Pathology of the dentate gyrus in neurodegenerative disease

The dentate gyrus (DG) is an important part of the hippocampal formation and is believed to be involved in a variety of brain functions including episodic and spatial memory and the exploration of novel environments. In several neurodegenerative disorders, significant pathology occurs in the DG which may be involved in the development of clinical dementia. Based on the abundance of pathological change, neurodegenerative disorders can be divided into three groups: (1) those in which high densities of neuronal cytoplasmic inclusions (NCI) are present in DG granule cells, e.g., Pick’s disease (PiD), frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP), and neuronal intermediate filament inclusion disease (NIFID), (2) those in which aggregated protein deposits are distributed throughout the hippocampal formation including the molecular layer of the DG, e.g., Alzheimer’s disease (AD), Down’s syndrome (DS), and variant Creutzfeldt-Jakob disease (vCJD), and (3) those in which in there is significantly less pathology in the DG, e.g., Parkinson’s disease dementia (PD-Dem), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and sporadic CJD (sCJD). Hence, DG pathology varies significantly among disorders which could contribute to differences in clinical dementia. Pathological differences among disorders could reflect either differential vulnerability of the DG to specific molecular pathologies or variation in the degree of spread of pathological proteins into the hippocampal formation from adjacent regions.

Detecting and monitoring the symptoms of Parkinson's disease using smartphones:a pilot study

Background: Remote, non-invasive and objective tests that can be used to support expert diagnosis for Parkinson's disease (PD) are lacking. Methods: Participants underwent baseline in-clinic assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS), and were provided smartphones with an Android operating system that contained a smartphone application that assessed voice, posture, gait, finger tapping, and response time. Participants then took the smart phones home to perform the five tasks four times a day for a month. Once a week participants had a remote (telemedicine) visit with a Parkinson disease specialist in which a modified (excluding assessments of rigidity and balance) UPDRS performed. Using statistical analyses of the five tasks recorded using the smartphone from 10 individuals with PD and 10 controls, we sought to: (1) discriminate whether the participant had PD and (2) predict the modified motor portion of the UPDRS. Results: Twenty participants performed an average of 2.7 tests per day (68.9% adherence) for the study duration (average of 34.4 days) in a home and community setting. The analyses of the five tasks differed between those with Parkinson disease and those without. In discriminating participants with PD from controls, the mean sensitivity was 96.2% (SD 2%) and mean specificity was 96.9% (SD 1.9%). The mean error in predicting the modified motor component of the UPDRS (range 11-34) was 1.26 UPDRS points (SD 0.16). Conclusion: Measuring PD symptoms via a smartphone is feasible and has potential value as a diagnostic support tool.

The human hippocampus and its significance in neuropsychology and disease

This article discusses the structure, anatomical connections, and functions of the hippocampus (HC) of the human brain and its significance in neuropsychology and disease. The HC is concerned with the analysis of highly abstract data derived from all sensory systems but its specific role remains controversial. Hence, there have been three major theories concerning its function, viz., the memory theory, the spatial theory, and the behavioral inhibition system (BIS) theory. The memory theory has its origin in the surgical destruction of the HC, which results in severe anterograde and partial retrograde amnesia. The spatial theory has its origin in the observation that neurons in the HC of animals show activity related to their location within the environment. By contrast, the behavioral inhibition theory suggests that the HC acts as a ‘comparator’, i.e., it compares current sensory events with expected or predicted events. If a set of expectations continues to be verified then no alteration of behavior occurs. If, however, a ‘mismatch’ is detected then the HC intervenes by initiating appropriate action by active inhibition of current motor programs and initiation of new data gathering. Understanding the anatomical connections of the hippocampus may lead to a greater understanding of memory, spatial orientation, and states of anxiety in humans. In addition, HC damage is a feature of neurodegenerative diseases such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Pick’s disease (PiD), and Creutzfeldt-Jakob disease (CJD) and understanding HC function may help to explain the development of clinical dementia in these disorders.

