Hallucinations and signs of parkinsonism help distinguish patients with dementia and cortical Lewy bodies from patients with Alzheimer's disease at presentation: a clinicopathological study.

OBJECTIVES: To compare, in a retrospective clinicopathological study, the presentation features of patients with dementia and cortical Lewy bodies (Lewy body dementia) with those of patients with Alzheimer's disease. METHODS: From a population of 426 cases from the dementia brain bank, 39 cases of Lewy body dementia and 61 cases of Alzheimer's disease with presentation details were identified. RESULTS: The Lewy body dementia group had significantly more frequent hallucinations (23% v 3%, P = 0.006) and signs of parkinsonism (41% v 5%, P < 0.0001) than the Alzheimer's disease group. The Lewy body dementia group also had a greater proportion of men (62% v 34%, P = 0.013). CONCLUSION: Hallucinations and signs of parkinsonism help distinguish Lewy body dementia from Alzheimer's disease at presentation. These indicators may not be very sensitive, because they were reported for less than half of the patients with Lewy body dementia.     

Dementia in rural primary care practices in Lake County, Oregon

Procedures used in assessing patients with dementia in rural settings are little studied. Among all patients aged 65 years and older in the four primary care practices in Lake County, Oregon, dementia cases were identified from computerized office databases using preselected International Classification of Diseases, Ninth Edition, codes. A semi-structured chart review determined (1) a dementia diagnosis, (2) cognitive and functional domains assessed, and (3) diagnostic studies performed. Of 1540 available records, 30 had dementia. Nineteen of them met National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association criteria for Alzheimer's disease (AD). Cognitive impairment was documented in 73% of the 51 identified charts and all with AD. Laboratory studies were recorded in 33% overall and in 42% with AD. Neuroimaging was documented in 18% overall and in 16% with AD. The prevalence of documented dementia in these rural practices may be low, possibly because cases of mild dementia may not be labeled as such. Laboratory studies were performed in a minority of cases of dementia.     

Family conflict in dementia: prodigal sons and black sheep

OBJECTIVE: To describe family conflict in cases of dementia referred to the Guardianship Tribunal of New South Wales, Australia. METHOD: The file notes of 50 cases of family and systems conflict in cases of dementia presented to the Guardianship Tribunal were examined. Demographics, MMSE score, and type and severity of dementia were recorded. The documents and evidence presented to the Tribunal were coded and subjected to thematic analysis to identify the themes of the conflict, the protagonists and the position of the person with dementia with respect to the conflict. RESULTS: Family conflict was most commonly seen in mild to moderate dementia. Conflict occurred most frequently between siblings (with a group of siblings allied against a 'black sheep' member) and involved other systems such as service providers in 25% of cases. The person with dementia was usually involved in the conflict or in alliance with one or other of the family members in conflict, especially when paranoid ideation was fuelled by family members. Common themes included accusations of neglect, exploitation, lack of communication or sequestration of the person with dementia. No family had received family therapy prior to the application; conciliation during the hearing was successful in 30% of cases. Legal transactions such as Powers of Attorney were frequently made and frequently revoked by persons with dementia involved in family conflict. CONCLUSION: Dementia may be a great family divider, particularly when there are cracks in family solidarity. The understanding of family conflict in dementia has ramifications for both clinical and medico-legal practice. These findings may encourage family-centered interventions which address family dynamics and interpersonal conflict. They may also assist in capacity assessments of persons with dementia who change legal documents because of family conflict.     

Why are stroke patients prone to develop dementia?

Stroke patients are more likely to develop dementia than age- and sex-matched controls but the pathogenesis of dementia remains unresolved in most of them. The aim of this review is to determine, from the available literature, the theoretical reasons for a stroke patient to become demented. We found three distinct factors that may explain the occurrence of dementia after a stroke. Firstly, post-stroke dementia may be the direct consequence of the vascular lesions of the brain: this is the most likely cause in patients with normal cognitive functions before a strategic infarct, especially in young patients, in Icelandic-type hereditary amyloid angiopathy and in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Secondly, post-stroke dementia may be due to an associated asymptomatic Alzheimer pathology; the reasons for such an association are that (1) some cases of dementia occurring after a stroke are progressive and Alzheimer’s disease (AD) is the most frequent cause of progressive dementia; (2) age and APOE ɛ 4 genotype are risk factors for both AD and ischaemic stroke; (3) a vasculopathy is often associated with AD. Lastly, white matter changes may also contribute to dementia because they often indicate small-vessel disease and a higher risk of stroke recurrence, and may lead to slight cognitive impairment. Finally, the summation of vascular lesions of the brain, white matter changes, and Alzheimer pathology might lead to dementia, even when each type of lesion, on its own, is not severe enough to induce dementia. Therefore, in patients followed up after a stroke, the term “post-stroke dementia” is probably more appropriate than that of vascular dementia because it includes all possible causal factors. Received: 15 July 1996 Accepted: 19 October 1996     

