascular dementia, and other degenerative dementias and against affective disorders and psychotic reactions are discussed.     

Coexisting cerebral infarction in Alzheimer's disease is associated with fast dementia progression: applying the National Institute for Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences Neuroimaging Criteria in Alzheimer's Disease with Concomitant Cerebral Infarction

OBJECTIVES: To determine whether patients with Alzheimer's disease (AD) and coexisting cerebral infarction (CI) that satisfy the National Institute for Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) neuroimaging criteria for vascular dementia (VaD) progress faster than those who do not satisfy the neuroimaging criteria. DESIGN: Retrospective cohort study. SETTING: Multidisciplinary memory clinic in a tertiary hospital. PARTICIPANTS: One hundred thirty consecutive patients with AD, with or without CI, followed up regularly for more than 1 year. MEASUREMENTS: The patients were classified according to the distribution and severity of CI as defined according to the NINDS-AIREN neuroimaging criteria into those with AD and no CI (AD-N), those with AD and CI not fulfilling neuroimaging criteria (AD-I), and those with AD and CI fulfilling neuroimaging criteria (AD-V), and their differences in dementia progression were tested. The loss of independence, indicated by institution admission or a clinical dementia rating (CDR) score of 3, was defined as the endpoint for a poor outcome. RESULTS: The mean age was 75.8, and 68.5% were women. The initial Mini-Mental State Examination (MMSE) score was 15.3+/-0.4, and the average duration of follow up was 30.4 months. Fifty-four patients had reached study endpoint at the time of analysis. AD-V (hazard ratio (HR)=3.1, 95% confidence interval (CI)=1.2-8.2), use of psychotropic drugs (HR=2.7, 95% CI=1.1-6.4), and initial MMSE score (HR=0.9, 95% CI=0.8-1.0) were independent predictors of poor outcome in the Cox regression model. CONCLUSION: In AD, co-occurrence of CI with distribution and severity as defined in the NINDS-AIREN neuroimaging criteria for VaD is associated with faster dementia progression.