The human hippocampus:structure, function and its significance in neuropsychology and disease

This article discusses the structure, anatomical connections, and functions of the hippocampus (HC) of the human brain and its significance in neuropsychology and disease. The HC is concerned with the analysis of highly abstract data derived from all sensory systems but its specific role remains controversial. Hence, there have been three major theories concerning its function, viz., the memory theory, the spatial theory, and the behavioral inhibition system (BIS) theory. The memory theory has its origin in the surgical destruction of the HC, which results in severe anterograde and partial retrograde amnesia. The spatial theory has its origin in the observation that neurons in the HC of animals show activity related to their location within the environment. By contrast, the behavioral inhibition theory suggests that the HC acts as a 'comparator', i.e., it compares current sensory events with expected or predicted events. If a set of expectations continues to be verified then no alteration of behavior occurs. If, however, a 'mismatch' is detected then the HC intervenes by initiating appropriate action by active inhibition of current motor programs and initiation of new data gathering. Understanding the anatomical connections of the hippocampus may lead to a greater understanding of memory, spatial orientation, and states of anxiety in humans. In addition, HC damage is a feature of neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Pick's disease (PiD), and Creutzfeldt-Jakob disease (CJD) and understanding HC function may help to explain the development of clinical dementia in these disorders.

Oculo-visual changes and clinical considerations affecting older patients with dementia

Purpose: Dementia is associated with various alterations of the eye and visual function. Over 60% of cases are attributable to Alzheimer's disease, a significant proportion of the remainder to vascular dementia or dementia with Lewy bodies, while frontotemporal dementia, and Parkinson's disease dementia are less common. This review describes the oculo-visual problems of these five dementias and the pathological changes which may explain these symptoms. It further discusses clinical considerations to help the clinician care for older patients affected by dementia. Recent findings: Visual problems in dementia include loss of visual acuity, defects in colour vision and visual masking tests, changes in pupillary response to mydriatics, defects in fixation and smooth and saccadic eye movements, changes in contrast sensitivity function and visual evoked potentials, and disturbance of complex visual functions such as in reading ability, visuospatial function, and the naming and identification of objects. Pathological changes have also been reported affecting the crystalline lens, retina, optic nerve, and visual cortex. Clinically, issues such as cataract surgery, correcting the refractive error, quality of life, falls, visual impairment and eye care for dementia have been addressed. Summary: Many visual changes occur across dementias, are controversial, often based on limited patient numbers, and no single feature can be regarded as diagnostic of any specific dementia. Nevertheless, visual hallucinations may be more characteristic of dementia with Lewy bodies and Parkinson's disease dementia than Alzheimer's disease or frontotemporal dementia. Differences in saccadic eye movement dysfunction may also help to distinguish Alzheimer's disease from frontotemporal dementia and Parkinson's disease dementia from dementia with Lewy bodies. Eye care professionals need to keep informed of the growing literature in vision/dementia, be attentive to signs and symptoms suggestive of cognitive impairment, and be able to adapt their practice and clinical interventions to best serve patients with dementia.

Visual signs and symptoms of corticobasal degeneration

Corticobasal degeneration is a rare, progressive neurodegenerative disease and a member of the 'parkinsonian' group of disorders, which also includes Parkinson's disease, progressive supranuclear palsy, dementia with Lewy bodies and multiple system atrophy. The most common initial symptom is limb clumsiness, usually affecting one side of the body, with or without accompanying rigidity or tremor. Subsequently, the disease affects gait and there is a slow progression to influence ipsilateral arms and legs. Apraxia and dementia are the most common cortical signs. Corticobasal degeneration can be difficult to distinguish from other parkinsonian syndromes but if ocular signs and symptoms are present, they may aid clinical diagnosis. Typical ocular features include increased latency of saccadic eye movements ipsilateral to the side exhibiting apraxia, impaired smooth pursuit movements and visuo-spatial dysfunction, especially involving spatial rather than object-based tasks. Less typical features include reduction in saccadic velocity, vertical gaze palsy, visual hallucinations, sleep disturbance and an impaired electroretinogram. Aspects of primary vision such as visual acuity and colour vision are usually unaffected. Management of the condition to deal with problems of walking, movement, daily tasks and speech problems is an important aspect of the disease.

Overlap between neurodegenerative disorders

Neurodegenerative disorders are characterized by the formation of distinct pathological changes in the brain, including extracellular protein deposits, cellular inclusions, and changes in cell morphology. Since the earliest published descriptions of these disorders, diagnosis has been based on clinicopathological features, namely, the coexistence of a specific clinical profile together with the presence or absence of particular types of lesion. In addition, the molecular profile of lesions has become an increasingly important feature both in the diagnosis of existing disorders and in the description of new disease entities. Recent studies, however, have reported considerable overlap between the clinicopathological features of many disorders leading to difficulties in the diagnosis of individual cases and to calls for a new classification of neurodegenerative disease. This article discusses: (i) the nature and degree of the overlap between different neurodegenerative disorders and includes a discussion of Alzheimer's disease, dementia with Lewy bodies, the fronto-temporal dementias, and prion disease; (ii) the factors that contribute to disease overlap, including historical factors, the presence of disease heterogeneity, age-related changes, the problem of apolipoprotein genotype, and the co-occurrence of common diseases; and (iii) whether the current nosological status of disorders should be reconsidered.

