[Clinical heterogeneity of Alzheimer's disease. Different clinical profiles can predict the progression rate]. / Heterogeneidad clinica de la enfermedad de Alzheimer. Diferentes perfiles clinicos pueden predecir el intervalo de progresion.

INTRODUCTION: Alzheimer's disease (AD) is a degenerative dementia that may disclose different cognitive, behavioral, psychiatric and functional symptoms since onset. These distinct cognitive profiles support the conception of clinical heterogeneity and account for AD's highly variable rate of progression. In spite of strict diagnostic criteria NINCS ADRDA's and DSM IV the clinical certainty is only about 85%. Mayeux define 4 subtypes: a). Benign: mild cognitive and functional impairment without focal signs and late onset behavioral signs, slow progression; b). Myoclonic: usually of presenile onset with severe cognitive deterioration, mutism and early onset myoclonus; c). Extrapyramidal: early onset akineto rigid signs with severe cognitive, behavioral and psychiatric involvement; d). Typical: gradual and progressive cognitive, behavioral and functional impairment. The differentiation of these subtypes will allow us to define discrete patterns of progression, to define prognostic subgroups, and to homogenize them for clinical research and drug trials. DEVELOPMENT: We examined 1000 charts of probable AD patients from the Santojanni Center. We found 42% extrapyramidal, 35% typical, 15% benign and 8% myoclonic. The early onset of parkinsonism and myoclonus predict a rapidly evolving cognitive impairment and a more severe rate of progression with psychiatric disorders and dependency in activities of daily living. (DADL) Patients with low level of education, low cognitive performance at entry as well as those with rapid rate of cognitive deterioration had a faster rate of progression to DADL. CONCLUSION: Delusions, low level of education, extrapyramidal signs and motor hyperactivity but not hallucinations, and anosognosia were the best non cognitive predictors of DADL.

Heterogeneidad clínica de la enfermedad de Alzheimer. Diferentes perfiles clínicos pueden predecir el intervalo de progresión / Clinical heterogeneity of Alzheimer's disease. Different clinical profiles can predict the progression rate

Introducción. La enfermedad de Alzheimer es una demencia degenerativa que puede presentar desde su inicio diferentes crisoles de síntomas cognitivos, conductuales y funcionales apoyando su heterogeneidad clínica e intervalo de progresión. A pesar de unos criterios diagnósticos rígidos (NINCDS-ADRDA y DSM IV), la certeza diagnóstica es del 85 por ciento. Mayeux define cuatro subtipos clinicoevolutivos: 1. Benigno: deterioro cognitivo y funcional leve, tardía aparición de signos neurológicos focales y trastornos conductuales con progresión lenta; 2. Mioclónico: frecuente aparición presenil, con un grave intervalo de deterioro cognitivo, mutismo y mioclonías precoces; 3. Extrapiramidal: precoz aparición de signos acinéticos rígidos con un grave deterioro cognitivo, conductual y funcional, y 4.Típico: deterioro gradual y progresivo cognitivo, conductual y funcional. La identificación de estos subgrupos nos permitirá definir el pronóstico y homogeneizarlos grupos de pacientes para la investigación clínica y farmacológica. Desarrollo. Para demostrar mejor esta heterogeneidad, se revisan 1.000 historias clínicas de pacientes asistidos en el centro con el diagnóstico de enfermedad de Alzheimer probable. El 42 por ciento presentó el subgrupo extrapiramidal; el 35 por ciento, el típico;el15 por ciento,elbenigno,yel8 por ciento, el mioclónico. La aparición precoz de parkinsonismo y mioclonías predice un deterioro cognitivo rápido, con una progresión precoz a síntomas conductuales y dependencia en las actividades de la vida diaria (AVD). Los pacientes con baja escolaridad, pobre funcionamiento cognitivo desde el inicio, así como los que presentan un rápido intervalo de deterioro cognitivo, muestran un precoz inicio de la dependencia en las AVD. Conclusión. La baja escolaridad, los delirios, el extrapiramidalismo y la hiperactividad motora aberrante, pero no las alucinaciones o la anosognosia, fueron los mejores predictores no cognitivos de la dependencia en las AVD (AU)

Vascular dementia: the Latin American perspective.

Population aging is a process that is especially accelerated in some parts of the world. One example is in Latin America. As with other developing regions, Latin America has to confront population "graying" in the context of an emerging economy. As a result of this and of their health history, the prevalence and incidence of age-related pathologies are different than those in the developed world. The burden of dementia is significant for patients, families, health systems, and public health. The aim of this paper was to summarize data from the scarce dementia epidemiological studies available in Latin America, the diagnostic criteria used in most countries and the most widely used diagnostic tools and neuropsychological assessment instruments (some of them translated, validated, and harmonized). Reference is made to the approval process and availability in Argentina of dementia and cognitive decline-related drugs.

Dementia in Argentina and other Latin-American countries: An overview.

Latin-American countries are expected to experience an expansion of the elderly population, as life expectancy increases. We reviewed the literature to determine the frequency of dementia in our region and surveyed selected Latin-American countries to determine the availability of diagnostic and treatment services and long-term care facilities. Latin-American countries face a challenge to develop public health strategies to cope with the anticipated heightened number of elderly with cognitive impairment.

Loss of motor units in Alzheimer's disease.

Little attention has been paid in the literature to the state of the peripheral nervous system (PNS) in Alzheimer's disease (AD). We conducted a comprehensive electrophysiological study in 15 AD patients looking for functional abnormalities within their PNSs. A reduction of the number of functioning motor units (MU) was found in the thenar and soleus muscles of most of these patients without enlargement of the remaining MUs territories, while the motor and sensory conduction velocities of the peripheral nerves were preserved. These results suggest dysfunction of the spinal motoneurones in patients afflicted with this condition.

Presenilin 1 Met146Leu variant due to an A --> T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina.

Most of the cases of early-onset familial Alzheimer's disease (FAD) are related to missense mutations in the presenilin 1 (PS-1) gene on chromosome 14. Although PS-1 mutations are distributed throughout the entire open reading frame, most mutations are found in transmembrane region II and hydrophilic loop VI encoded by exons 5 and 8, respectively. These two groups of substitutions are associated with an age of onset of 40-43 years for exon 5 and 45-55 years for exon 8, respectively. We have previously described a South American pedigree from Argentina with early-onset FAD (mean age of onset 38.9 +/- 3.9 years) with no mutations in exons 16 and 17 of the beta-protein precursor gene (betaPP770 transcript). Here we report the identification of an A --> T transversion at the first position of codon 146 of PS-1 in these patients. This missense mutation results in a Met --> Leu substitution, as reported for the Italian pedigrees Tor1.1 and FAD4. The significant differences in ages of onset and death among members of generations II-III and IV suggest that other genetic and/or environmental factors may influence disease phenotype in this pedigree.

Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination.

OBJECTIVE: To analyse the natural history and survival of corticobasal degeneration by investigating the clinical features of 14 cases confirmed by postmortem examination. METHODS: Patients with definite corticobasal degeneration were selected from the research and clinical files of seven tertiary medical centres in Austria, the United Kingdom, and the United States. Clinical features were analysed in detail. RESULTS: The sample consisted of eight female and six male patients; mean age at symptom onset was 63 (SD 7.7) years, and mean disease duration was 7.9 (SD 2.6) years. The most commonly reported symptom at onset included asymmetric limb clumsiness with or without rigidity (50%) or tremor (21%). At the first neurological visit, on average 3.0 (SD 1.9) years after symptom onset, the most often encountered extrapyramidal features included unilateral limb rigidity (79%) or bradykinesia (71%), postural imbalance (45%), and unilateral limb dystonia (43%). Ideomotor apraxia (64%), and to a lesser extent cortical dementia (36%), were the most common cortical signs present at the first visit. During the course of the disease, virtually all patients developed asymmetric or unilateral akinetic rigid parkinsonism and a gait disorder. No patient had a dramatic response to levodopa therapy. Median survival time after onset of symptoms was 7.9 (SD 0.7) (range, 2.5-12.5) years, and, after the first clinic visit, 4.9 (SD 0.7) (range, 0.8-10) years. Early bilateral bradykinesia, frontal syndrome, or two out of tremor, rigidity, and bradykinesia, predicted a shorter survival. CONCLUSION: The results confirm that unilateral parkinsonism unresponsive to levodopa and limb ideomotor apraxia are the clinical hallmarks of corticobasal degeneration, and only a minority of patients with corticobasal degeneration present with dementia. The study also suggests that a focal cognitive and extrapyramidal motor syndrome is indicative of corticobasal degeneration. Survival in corticobasal degeneration was shortened by the early presence of (more) widespread parkinsonian features or frontal lobe syndrome.