Mitochondrial control of autophagic lysosomal pathway in Alzheimer's disease

When first described by Alois Alzheimer in 1907, AD was seen as a disorder that causes dementia and characterized by two defining neuropathological lesions, later associated with all forms of AD. While the etiology of AD remains largely unclear, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in AD. Mitochondria are exceptionally poised to play a crucial role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between mitochondrial dysfunction, autophagy impairment and amyloid-β accumulation in Alzheimer's disease pathophysiology. The knowledge that autophagic insufficiency may compromise the cellular degradation mechanisms that may culminate in the progressive accumulation of dysfunctional mitochondria, aberrant protein aggregates buildup and lysossomal burden shield new insights to the way we address Alzheimer's disease. In line with this knowledge an innovative window for new therapeutic strategies aimed to activate or ameliorate macroautophagy may be opened.     

Where fronto-temporal dementia should be placed in the history of Pick's disease and related disorders]

Pick syndrome, non-Alzheimer type dementia with primary degeneration in the anterior portion of the brain, has been shown to include several disease-entities besides classic Pick's disease. Fronto-temporal dementia (FTD) proposed by Lund & Manchester group is a concept that includes Pick's disease, and its "clinical diagnostic features" are useful because they distinguish dementia with frontal and anterior temporal involvement from Alzheimer type dementia. FTD is classified into three types, the frontal lobe degeneration (FLD) type, Pick type and motor neuron disease (MND) type, and neuropathological diagnostic features of each type are presented. In Japan, however, cases neuropathologically corresponding to the FLD type, which has mild frontal dominant degeneration with heavy heredity, have not been previously reported. Classic Japanese Pick's disease is consistent with Pick type, however, cases of Pick's disease with and without Pick body exist in nearly the same number in Japan. The latter may include heterogeneous types, which should be elucidated. MND type corresponds to Japanese cases, called Yuasa-Mitsuyama disease or dementia with motor neuron disease, and could be actually diagnosed because such patients do not exhibit severe personality change and accompany symptoms of amyotrophic lateral sclerosis or spinal progressive muscular atrophy in their clinical course. In addition, Pick syndrome includes progressive subcortical gliosis, corticobasal degeneration, basophilic inclusion body disease and fronto-temporal dementia with parkinsonism linked chromosome 17. Progressive aphasia and semantic dementia are neuropsychologically important concepts, however, they are symptom-complex and are dominated only by where the degeneration begins and how it progresses. They should not be confused with pathologically confirmed disease-entities.     

A vascular risk factor index in relation to mortality and incident dementia

To develop a method for quantifying risks of death and dementia in relation to vascular risk factors the Gothenburg H-70 1901-02 birth cohort was studied (n=380, was followed over 20 years, with 103 incident dementia cases). Separate vascular risk factor indices were calculated using 23 vascular risk factors to predict: (i) dementia-free-survival, and (ii) incident dementia derived from post hoc optimal separation of affected and unaffected cases. Classification of adverse outcomes (dementia/non-dementia; alive/dead) was assessed using receiver-operator characteristic (ROC) curves, and the area under the curve (AUC). Each index showed high separation between affected and unaffected cases. For dementia/non-dementia, the AUC was 0.74+/-0.02 for 10 year and 0.67+/-0.02 for 20 year; for death/survival, the AUC was 0.75+/-0.02 for 10 years and 0.79+/-0.03 for 20 years. Of note, few items were important in both indexes, and most showed reciprocal effects (e.g. decreased the risk of death but increased the risk of dementia). Our results suggest that vascular risk factor indexes can give robust estimates of dementia and life span prognoses in elderly people, but death and dementia have different risk profiles. This may be because of death being a competing risk for incident late-onset dementia.     