Quantifying the pathology of neurodegenerative disorders:Quantitative measurements, sampling strategies and data analysis

The use of quantitative methods has become increasingly important in the study of neurodegenerative disease. Disorders such as Alzheimer's disease (AD) are characterized by the formation of discrete, microscopic, pathological lesions which play an important role in pathological diagnosis. This article reviews the advantages and limitations of the different methods of quantifying the abundance of pathological lesions in histological sections, including estimates of density, frequency, coverage, and the use of semiquantitative scores. The major sampling methods by which these quantitative measures can be obtained from histological sections, including plot or quadrat sampling, transect sampling, and point-quarter sampling, are also described. In addition, the data analysis methods commonly used to analyse quantitative data in neuropathology, including analyses of variance (ANOVA) and principal components analysis (PCA), are discussed. These methods are illustrated with reference to particular problems in the pathological diagnosis of AD and dementia with Lewy bodies (DLB).

What does the study of the spatial patterns of pathological lesions tell us about the pathogenesis of neurodegenerative disorders?

Discrete pathological lesions, which include extracellular protein deposits, intracellular inclusions and changes in cell morphology, occur in the brain in the majority of neurodegenerative disorders. These lesions are not randomly distributed in the brain but exhibit a spatial pattern, that is, a departure from randomness towards regularity or clustering. The spatial pattern of a lesion may reflect pathological processes affecting particular neuroanatomical structures and, therefore, studies of spatial pattern may help to elucidate the pathogenesis of a lesion and of the disorders themselves. The present article reviews first, the statistical methods used to detect spatial patterns and second, the types of spatial patterns exhibited by pathological lesions in a variety of disorders which include Alzheimer's disease, Down syndrome, dementia with Lewy bodies, Creutzfeldt-Jakob disease, Pick's disease and corticobasal degeneration. These studies suggest that despite the morphological and molecular diversity of brain lesions, they often exhibit a common type of spatial pattern (i.e. aggregation into clusters that are regularly distributed in the tissue). The pathogenic implications of spatial pattern analysis are discussed with reference to the individual disorders and to studies of neurodegeneration as a whole.

The spatial patterns of pathological brain lesions in 12 patients with corticobasal degeneration

Corticobasal degeneration (CBD) is a rare and progressive neurological disorder characterised by the presence of ballooned neurons (BN) and tau positive inclusions in neurons and glial cells. We studied the spatial patterns of the BN, tau positive neurons with inclusions (tau + neurons), and tau positive plaques in the neocortex and hippocampus in 12 cases of CBD. All lesions were aggregated into clusters and in many brain areas, the clusters were distributed in a regular pattern parallel to the tissue boundary. In the majority of cortical areas, the clusters of BN were larger in the lower compared with the upper laminae while the clusters of tau + neurons were larger in the upper laminae. Clusters of BN and tau + neurons were either negatively correlated or not significantly correlated in the upper and lower cortical laminae. Hence, BN and tau + lesions in CBD exhibit similar spatial patterns as lesions in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Pick's disease (PD). The location, sizes and distribution of the clusters in the neocortex suggest that the tau + lesions may be associated with the degeneration of the feedforward and the BN the feedback cortico-cortical and/or the efferent cortical pathways. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

General features of Multiple System Atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of a group of neurodegenerative diseases referred to collectively as the ‘parkinsonian syndromes’. Characteristic of these syndromes is that the patient exhibits symptoms of ‘parkinsonism’, viz., a range of problems involving movement, most typically manifest in Parkinson’s disease (PD) itself1, but also seen in progressive supranuclear palsy (PSP), and to some extent in dementia with Lewy bodies (DLB). MSA is a relatively ‘new’ descriptive term and is derived from three previously described diseases, viz., olivopontocerebellar atrophy, striato-nigral degeneration, and Shy-Drager syndrome. The classical symptoms of MSA include parkinsonism, ataxia, and autonomic dysfunction.6 Ataxia describes a gross lack of coordination of muscle movements while autonomic dysfunction involves a variety of systems that regulate unconscious bodily functions such as heart rate, blood pressure, bladder function, and digestion. Although primarily a neurological disorder, patients with MSA may also develop visual signs and symptoms that could be useful in differential diagnosis. The most important visual signs may include oculomotor dysfunction and problems in pupil reactivity but are less likely to involve aspects of primary vision such as visual acuity, colour vision, and visual fields. In addition, the eye-care practitioner can contribute to the management of the visual problems of MSA and therefore, help to improve quality of life of the patient. Hence, this first article in a two-part series describes the general features of MSA including its prevalence, signs and symptoms, diagnosis, pathology, and possible causes.