A double-blind, randomized, fixed-dose trial of fluoxetine vs. amitriptyline in the treatment of major depression complicating Alzheimer's disease.

The objective of this study was to determine the relative efficacy and safety of fluoxetine and amitriptyline in the treatment of major depression complicating Alzheimer's disease (AD). The sample included 37 patients with AD and major depression. The study design was a double-blind, fixed-dose, randomized clinical trial with 45 days of follow-up. The outcome measures were the Hamilton Depression Rating Scale (Ham-D), the Mini-Mental State Exam (MMSE), and the number of dropouts from each arm of the study. Efficacy was similar for fluoxetine and amitriptyline. At Day 45, there was a mean 9.4-point reduction in Ham-D scores (t[df,62] = 9.68, P < 0.0001) and a 2.4-point mean increase in MMSE scores as compared to baseline (t[df,2] = 2.69, P = 0.009). Eleven (58%) of the amitriptyline-treated patients dropped out, compared with 4 (22%) of the fluoxetine-treated patients (chi 2[df,2] = 8.9, P = 0.017). The authors conclude that antidepressant treatment for major depression complicating AD is effective. While fluoxetine and amitriptyline are equally effective, fluoxetine is better tolerated.

Clinical global measures of dementia. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.

Following is the report of the committee working on clinical global measures for antidementia drug guidelines. The concepts involved in global scales, the distinctions between change and severity scales, advantages and disadvantages of structured interviews, and anchoring of change scores are discussed, and selected existing clinical global scales are described. In addition, the committee assessed the utility of global scales in clinical trials for antidementia drugs. There was a consensus among the members of the working group on the following: (1) Clinical global scales are interview based; in most cases, they include information obtained from caregivers as well as directly from patients, but they can rely on information from the subject only. (2) Clinicians' global ratings are intended to assess clinically meaningful change based on multidimensional clinical assessment and take into account the clinical heterogeneity of dementia by assessing at least cognition, behavior, and functioning. (3) There are two distinct types of clinical global measures: (a) clinicians' interview-based global severity scales, which generally incorporate classification by stage or severity of illness and (b) clinicians' interview-based global change scales, which incorporate global assessment ratings of clinical change. The committee could not reach a consensus on whether global scales should be required in phase II and phase III clinical trials, or whether other specific assessments such as well-designed activities of daily living, cognition, and behavior measures could, when used in appropriate combinations, replace the global as assessments of clinical meaningfulness.

Which clinical features differentiate progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) from related disorders? A clinicopathological study.

The difficulty in differentiating progressive supranuclear palsy (PSP, also called Steele-Richardson-Olszewski syndrome) from other related disorders was the incentive for a study to determine the clinical features that best distinguish PSP. Logistic regression and classification and regression tree analysis (CART) were used to analyse data obtained at the first visit from a sample of 83 patients with a clinical history of parkinsonism or dementia confirmed neuropathologically, including PSP (n = 24), corticobasal degeneration (n = 11), Parkinson's disease (PD, n = 11), diffuse Lewy body disease (n = 14). Pick's disease (n = 8) and multiple system atrophy (MSA, n = 15). Supranuclear vertical gaze palsy, moderate or severe postural instability and falls during the first year after onset of symptoms classified the sample with 9% error using logistic regression analysis. The CART identified similar features and was also helpful in identifying particular attributes that separate PSP from each of the other disorders. Unstable gait, absence of tremor-dominant disease and absence of a response to levodopa differentiated PSP from PD. Supranuclear vertical gaze palsy, gait instability and the absence of delusions distinguished PSP from diffuse Lewy body disease. Supranuclear vertical gaze palsy and increased age at symptom-onset distinguished PSP from MSA. Gait abnormality, severe upward gaze palsy, bilateral bradykinesia and absence of alien limb syndorme separated PSP from corticobasal degeneration. Postural instability successfully classified PSP from Pick's disease. The present study may help to minimize the difficulties neurologists experience when attempting to classify these disorders at early stages.

Reliability of the NINDS Myotatic Reflex Scale.

The assessment of deep tendon reflexes is useful for localization and diagnosis of neurologic disorders, but only a few studies have evaluated their reliability. We assessed the reliability of four neurologists, instructed in two different countries, in using the National Institute of Neurological Disorders and Stroke (NINDS) Myotatic Reflex Scale. To evaluate the role of training in using the scale, the neurologists randomly and blindly evaluated a total of 80 patients, 40 before and 40 after a training session. Inter- and intraobserver reliability were measured with kappa statistics. Our results showed substantial to near-perfect intraobserver reliability, and moderate-to-substantial interobserver reliability of the NINDS Myotatic Reflex Scale. The reproducibility was better for reflexes in the lower than in the upper extremities. Neither educational background nor the training session influenced the reliability of our results. The NINDS Myotatic Reflex Scale has sufficient reliability to be adopted as a universal scale.

Síndromes neuropsiquiátricos por lesión en el hemisferio cerebral derecho / Neuropsychiatric syndroms produced by lesions in the right brain hemisphere

El estudio de la dominancia cerebral desempeña un papel importante en el contexto de las desórdenes de las funciones cerebrales superiores. No sólo las neuropsicológicas se encuentran lateralizadas sino también las neuropsiquiátricas. El objetivo de nuestro trabajo es la presentación de tres pacientes con trastornos psiquiátricos secundarios a una lesión del hemisferio cerebral derecho. El caso 1 es una paciente con un síndrome de Capgras, los casos 2 y 3 un síndrome de hemidespersonalización. Es frecuente que lesiones en el hemisferio derecho sean responsables de síndromes neuropsiquiátricas. El hecho de que ni las alteraciones funcionales, ni las estructurales puedan explicar por sí solas todas las características de los síndromes en estos pacientes, hace suponer que es necesaria la conjunción de ambas em proporciones variables según los casos. Probablemente aparezca en un sujeto con terreno paranoide con ligeros desórdenes perceptivos; o a la inversa, en un paciente con importantes alteraciones perceptivas como nuestros pacientes (visual en el caso 1; y sensitivas en los casos 2 y 3), bastará un pequeño trastorno afectivo para que surja la idea delirante. (AU)

Síndromes neuropsiquiátricos por lesión en el hemisferio cerebral derecho / Neuropsychiatric syndroms produced by lesions in the right brain hemisphere

El estudio de la dominancia cerebral desempeña un papel importante en el contexto de las desórdenes de las funciones cerebrales superiores. No sólo las neuropsicológicas se encuentran lateralizadas sino también las neuropsiquiátricas. El objetivo de nuestro trabajo es la presentación de tres pacientes con trastornos psiquiátricos secundarios a una lesión del hemisferio cerebral derecho. El caso 1 es una paciente con un síndrome de Capgras, los casos 2 y 3 un síndrome de hemidespersonalización. Es frecuente que lesiones en el hemisferio derecho sean responsables de síndromes neuropsiquiátricas. El hecho de que ni las alteraciones funcionales, ni las estructurales puedan explicar por sí solas todas las características de los síndromes en estos pacientes, hace suponer que es necesaria la conjunción de ambas em proporciones variables según los casos. Probablemente aparezca en un sujeto con terreno paranoide con ligeros desórdenes perceptivos; o a la inversa, en un paciente con importantes alteraciones perceptivas como nuestros pacientes (visual en el caso 1; y sensitivas en los casos 2 y 3), bastará un pequeño trastorno afectivo para que surja la idea delirante.

Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological study.

OBJECTIVE--To analyse the natural history of progressive supranuclear palsy (PSP or Steele-Richardson-Olszewski syndrome) and clinical predictors of survival in 24 patients with PSP confirmed by necropsy, who fulfilled the NINDS criteria for a neuropathological diagnosis of typical PSP. METHODS--Patients were selected from the research and clinical files of seven medical centres involving tertiary centres of Austria, England, France, and the United States. Clinical features were analysed in detail. The patients' mean age at onset of PSP was 63 (range 45-73) years. RESULTS--The most frequent clinical features (occurring in at least 75% of the patients) were early postural instability and falls, vertical supranuclear palsy, akinetic-rigid predominant parkinsonian disorder characterised by symmetric bradykinesia and axial rigidity unrelieved by levodopa, pseudobulbar palsy, and frontal release signs. Occasionally, segmental dystonia or myoclonus were described, but neither aphasia nor alien limb syndrome was reported. Fractures occurred in 25% of the patients but were unrelated to the severity of the gait or to the presence of falls. Median survival time was 5.6 (range 2-16.6) years. Onset of falls during the first year, early dysphagia, and incontinence predicted a shorter survival time. Age at onset, sex, early onset of dementia, vertical supranuclear palsy, or axial rigidity had no effect on prognosis of survival. Pneumonia was the most common immediate cause of death. PSP was most often clinically misdiagnosed as Parkinson's disease. Errors in diagnosis suggest that PSP is underdiagnosed. CONCLUSION--Progressive onset of early postural instability with falls or supranuclear vertical palsy in the fifth decade, should suggest the diagnosis of PSP. Onset of falls during the first year are emphasised, as they could lead to an early diagnosis and influence the prognosis of patients with PSP. Whether appropriate treatment of the dysphagia could prolong the survival of PSP patients needs to be explored.

Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome).

We assessed the validity and interrater reliability of neurologists who, using four different sets of previously published criteria for the clinical diagnosis of progressive supranuclear palsy (PSP), also called Steele-Richardson-Olszewski syndrome, rated 105 autopsy-proven cases of PSP (n = 24), Lewy body disease (n = 29), corticobasal ganglionic degeneration (n = 10), postencephalitic parkinsonism (n = 7), multiple system atrophy (n = 16), Pick's disease (n = 7), and other parkinsonian or dementia disorders (n = 12). Cases were presented in random order to six neurologists. Information from each patient's first and last visits to the medical center supplying the case was presented sequentially to the rater, and the rater's diagnosis was compared with the neuropathologic diagnosis of each case. Interrater agreement for the diagnosis of PSP varied from substantial to near perfect, but none of the criteria had both high sensitivity and high predictive value. Because of these limitations, we used a logistic regression analysis to identify the variables from the data set that would best predict the diagnosis. This analysis identified vertical supranuclear palsy with downward gaze abnormalities and postural instability with unexplained falls as the best features for predicting the diagnosis. From the results of the regression analysis and the addition of exclusionary features, we propose optimal criteria for the clinical diagnosis of PSP.

Síndrome de Capgras por lesión cerebral posterior derecha / Capgras Syndrome for cerebral lesion right hemisphere stroke

En 1923 el psiquiatra francés Joseph Capgras describió un cuadro clínico cuyo síntoma central era la firme creencia del paciente de que personas muy conocidas, generalmente familiares, habían sido reemplazadsa por dobles, impostores. Los pacientes reconocían su exacta similitud fisonómica, si bien negaban su identidad. Se describe una mujer de 59 años, diestra, sin historia psiquiátrica o neurológica previa, que luego de un accidente cerebrovascular isquémico cerebral posterior derecho (RM cerebro) refiere compartir algunos momentos de su actividad diaria con su marido, y más tarde con otra persona de igual fisonomía (que en realidad era su marido) a quien se refería como "el otro Manolo" o el "muchacho". En la evaluación cognitiva mostró una hemi-inatención izquierda, trastornos visuoperceptivos y visuoconstructivos, alteraciones mnésicas y severos fenómenos perseverativos. Desde su descripción original esta patología fué considerada como una manifestación exclusivamente psiquiátrica. A principios de la década del 70 comenzaron a publicarse trabajos que la asociaban a daño cerebral orgánico, referido casi siempre a lesiones hemisféricas derechas. Se relacionó a los desórdenes en la representación afectiva o de familiaridad o a fallas en el procesamiento perceptivo preconciente, ligados a una base paranoide como disparadores de este síndrome (AU)

Estrategias de codificación de la memoria visual en la enfermedad de Alzheimer y en el deterioro de memoria asociado a la edad / Visual memory encoding strategies in Alzheimers disease and in age-related memory impairment

Objetivo: 1. Determinar las diferencias en las estrategias de codificación en la memoria visual entre un grupo control de sujetos normales, y pacientes con Enfermedad de Alzheimer (EA) y con Deterioro de Memoria Asociada a la Edad (DMAE). 2. Definir las estrategias de codificación autogestadas aún presentes. Metodología: Comparemos 14 pacientes con EA (criterios del NINCDS-ADRDA 3-4); 14 pacientes con DMAE (criterios de Crook, GDS 2) y 16 sujetos control respecto a las estrategias de codificación de la memoria visual usando la Figura Compleja de Rey (FCR). Las diferencias intergrupales fueron estudiadas con el test de Kruskall Wallis y las correlaciones con coeficiente de Spearman. Resultados: Observamos diferencias intergrupales en el recuerdo inmediato de la FCR (KW = 7,49; p < 0,002) y en el recuerdo diferido (KW = 5,96; p < 0,05). La producción en la copia y en la evocación inmediata de la FCR presentó correlaciones negativas con el nivel de deterioro cognitivo (r = -0,70 p < 0,001). Los controles y los pacientes con DMAE mostraron alta frecuencia de uso de la estrategia sintética en el recuerdo diferido de la FCR mientras que los EA usaron mayormente estrategia no sintéticas o caóticas (x² Fisher = 3,50 p < 0,03). Conclusiones: Los resultados sugieren la mantención de las estrategias de codificación autogestadas presentes puede tener una influencia positiva sobre la memoria en el DMAE, pero es poco probable en la EA. (AU)

Síndrome de Capgras por lesión cerebral posterior derecha / Capgras Syndrome for cerebral lesion right hemisphere stroke

En 1923 el psiquiatra francés Joseph Capgras describió un cuadro clínico cuyo síntoma central era la firme creencia del paciente de que personas muy conocidas, generalmente familiares, habían sido reemplazadsa por dobles, impostores. Los pacientes reconocían su exacta similitud fisonómica, si bien negaban su identidad. Se describe una mujer de 59 años, diestra, sin historia psiquiátrica o neurológica previa, que luego de un accidente cerebrovascular isquémico cerebral posterior derecho (RM cerebro) refiere compartir algunos momentos de su actividad diaria con su marido, y más tarde con otra persona de igual fisonomía (que en realidad era su marido) a quien se refería como "el otro Manolo" o el "muchacho". En la evaluación cognitiva mostró una hemi-inatención izquierda, trastornos visuoperceptivos y visuoconstructivos, alteraciones mnésicas y severos fenómenos perseverativos. Desde su descripción original esta patología fué considerada como una manifestación exclusivamente psiquiátrica. A principios de la década del 70 comenzaron a publicarse trabajos que la asociaban a daño cerebral orgánico, referido casi siempre a lesiones hemisféricas derechas. Se relacionó a los desórdenes en la representación afectiva o de familiaridad o a fallas en el procesamiento perceptivo preconciente, ligados a una base paranoide como disparadores de este síndrome