Progressive myoclonic ataxia (the Ramsay Hunt syndrome)

It has been suggested from studies of patients with progressive myoclonus epilepsy that the term Ramsay Hunt syndrome should be abandoned, as its use has led to nosologic confusion, and because, in the light of modern diagnostic techniques, the majority of cases can be allocated to specific disease categories, chiefly, Unverricht-Lundborg disease (Baltic myoclonus) and mitochondrial encephalomyopathy. Review of 30 cases of this syndrome, defined as progressive ataxia and myoclonus and infrequent seizures in the absence of dementia, showed that a clinical or biochemically supported diagnosis could not be made in 43%. This low diagnostic yield probably reflects differences in ascertainment of patients; those described here were referred with a syndrome of progressive myoclonic ataxia (the Ramsay Hunt syndrome) rather than progressive myoclonus epilepsy. These two syndromes share common causes, but a smaller proportion of patients with progressive myoclonic ataxia can currently be diagnosed precisely during life.     

Precautions in familial transmissible dementia: including familial Alzheimer's disease.

Recent studies suggest that some cases of familial Alzheimer's disease may be associated with a transmissible dementia. Animal experiments show that presymptomatic carriers of "slow virus" agents can transmit disease. Because of these findings, we have extended the precautions previously delineated to include those at risk of acquiring transmissible dementia, specifically, to the descendants of those affected with familial Alzheimer's disease or familial Creutzfeldt-Jakob's disease. Blood donation from such persons may pose a danger, because transmissible spongioform encephalopathy has been passed from animal to animal by blood serum and by the WBC layer of frozen whole blood.     

Mitochondrial myopathy and encephalopathy: three cases--a deficiency of NADH-CoQ dehydrogenase?

We describe three patients with mitochondrial myopathy, dementia, loss of vision and hearing, seizure disorder with myoclonus, intermittent headaches of a vascular type, visual hallucinations, cerebellar dysfunction, and lactic acidosis. Muscle biopsies in all patients and liver biopsy in one revealed abnormal mitochondria. The disorder may be due to a deficiency of mitochondrial NADH-CoQ dehydrogenase.     

Melas: an original case and clinical criteria for diagnosis.

We describe the full history and postmortem findings in one of the first identified cases of mitochondrial encephalomyopathy with stroke-like episodes (MELAS). To clarify diagnostic criteria, we analyzed 69 reported cases. The syndrome should be suspected by the following three invariant criteria: (1) stroke-like episode before age 40 yr; (2) encephalopathy characterized by seizures, dementia, or both; and (3) lactic acidosis, ragged-red fibers (RRF), or both. The diagnosis may be considered secure if there are also at least two of the following: normal early development, recurrent headache, or recurrent vomiting. There are incomplete syndromes in relatives of patients with the full syndrome and incomplete syndromes might also be encountered in sporadic cases. Some MELAS patients have features of the Kearns-Sayre syndrome (KSS) or myoclonic epilepsy with ragged-red fibers (MERRF), but none had the full KSS syndrome. In partial or confusing cases, analysis of mitochondrial DNA (mtDNA) may point to the correct diagnosis; however, not all patients with clinical MELAS have had the typical mtDNA point mutation and some patients with the mutation have clinical syndromes other than MELAS.     

Is the dementia rate increasing in Beijing? Prevalence and incidence of dementia 10 years later in an urban elderly population

OBJECTIVE: To examine the time trend of dementia morbidity over the past decade in Beijing, China. METHOD: In 1997, 1593 community-dwelling elderly aged 60+ years were examined and followed-up over 2-years to identify incident dementia. A similar cohort study of dementia conducted in the same district 10 years prior was used as historical comparison to examine the time trend of dementia incidence. RESULTS: Forty prevalent dementia cases were identified at the initial examination for a prevalence of 2.51% (95% CI: 1.74-3.28) and 25 incident cases were identified at the follow-up visit for an incidence of 0.90% (0.55-1.25) among residents aged 60+ years. Alzheimer's dementia (AD) was the most common type of dementia in both prevalent and incident cases. CONCLUSION: The prevalence and incidence rates of dementia in Beijing were slightly higher than those 10 years ago, which was partly because of population aging. AD became the most common subtype of dementia.     

No antibodies to HTLV-I and HIV in patients with dementia in Finland

Patients with human immunodeficiency virus (HIV) have often progressive dementia. Human T cell lymphotropic virus Type I (HTLV-I) infection has not been reported to cause dementia. We tested antibodies to HTLV-I and HIV in serum and cerebrospinal fluid in 69 Finnish patients referred because of dementia to an outpatient department of neurology. No antibodies to HTLV-I and HIV were detected in patients with the clinical diagnosis of Alzheimer's disease, vascular dementia, secondary dementia due to a specific cause, or in cases of atypical dementia.     

MELAS: a neuropsychological and radiological follow-up study. Mitochondrial encephalomyopathy,lactic acidosis and stroke

We report on a patient with long standing, full-blown mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). In contrast to earlier publications, detailed neuropsychological assessment revealed no dementia but a pattern of distinct cognitive deficits with marked impairment of visuo-constructive and executive functions. Focal lesions and progressing atrophy mainly of the basal ganglia and the temporo-parieto-occipital area with preservation of hippocampal and entorhinal structures were present. Furthermore, a 4-year follow-up assessment revealed an increasing deterioration of distinct cognitive functions, including phasic alertness, tactile functions and the discrimination of tone pitch and rhythm. This may be because of chronic regional metabolic disturbances, as there was no further stroke-like episode in that period of time.     

Dementia disclosing primary Gougerot-Sj?gren syndrome]

Two cases of primary Sj?gren's syndrome revealed by dementia are reported. The patients had progressive or subacute memory dysfunction and psychiatric disorders with depression and delirium. The diagnosis of Sj?gren's syndrome was established by biopsy of the minor salivary glands. Both patients were treated with corticosteroids. The neuropsychiatric symptoms improved dramatically in one case and remained unchanged in the other case. Dementia in Sj?gren's syndrome seems to be without aphasia, apraxia or agnosia, and associated with psychiatric features, particularly depressive symptoms, thus including some characteristics of subcortical dementia. Diagnosis may be difficult because, as shown in our cases, symptoms of ocular and buccal dryness can be absent. Salivary gland biopsy can be useful in the evaluation of patients with dementia of undetermined etiology.     

Immunohistochemical localization of X-linked inhibitor of apoptosis protein in brainstem-type and cortical Lewy bodies

X-linked inhibitor of apoptosis protein (XIAP) blocks the apoptosis by binding to and inhibiting caspases-3, 7, and 9. XIAP is negatively regulated by the mitochondrial serine protease, HtrA2/Omi. The aim of this study was to investigate the role of XIAP and the relationship between XIAP and HtrA2/Omi in patients with Parkinson's disease or dementia with Lewy bodies. We conducted immunohistochemical studies on XIAP in formalin-fixed, paraffin-embedded sections from eight normal participants, 10 patients with Parkinson's disease, five patients with dementia with Lewy bodies, and seven patients with Alzheimer's disease, and then double-labeling immunohistochemistry for XIAP and HtrA2/Omi in sections from the Parkinson's disease and dementia with Lewy bodies cases. Brainstem-type and cortical Lewy bodies were intensely immunostained for XIAP, and XIAP immunoreactivity was localized to the halos of brainstem-type Lewy bodies and to the entire bodies of cortical Lewy bodies. Double immunofluorescence analyses showed that XIAP and HtrA2/Omi immunoreactivities were colocalized to both types of Lewy bodies. Our results suggest that XIAP may be partially associated with the pathogenesis of Parkinson's disease and dementia with Lewy bodies.     

Neuroradiologic and pathologic approaches to the diagnosis of dementia syndrome]

"Dementia" is the general term used to describe the symptom complex of intellectual deterioration in adult. Interest in accurately diagnosing dementia is a relatively recent phenomenon. This is reflected in both the development of neuroradiologic examinations, including MRI and SPECT as well as PET, and marked increase in both the incidence and prevalence of dementia associated with increase of the elderly population. The clinical evaluation remains the key to the differential diagnosis. Most cases of "typical dementia" can be diagnosed accurately by clinical criteria. However, the definitive diagnosis of "atypical dementia" still requires intensive neuroradiologic studies and histologic examination of brain to identify characteristic structural changes. In this study, we presented both neuroradiologic and neuropathologic information, which is important in diagnosing diseases that present atypical dementia syndrome. These diseases are as follows; AIDS, isolated CNS angiitis, CO intoxication. Wernicke encephalopathy, adrenoleukodystrophy, Nasu disease, CADASIL, CARASIL, glioblastoma, primary CNS lymphoma, antiphospholipid antibody syndrome, reversible posterior leukoencephalopathy syndrome, mitochondrial encephalopathy (MELAS), and subcortical vascular dementias.     

Perivascular deposits of serum proteins in cerebral cortex in vascular dementia

Summary Immunocytochemical techniques were used to study the histopathologic changes in vascular dementia, i. e., both multi-infarct dementia (MID) and MID combined with Alzheimer changes (MID/SDAT). In eight of 13 of the dementia cases strongly immunostained deposits of plasma proteins were observed around numerous capillaries of layers I–IV of frontal grey matter. Each of these deposits contained albumin, prealbumin, IgG, C1q, C3c, and fibrinogen. No such deposits were found in any of the seven nondemented aged controls. In contrast, in white matter in both demented and normal aged control cases only weak immunostaining of serum proteins was observed which gradually decreased with the distance from the vessels. The presence of heavy deposits of serum proteins exclusively around the capillaries of the gray matter in cases with vascular dementia may indicate a defect of the cortical capillary system which might play a role in the clinical symptoms seen in vascular dementia. The enrichment of C1q within the deposits is intriguing as this might occur because of the binding of C1 through its subunit C1q to the antibody-antigen complex and thereby support a possible immunologic involvement in the formation of these deposits.Supported by grants from the Swedish Medical Research Council, King Gustaf Vth and Queen Victoria's foundation, Osterman's, Pfannenstill's, Mångberg's, and Thuring's foundations     

Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism

BACKGROUND: Parkinson disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Genes contributing to rare mendelian forms of PD have been identified, but the genes involved in the more common idiopathic PD are not well understood. OBJECTIVES: To identify genes important to PD pathogenesis using microarrays and to investigate their potential to aid in diagnosing parkinsonism. DESIGN: Microarray expression analysis of postmortem substantia nigra tissue. PATIENTS: Substantia nigra samples from 14 unrelated individuals were analyzed, including 6 with PD, 2 with progressive supranuclear palsy, 1 with frontotemporal dementia with parkinsonism, and 5 control subjects. MAIN OUTCOME MEASURES: Identification of genes significantly differentially expressed (P<.05) using Affymetrix U133A microarrays. RESULTS: There were 142 genes that were significantly differentially expressed between PD cases and controls and 96 genes that were significantly differentially expressed between the combined progressive supranuclear palsy and frontotemporal dementia with parkinsonism cases and controls. The 12 genes common to all 3 disorders may be related to secondary effects. Hierarchical cluster analysis after exclusion of these 12 genes differentiated 4 of the 6 PD cases from progressive supranuclear palsy and frontotemporal dementia with parkinsonism. CONCLUSIONS: Four main molecular pathways are altered in PD substantia nigra: chaperones, ubiquitination, vesicle trafficking, and nuclear-encoded mitochondrial genes. These results correlate well with expression analyses performed in several PD animal models. Expression analyses have promising potential to aid in postmortem diagnostic evaluation of parkinsonism.     

Neuropathological discrepancy between Japanese Pick’s disease without Pick bodies and frontal lobe degeneration type of frontotemporal dementia proposed by Lund and Manchester Group

The concept of frontotemporal dementia (FTD) proposed by the Lund and Manchester group is useful because it distinguishes dementia with frontal and anterior temporal involvement from Alzheimer‐type dementia. The classification and definition of FTD and related disorders, however, are controversial. One point of controversy is the neuropathology of the frontal lobe degeneration (FLD) type of FTD. The FLD type is described as having mild frontal and anterior temporal atrophy and no accompanying tau or ubiquitin pathology. We investigated cases of Japanese Pick’s disease without Pick bodies (PB), the majority of which are thought to correspond to FLD type, in order to clarify whether the nature of the degeneration in these cases could be distinguishable from that in Japanese Pick’s disease with PB, which corresponds approximately to the Pick type of the Lund and Manchester group. Except for the presence of tau‐pathology, no obvious differences were noted between Pick’s disease without PB (FLD type) and Pick’s disease with PB (Pick type) either on neuropathological examination of own cases or a questionnaire survey of Japanese neuropathologists. The reason for this discrepancy may be based on the role of heredity, namely, most Japanese cases of Pick’s disease are solitary, while the FTD cases of the Lund and Manchester group were reportedly accompanied by extensive familial history. There is a possibility that Japanese, British, and Swedish neuropathologists deal with heterogeneous groups of dementia characterized as FTD without tau or ubiquitin pathology.