Size frequency distributions of β-amyloid (Aβ) deposits:a comparative study of four neurodegenerative disorders

Deposition of ß-amyloid (Aß ), a 'signature' pathological lesion of Alzheimer's disease (AD), is also characteristic of Down's syndrome (DS), and has been observed in dementia with Lewy bodies (DLB) and corticobasal degeneration (CBD). To determine whether the growth of Aß deposits was similar in these disorders, the size frequency distributions of the diffuse ('pre-amyloid'), primitive ('neuritic'), and classic ('dense-cored') A ß deposits were compared in AD, DS, DLB, and CBD. All size distributions had essentially the same shape, i.e., they were unimodal and positively skewed. Mean size of Aß deposits, however, varied between disorders. Mean diameters of the diffuse, primitive, and classic deposits were greatest in DS, DS and CBD, and DS, respectively, while the smallest deposits, on average, were recorded in DLB. Although the shape of the frequency distributions was approximately log-normal, the model underestimated the frequency of smaller deposits and overestimated the frequency of larger deposits in all disorders. A 'power-law' model fitted the size distributions of the primitive deposits in AD, DS, and DLB, and the diffuse deposits in AD. The data suggest: (1) similarities in size distributions of Aß deposits among disorders, (2) growth of deposits varies with subtype and disorder, (3) different factors are involved in the growth of the diffuse/primitive and classic deposits, and (4) log-normal and power-law models do not completely account for the size frequency distributions.

Eye movement problems and differential diagnosis of the parkinsonian syndromes

Differential clinical diagnosis of the parkinsonian syndromes, viz., Parkinson’s disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) can be difficult. Eye movement problems, however, are a chronic complication of many of these disorders and may be a useful aid to diagnosis. Hence, the presence in PSP of vertical supranuclear gaze palsy, fixation instability, lid retraction, blepharospasm, and apraxia of eyelid opening and closing is useful in separating PD from PSP. Moreover, atypical features of PSP include slowing of upward saccades, moderate slowing of downward saccades, the presence of a full range of voluntary vertical eye movements, a curved trajectory of oblique saccades, and absence of square-wave jerks. Downgaze palsy is probably the most useful diagnostic clinical symptom of PSP. By contrast, DLB patients are specifically impaired in both reflexive and saccadic execution and in the performance of more complex saccadic eye movement tasks. Problems in convergence in DLB are also followed by akinesia and rigidity. Abnormal ocular fixation may occur in a significant proportion of MSA patients along with excessive square-wave jerks, a mild supranuclear gaze palsy, a gaze-evoked nystagmus, a positioning down-beat nystagmus, mild-moderate saccadic hypometria, impaired smooth pursuit movements, and reduced vestibulo-ocular reflex (VOR) suppression. There may be considerable overlap between the eye movement problems characteristic of the various parkinsonian disorders, but taken together with other signs and symptoms, can be a useful aid in differential diagnosis, especially in the separation of PD and PSP.

Neuropathology of Basal Ganglia and its role in the Parkinsonian syndromes with special reference to the Globus pallidus

The globus pallidus, together with the striatum (caudate nucleus and putamen), substantia nigra, nucleus accumbens, and subthalamic nucleus constitute the basal ganglia, a group of nuclei which act as a single functional unit. The basal ganglia have extensive connections to the cerebral cortex and thalamus and exert control over a variety of functions including voluntary motor control, procedural learning, and motivation. The action of the globus pallidus is primarily inhibitory and balances the excitatory influence of other areas of the brain such as the cerebral cortex and cerebellum. Neuropathological changes affecting the basal ganglia play a significant role in the clinical signs and symptoms observed in the ‘parkinsonian syndromes’ viz., Parkinson’s disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD). There is increasing evidence that different regions of the basal ganglia are differentially affected in these disorders. Hence, in all parkinsonian disorders and especially PD, there is significant pathology affecting the substantia nigra and its dopamine projection to the striatum. However, in PSP and MSA, the globus pallidus is also frequently affected while in DLB and CBD, whereas the caudate nucleus and/or putamen are affected, the globus pallidus is often spared. This chapter reviews the functional pathways of the basal ganglia, with special reference to the globus pallidus, and the role that differential pathology in these regions may play in the movement disorders characteristic of the parkinsonian syndromes.

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders.