Dementias☆ HS Anderson, University of Kansas, Kansas City, KS, USA ã 2015 Elsevier Inc. All rights reserved. Introduction Definition Classification C...

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Dementias☆ HS Anderson, University of Kansas, Kansas City, KS, USA ã 2015 Elsevier Inc. All rights reserved.

Introduction Definition Classification Consequences Associated Disorders Etiology Alzheimer’s Disease Familial Cases Sporadic Cases Vascular Dementia (VaD) Familial Cases Sporadic Cases Dementia With Lewy Bodies (DLB) Familial Cases Sporadic Cases Frontotemporal Dementia (FTD) Familial Cases Sporadic Cases Epidemiology Pathophysiology Alzheimer’s Disease (AD) Vascular Dementia (VaD) Dementia With Lewy Bodies (DLB) Frontotemporal Dementia (FTD) Signs and Symptoms Alzheimer’s Disease (AD) Vascular Dementia (VaD) Dementia With Lewy Bodies (DLB) Frontotemporal Dementia (FTD) Standard Therapies Experimental Therapies Animal Models References

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Introduction The term senile dementia was used for many years to describe older individuals who suffered from cognitive decline, particularly memory loss. This term actually reflects a long history of not understanding dementia, its causes, or its treatment. The nineteenth century concept of ‘senility,’ meaning cognitive changes occurring after the age of 65 years and considered to be part of normal aging, flew in the face of the cognitive accomplishments of well-known septuagenarians such as Michelangelo, Rossini, and others. As such, individuals over the age of 65 were dismissed as having senile dementia, while those under the age of 65 years who suffered a cognitive decline were considered to be undergoing a premature aging process or ‘presenile dementia,’ the leading cause of which was Alzheimer’s disease (AD). Individuals over the age of 65 years thought to have symptoms similar to those of AD patients were said to have senile dementia of the Alzheimer type. Currently, these distinctions are of historical significance only, with the term dementia now used to define the progressive loss of cognitive function that occurs in association with a variety of disorders that affect the brain at any age (Brumback, 2004). While most cases of dementia are associated with aging, dementia must be distinguished from the normal changes of aging. It has been suggested that some memory changes can occur in healthy aging, such as reduced processing speed with age (Clay et al., 2009). Dementia is also distinguished from the more severe memory loss occurring in mild cognitive impairment, a condition similar to that of very mild AD. In fact, the definitions of, and criteria used, to diagnose dementia involve much more than just ☆

Change History: October 2014. H Anderson updated the text and further readings to this entire article.

Reference Module in Biomedical Research




memory loss. Dementia is not a single disease entity, but rather a syndrome, and discerning the etiology of the dementia syndrome depends on other associated factors such as age of onset, timing, and progression of the disease as well as symptoms such as motor, gait, or other neurologic symptoms. The symptoms of dementia are diverse and, in addition to cognitive decline, can involve psychiatric, neurologic, and behavioral disturbances. Individuals with dementia often exhibit personality changes, anxiety, depression, and even psychotic symptoms such as delusions and hallucinations. The appearance of these symptoms varies widely among the types of dementia with, for example, severe depression being associated with increased risk of developing AD (GraciaGarcia et al., 2013). In broad terms, dementias can be classified as reversible or degenerative. The reversible (or treatable) dementias are the result of some underlying cause, such as hypothyroidism, that may or may not be associated with normal aging. While AD is the most common cause of degenerative dementia in North America and Europe, there are more than 100 diseases that can cause degenerative dementia. Vascular dementia (VaD) is a degenerative condition for which there is considerable controversy as to the appropriate criteria for diagnosis and the proper differentiation from stroke syndromes. Several pharmacological and nutritional approaches are used to treat degenerative dementias. Much attention is being given to the relationship between type 2 diabetes and dementia, because the risk of the latter increases when an individual suffers from the former. If this is true, it may be possible that in some cases AD may be a preventable condition.

Definition According to the International Classification of Diseases WHO (1993): Dementia (F00-F03) is a syndrome due to disease of the brain, usually of a chronic or progressive nature, in which there is disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment. Consciousness is not clouded. The impairments of cognitive function are commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior, or motivation. This syndrome occurs in Alzheimer’s disease, in cerebrovascular disease, and in other conditions primarily or secondarily affecting the brain. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) American Psychiatric Association (2013): Major Neurocognitive Disorder (formerly ‘dementia’ in DSM-IV) is a clinical state characterized by significant cognitive decline in one or more cognitive domains, with impairment in independent living.

Classification Although dementia is classified by the International Classification of Diseases WHO (1993) as dementia in Alzheimer’s disease (AD), vascular dementia, dementia in other disease, or unspecified dementia, it is clinically more useful to classify dementias as degenerative (either primary or vascular) or as secondary to some other condition or disorder, which would include reversible or treatable dementia. The primary degenerative dementias include AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). FTD can be further classified as dementia of frontal type, progressive non-fluent aphasia, and semantic dementia, which includes Pick’s disease. The primary degenerative dementias are characterized by a loss of cerebral cortical neuronal function as the core pathophysiological event. In contrast, vascular dementia (VaD) results from subtle but insidiously progressive hypoxic/ ischemic injury involving cortical areas, subcortical white matter, and subcortical gray matter structures (basal ganglia, thalamus, brainstem) Kalaria et al (2004). The subtypes of VaD include multi-infarct dementia, where disease occurs in large vessels and causes multiple strokes, small vessel disease, which is associated with microinfarcts, and cerebral autosomal dominant arteriopathy with subcortical ischemic leukoencephalopathy (CADASIL) (Thal et al., 2012). Reversible dementia can be caused by many conditions, some of which can be treated surgically, such as hydrocephalus, brain tumors, subdural hematomas, or medically, such as hypothyroidism, alcoholism, vitamin B12 deficiency, chronic hypoxia, cerebral vasculitis, and central nervous system (CNS) infections. Mixed dementia is a condition in which AD and another type of dementia, often VaD co-exist (Alzheimer’s Association, 2013).

Consequences While dementia is associated with a decline in several higher cortical functions, memory loss receives the most attention. This is particularly true for Alzheimer’s disease (AD), where the earliest and most apparent cognitive impairment is typically the loss of short-term memory. However, dementia cannot be diagnosed based solely on the basis of memory loss. According to the Diagnostic and Statistical Manual for Mental Disorders (DSM-V) American Psychiatric Association (2013), diagnostic features of major neurocognitive disorder (formerly ‘dementia’ in DSM-IV) include the development of significant cognitive decline in one or more cognitive domains, including memory impairment (long or short-term), the inability to learn new information or the inability to recall previously learned information, aphasia (language disturbance), apraxia (impaired ability to carry out motor activities despite intact motor function), agnosia (failure to recognize or identify objects despite intact sensory function), or disturbance in executive function (planning, organizing, sequencing, abstracting). These cognitive deficits must be severe enough



to cause impaired social and occupational functioning, and must represent a significant decline from a previous level of functioning. Thus, dementia produces a global impairment of cognitive function, rather than just memory loss. Along with cognitive deficits, consequences of the pathological processes in dementia include psychiatric symptoms, including anxiety and depression, psychotic symptoms, and behavioral changes, which vary considerably depending on the type of dementia, that substantially interfere with activities of daily living. The involvement of the frontal lobes in patients with dementia causes a loss of insight, which can lead to frustration, irritability, and aggressive behavior (Brown and Hillam, 2004). The common symptoms of restlessness and ‘wandering off’ correlate with the severity of the dementia, and are the primary reason for institutionalization. Late in the disease course, individuals with AD might suffer from a loss of appetite, leading to malnutrition and severe weight loss. Symptom progression is slow and steady, with death occurring, on average, 8 years after diagnosis of AD.

Associated Disorders Progressive cognitive deficits or dementia can occur in a variety of neurodegenerative disorders, but are generally not the primary clinical features as in Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), or frontotemporal dementia (FTD). Down’s syndrome (DS), or trisomy 21, is a chromosomal disorder associated with a variety of systemic organ abnormalities and developmental delay. In addition, approximately 90% of patients with DS develop AD as they age (McCarron et al., 2013). While Parkinson’s disease (PD) is a movement disorder characterized by tremor, bradykinesia, and rigidity, many patients develop cognitive disturbances late in the course of the disorder. In contrast, patients with DLB present with dementia as the prominent clinical feature and can be found to have parkinsonian motor features. Another disorder with parkinsonian features is progressive supranuclear palsy (PSP). In this case patients have several additional motor disturbances along with later dementia. Individuals with corticobasal degeneration (CBD) typically have a variety of motor symptoms including a motor apraxia. Some CBD patients develop amnesia and visuospatial deficits, whereas others display personality and behavioral changes similar to those associated with FTD (Brown and Hillam, 2004). The typical adult-onset Huntington’s disease (HD) patient has the characteristic quick, jerky, involuntary movements of chorea, preceding by years the onset of cognitive changes evidenced as slowing of thought, personality changes, apathy, and depression. Cognitive difficulty in the common adult-onset motor neuron disease amyotrophic lateral sclerosis (ALS) is increasingly being recognized, with up to 50% of ALS patients exhibiting cognitive difficulty (McCluskey et al., 2014). In addition, cases involving overlapping signs of ALS and FTD have been reported (McCluskey et al., 2014). Several neurological disorders that primarily affect children and young adults are associated with progressive cognitive loss or dementia. These include storage and metabolic diseases, such as adrenoleukodystrophy. Multiple sclerosis (MS), a relapsingremitting disease causing demyelination of the white matter nerve tracts of the central nervous system, is associated with cognitive deficits as the condition progresses, affecting approximately 50% of patients with the disease (Calabrese and Penner, 2007). Features of the dementia in MS include progressive amnesia, psychiatric symptoms such as mania, hallucinations, or depression, and a frontal lobe syndrome with disinhibition and apathy (Brown and Hillam, 2004). Epilepsy can produce progressive cognitive loss. Primary brain tumors, such as gliomas and meningiomas, and metastatic cancers that travel to the brain can also produce dementia. Moreover, some non-central nervous system cancers induce a paraneoplastic neurological disease, in which antibodies, particularly glutamate receptor antibodies, cross-react with brain tissue and can cause significant damage (Panza et al., 2012). Substantial cognitive impairment has been reported in as many as 50% of individuals with paraneoplastic neurological disease.

Etiology A single underlying cause for dementia can be identified in some cases. This is particularly true for some treatable dementias and those associated with neurodegenerative disorders that are due to a known genetic mutation. However, the vast majority of neurodegenerative dementias are of unknown origin. In Alzheimer’s disease (AD), for example, no more than 10% of all cases are familial, which is caused by autosomal dominant gene mutation (Hutton et al., 1998; Lleo et al., 2004). The other 90% of AD cases are referred to as sporadic since no definite genetic link has been established. In general, sporadic and familial cases are pathologically indistinguishable, although the familial cases generally have an earlier age of onset. This is in contrast to Huntington’s disease (HD), where all cases are due to the inheritance of an autosomal dominant mutation in the huntingtin gene on chromosome 4. HD is, in fact, the most common single genetic cause of dementia. Because sporadic cases have no known cause, risk factors must be considered when trying to determine a predisposition for developing dementia. Among the risk factors are aging itself, a family history of dementia, and, for vascular dementia (VaD), anything that increases the risk for stroke (Langa et al., 2004). Known gene mutations and putative risk factors for the major age-related dementias include:

Alzheimer’s Disease Familial Cases – Mutations in the amyloid precursor protein (APP) gene on chromosome 21



– Mutations in the presenilin genes on chromosomes 14 (PSEN1) and 1 (PSEN2) – Other, as yet unidentified, genetic mutations

Sporadic Cases – – – – – – –

Inheritance of the apolipoprotein E (ApoE)-epsilon-4 allele Inheritance of triggering receptor expressed on myeloid cells 2 (TREM2) (rare variant) (Humphries and Kohli, 2014) Inheritance of phospholipase D3 (PLD3) (rare variant) (Humphries and Kohli, 2014) Type 2 diabetes and features of the metabolic syndrome (hypertension, hyperlipidemia) Cardiovascular risk factors (hyperhomocysteinemia) Herpes simplex virus type I infection in individuals with the ApoE-epsilon-4 allele Head trauma, stress, and chronic depression

Vascular Dementia (VaD) Familial Cases – Mutations in the Notch3 gene on chromosome 19 (CADASIL)

Sporadic Cases – – – –

Vascular risk factors (hypertension, hypercholesterolemia) Conditions such as atrial fibrillation and valvular heart disease Ischemic heart disease and peripheral vascular disease predispose to VaD Polycythemia, renal disease, and smoking

Dementia With Lewy Bodies (DLB) Familial Cases – Missense mutations in the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson’s disease (PD), but one such mutation has been identified in DLB (Zarranz et al., 2004) – Triplication of the SNCA locus causes autosomal dominant DLB (Farrer et al., 2004) – Mutations in the beta-synuclein gene may also predispose to DLB (Ohtake et al., 2004)

Sporadic Cases – Mitochondrial DNA haplotype H is overrepresented in DLB (Chinnery et al., 2000) – The ApoE-epsilon-4 allele is a strong predictor of cognitive decline (Ballard et al., 2001), but it is usually associated with male cases that have accompanying AD pathology – A homozygous NURR1 polymorphism (NI6P) is weakly associated with DLB (Zheng et al., 2003) – Depression and low caffeine intake (Boot et al., 2013) – Other genetic polymorphisms

Frontotemporal Dementia (FTD) Familial Cases – FTD is a highly heritable disease with a strong family history being more common in FTD (17.2%) vs. AD (5.1%) (Po et al., 2014) – Mutations in the gene encoding the microtubule-associated protein tau (MAP-tau) cause familial FTD with parkinsonism linked to chromosome 17 (Goedert and Jakes, 2005) – MAP-tau gene mutations may occur in up to 50% of hereditary cases – Mutations in the gene encoding valosin-containing protein on chromosome 9 cause a novel type of autosomal dominant FTD (Schroder et al., 2005)

Sporadic Cases – Majority of cases have no known cause and poorly identified risk factors



Epidemiology The aging population and dramatically rising numbers of individuals with Alzheimer’s disease (AD) have prompted some to characterize dementia as a pandemic. Unfortunately, this is an accurate characterization given the immense economic and medical demands that the large numbers of dementia patients will place on society in the coming decades. AD is by far the most common cause of dementia in North America and Europe. It is estimated that 5.2 million people in the United States have this condition, and this number is projected to nearly triple to 13.8 million by the year 2050 (Alzheimer’s Association, 2013). The prevalence dramatically increases with age, such that 1 in 9 individuals over 65 years of age (11%) have AD, with almost one-third of individuals afflicted at 85 years of age and older (32%). Because women live longer than men, AD is more common in women than in men (Seshadri et al., 1997; Hebert et al., 2001), in contrast to vascular dementia (VaD) which is more common in men than in women. VaD is the second most common cause of dementia in North America and Europe, accounting for as many as 20% of all cases of dementia (Roman, 2004), and its prevalence increases markedly over the age of 70. In Japan and China, VaD accounts for almost 50% of all dementias (Roman, 2004). Although estimates show that AD accounts for 75% of all dementias, this is likely to be an overestimate as VaD is increasingly diagnosed as a separate entity and the fact that AD and VaD co-exist in many cases as mixed dementia. Dementia with Lewy bodies (DLB) is estimated to account for up to 20% of all age-related dementias, making it the second most common type of degenerative dementia (McKeith et al., 2003). There is a wide range of estimates (2–20%) for the percentage of dementias due to Frontotemporal dementia (FTD) (Wilhelmsen, 1998). A major problem in obtaining estimates is that epidemiological data are limited and most prevalence estimates are based upon extrapolations from data on autopsy diagnoses. It is now widely believed that most cases of dementia, and in particular AD, arise from a combination of genetic and environmental factors. Alzheimer’s disease is a complex, heterogeneous disorder, making it virtually impossible to ascertain with any degree of certainty the true cause of the condition in sporadic cases. Because the incidence of AD is higher in North America and Europe, the focus has been on lifestyle and dietary influences more common or specific to these continents. For example, there is evidence that higher caloric intake is associated with increased risk of AD, particularly in those individuals with the ApoE-epsilon-4 allele (Luchsinger et al., 2002). Higher levels of plasma cholesterol, particularly in those with the ApoEepsilon-4 allele, have also been associated with the development of AD. It is possible that higher caloric intake and cholesterol levels, along with higher incidence of obesity and type 2 diabetes, could explain why AD is more prevalent in the United States than in most other countries.

Pathophysiology Dementia has been recognized as a distinct and important clinical entity for 100 years or more. However, it is only in the past 20 years or so, particularly the 1990s (‘Decade of the Brain’), that significant insights were gained into the pathogenesis and pathophysiology of dementias. This information has been derived from immunohistochemical analyses, genetic and molecular biological studies, the generation of animal models, and improved imaging and neurodiagnostic procedures. Despite the great deal of data accumulated, major challenges remain in understanding how specific pathophysiological processes lead to the clinical features of dementia (Brumback and Leech, 1994).

Alzheimer’s Disease (AD) AD is characterized by neuronal loss throughout the cerebral cortex, although this is most extensive in the medial temporal and frontal lobes. In the early course of the Alzheimer’s disease process there is selective loss of cholinergic neurons, particularly those having cell bodies in basal forebrain septal nuclei with projections to the hippocampus (the ‘septo-hippocampal pathway’). The hippocampus plays a critical role in short-term memory, and the loss of cholinergic input to this brain region has a profound effect on cognitive function. Invariant neuropathological features of AD are the formation of amyloid plaques primarily composed of the  4 kDa amyloid beta-peptide (A-beta), and neurofibrillary tangles composed of hyperphosphorylated MAP-tau. Numerous studies suggest that A-beta in an aggregated state is neurotoxic. However, the results of several studies have shown that the density of neurofibrillary tangles in AD, rather than the density of amyloid plaques, is more highly correlated with the degree of dementia. In fact, total A-beta immunoreactivity does not correlate well with either neuronal loss or degree of dementia in AD, and synaptic loss is now established as the best neuropathologic correlate of cognitive deficits in the disease (Coleman and Yao, 2003). One possible explanation is that diffusible, nonfibrillar ligands derived from A-beta, which have been shown to be neurotoxic (Lambert et al., 1998), contribute significantly to AD pathology and possibly initiate synaptic degeneration, followed by the ‘dying back’ of axons and cell bodies. Hyperphosphorylation and aggregation of MAP-tau could play a role in this process by inhibiting axonal transport, choking off the synapse and rendering it vulnerable to the toxic effects of A-beta (Mandelkow et al., 2003). The mechanisms explaining death of neurons in AD brain could involve oxidative stress, altered lipid metabolism, pro-inflammatory cytokines released from microglia, mitochondrial alterations, and the expression of pro-apoptotic genes.



Nonetheless, because A-beta plays a central role in the pathogenesis of AD, there has evolved the amyloid cascade hypothesis. Thus, the overwhelming majority of studies on the pathophysiology of AD have focused on the mechanisms of A-beta production and neurotoxicity. Amyloid precursor protein (APP) is processed in an amyloidogenic pathway (which results in A-beta through the sequential activities of beta-secretase and gamma-secretase) and in a non-amyloidogenic pathway (in which it is cleaved first within the A-beta sequence by alpha-secretase and then by gamma-secretase). Familial AD mutations in APP are located near the sites recognized by the secretases, and result in overproduction of A-beta. While it was once believed that members of the presenilin family are required for gamma-secretase activity, presenilin-independent gamma-secretase activity has been identified (Wilson et al., 2003). Mutations in PSEN1 and PSEN2 confer upon their respective proteins a gain-of-function that results in overproduction of A-beta. Increasing evidence supports an alternative hypothesis, the mitochondrial cascade hypothesis, in which genetic and environmental factors affect mitochondrial function, and baseline mitochondrial function and mitochondrial change rates affect AD onset and progression (Swerdlow et al., 2014). The mitochondrial cascade hypothesis is supported by reports of maternal family history being associated with increased risk of developing Alzheimer’s disease (Honea et al., 2012) and increased rates of precuneus and parahippocampus/hippocampus regional atrophy in cognitively normal adults with a maternal family history of AD (Honea et al., 2011). In sporadic cases of AD, cholesterol appears to regulate the production of A-beta, possibly by altering secretase cleavages (Puglielli et al., 2003) and clearance of A-beta. ApoE is the principal cholesterol carrier protein in the brain, which may explain the close association between ApoE genotype and the risk of AD, particularly in elderly individuals. Because ApoE is thought to regulate the amount of cholesterol present in membrane microdomains (lipid rafts) it could influence amyloidogenic processing of APP. Inasmuch as it preferentially associates with cholesterol-rich very low density lipoprotein (VLDL) particles, ApoE-epsilon-4 could influence brain cholesterol content by modifying lipoprotein-particle formation (Puglielli et al., 2003). The pathophysiological mechanisms involving cholesterol and ApoE are attractive because they provide a unified picture of the epidemiological data relating diet, plasma cholesterol levels, and inheritance of the ApoE-epsilon-4 allele in AD. However, many other roles for ApoE in AD have been proposed Crutcher (2004), Lane and Farlow (2005). Relative to other isoforms, ApoE-epsilon-4 is more effective at binding to and promoting aggregation of A-beta within cells, ApoE-epsilon-4-dependent synaptic remodeling following injury is less efficient, ApoE-epsilon-4 enhances MAP-tau phosphorylation through activation of glycogen synthase kinase-3beta, and ApoEepsilon-4 itself can give rise to toxic peptides. Moreover, of the three isoforms, ApoE-epsilon-4 has the least ability to protect neurons from A-beta-induced oxidative damage (Pedersen et al., 2000; Lauderback et al., 2002). Although the roles of ApoEepsilon-4 in AD are being studied, it must be emphasized that ApoE-epsilon-4 is a risk factor and is neither sufficient nor necessary to cause AD. Additional factors that influence A-beta generation and neurotoxicity, and other pathophysiological processes in AD remain to be characterized.

Vascular Dementia (VaD) Cerebrovascular disease can affect virtually any vessel that supplies blood to the brain, with clinical features varying according to which brain region is deprived of oxygen and vital nutrients in the infarct (stroke). Large vessel strokes that affect the posterior circulation cause damage to cortical regions involved in memory, whereas strokes that affect the anterior circulation damage cortical regions involved in expressive speech (Brown and Hillam, 2004). This contrasts with small vessel disease, where microinfarcts cause damage predominantly in subcortical and periventricular white matter. The pathophysiology of small vessel disease, therefore, involves the loss of white matter axonal tracts, degeneration of oligodendrocytes, and demyelination. In cerebral autosomal dominant arteriopathy with subcortical ischemic leukoencephalopathy (CADASIL), subcortical infarcts can actually produce clinical features that mimic multiple sclerosis (MS) (O’Riordan et al., 2002). Cholinergic deficits are a common occurrence in VaD, possibly resulting from ischemia in the small penetrating arteries of basal forebrain cholinergic nuclei, or from ischemic lesions in basal ganglia and subcortical white matter that sever cholinergic cortical projections (Roman, 2005). Consistent with these cholinergic deficits, atrophy and extensive neuronal loss in the hippocampus are known to be associated with small vessel disease (Kril et al., 2002). Indeed, it has been shown that there are elevated plasma concentrations of 24S-hydroxycholesterol, an oxidized product of cholesterol synthesized mainly in the brain, in individuals with either AD or VaD, indicating increased brain cholesterol turnover during neurodegeneration (Reiss et al., 2004). The fact that vascular risk factors predispose to both AD and VaD, and that these conditions co-exist in many cases as mixed dementia, indicates commonalities in their pathogenesis. Inheritance of the ApoE-epsilon-4 allele suggests there is an association between elevated plasma cholesterol, atherosclerosis, and cerebrovascular disease in many cases of AD. In fact, there is emerging evidence that the formation of amyloid plaques and neurofibrillary tangles in AD brain is due to ischemia resulting from cerebrovascular disease (Langa et al., 2004). The deposition of A-beta within cerebral blood vessel walls could be responsible for the white matter changes that are seen in AD brain. Cerebral amyloid angiopathy increases the risk of hemorrhagic stroke and VaD, and could explain cases of mixed dementia. However, while about 80% of AD cases have A-beta within cerebral blood vessel walls, the vast majority do not experience clinically important intracerebral hemorrhages (Castellani et al., 2004) and minor cerebrovascular lesions do not appear to be essential for the cognitive decline characteristic of this condition (Jellinger, 2005). Thus, despite sharing many risk factors, the pathophysiologies of AD and VaD appear to be largely distinct apart from the cases of mixed dementia.



CADASIL is a subtype of VaD and is caused by mutations in the Notch3 gene, encoding a transmembrane receptor that functions in cell-cell communication, such as that which occurs between endothelial and smooth muscle cells during the formation of arteries and veins. Notch3 mutations in CADASIL cause degeneration of arterial smooth muscle cells. Because these cells secrete vascular endothelial growth factor, hypopermeability, along with vessel wall hypotonia and a watershed hypoperfusion, are likely consequences (Ruchoux et al., 2002). The pathological hallmark of CADASIL is a nonatheromatous, nonamyloidogenic substance that deposits in the arterial walls of brain and peripheral vessels and appears as a granular osmiophilic material (GOM) in the electron microscope (LaPoint et al., 2000). Affected vessels undergo fibrosis and stenosis (Miao et al., 2004). Because the vascular pathology is clearly defined, studies of CADASIL have provided insight into the mechanisms of ischemic white matter changes in other types of VaD (Dichgans, 2002).

Dementia With Lewy Bodies (DLB) The pathological hallmark of DLB is the presence of Lewy bodies (LB) in the cerebral cortex and brainstem. LBs are also the pathological hallmark of Parkinson’s disease (PD), but in PD they are only present in pigmented brainstem nuclei (substantia nigra and locus ceruleus). Thus, DLB and PD appear to be clinically and pathologically related (Brown and Hillam, 2004). Lewy bodies are small intracellular inclusion bodies that appear round or oval shaped with a distinct halo. They are eosinophilic in sections stained with H and E and are immunoreactive to alpha-synuclein and ubiquitin. Since DLB and PD are thought to be due to an accumulation of alpha-synuclein, they are collectively known as alpha-synucleinopathies. In addition to alpha-synuclein, there are three other members of the synuclein family, beta-, gamma-, and delta-synuclein. While all four synucleins share significant homology in their amino acid sequences (Ma et al., 2003), only alpha-synuclein assembles into filaments (Goedert, 2001). Both alpha- and beta-synuclein are concentrated in synapses, particularly in presynaptic terminals, and alpha-synuclein is proposed to play a role in synaptic function, neuronal plasticity, learning, cell adhesion, and regulation of dopamine uptake (Ma et al., 2003). Missense mutations in the SNCA gene that result in accumulation of aggregated alpha-synuclein in DLB and PD are analogous to mutations in APP that cause accumulation of A-beta in AD. Thus, as occurs with A-beta in AD, accumulation of aggregated alphasynuclein is thought to disrupt synaptic function and promote synaptic degeneration in DLB and other alpha-synucleinopathies. The pathophysiologic mechanisms for sporadic cases of DLB probably involve factors that promote the aggregation, rather than overproduction, of alpha-synuclein. Such considerations are also potentially important in understanding the pathophysiology of sporadic versus familial forms of AD. Although the mechanisms underlying the aggregation of alpha-synuclein remain obscure, beta-synuclein could influence aggregation and neurotoxicity of alpha-synuclein in DLB (Ohtake et al., 2004). Several other factors may promote alpha-synuclein self-aggregation in vitro, one of which is the A-beta (25–35) fragment of A-beta (Ma et al., 2003). Interestingly, approximately 51–66% of cases of DLB are accompanied by AD pathology (Ferman et al., 2011; Barker et al., 2002), and DLB cases with more severe AD pathology have greater LB involvement (Jellinger, 2003). Notably, neurofibrillary tangle formation has a different distribution in DLB than in AD, often sparing the hippocampus (Ballard et al., 2004). Moreover, there is generally a poor correlation between LB formation and AD pathology in DLB (Gomez-Isla et al., 1999). At this point, the relationship between A-beta and LB formation in DLB cases with Alzheimer disease pathology is unclear, and the factors that contribute to LB formation in cases without AD pathology remain undefined.

Frontotemporal Dementia (FTD) The FTDs are characterized pathologically by prominent frontotemporal atrophy as a result of the extensive neuronal degeneration associated with intracellular filamentous deposits. As MAP-tau is the major component of these deposits, FTD is a member of the family of disorders known as tauopathies, which include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). As in the other degenerative dementias it was once believed that intraneuronal inclusions in FTD might be epiphenomena of the pathological process, rather than having a causal role in the disease. However, those mutations in the MAP-tau gene cause familial cases, suggesting that dysfunction of the protein can have a causative role in FTD. While insoluble, hyperphosphorylated MAP-tau is observed in neurons as well as glia, the mechanisms by which abnormal MAP-tau becomes toxic and evokes a neurodegenerative response in FTD remain unclear. There are clinical subtypes of FTD and several pathological processes that can produce clinical FTD. These different pathologies are linked to distinct sets of MAP-tau isoforms expressed in different neuronal populations (Sergeant et al., 2005). In familial FTD about half of the known MAP-tau gene mutations affect protein function, decreasing its affinity for microtubules and increasing its propensity to assemble into abnormal filaments (Goedert and Jakes, 2005). The other mutations affect RNA levels and alter the regulation of splicing by multiple mechanisms (D’Souza and Schellenberg, 2005). Although the mutations that affect RNA change the normal ratio of tau isoforms within cells (Goedert and Jakes, 2005), it is unclear how this would lead to a specific pathological process. Importantly, there are families with FTD linked to chromosome 17 that do not have MAP-tau gene mutations or accumulation of insoluble tau, whereas in other cases, MAP-tau gene mutations appear to cause FTD without accumulation of protein (Pickering-Brown, 2004). Along with the report of a novel type of FTD characterized by neuronal nuclear inclusions



containing ubiquitin and valosin-containing protein (Schroder et al., 2005), these findings suggest that abnormal MAP-tau is sufficient but not necessary to cause FTD.

Signs and Symptoms Even though encephalopathy and delirium can present with signs and symptoms of cognitive loss, they must be differentiated from the degenerative dementias because they are treatable. One of the distinguishing features is that while degenerative dementia evolves over months to years, the onset of encephalopathy and delirium is more rapid. Depression can lead to clinical features that are often mistaken for dementia, and conversely dementia can mimic depression in the early stages. Those suffering from depression have variable cognitive performance and are aware of their condition, whereas patients with dementia show consistent deterioration of cognitive performance and are often unaware of or defiant about their condition (Brown and Hillam, 2004). The symptoms of dementia usually progress slowly, while cognitive symptoms appear early in depression. The term pseudodementia is applied to chronically depressed individuals with severe cognitive deficits. In elderly individuals depressive pseudodementia presents a major diagnostic challenge. The degenerative dementias share many signs and symptoms. Anxiety, irritability, and depressed mood are common in all forms of dementia, and in the early stages of disease are likely related to the extent to which the individual is aware of the condition. Symptoms of depression occur in up to 50% of patients with dementia (Chi et al., 2014). While in the early stages of disease when cognitive function is still largely intact this is probably a response to the diagnosis and awareness of the impairments, whereas in later stages it is probably more associated with the underlying pathological changes that are occurring. The same is true for psychotic symptoms, including hallucinations (mostly visual) and delusions. The common signs and symptoms of age-related dementias include (Brown and Hillam, 2004):

Alzheimer’s Disease (AD) – – – – – – – – –

Impairment in short-term memory Disorientation to time and place Poor judgment and problems with abstract thinking Loss of recognition for familiar objects and faces Difficulty in performing complex motor tasks Behavioral and personality changes Poor sleep patterns and nocturnal wandering Visual hallucinations (in 20–30% of cases) Language function impairment in later stages

Vascular Dementia (VaD) – – – – – –

Depression is more common than in AD Emotional lability, manifested by unpredictable and extreme emotional changes Visual hallucinations and delusional beliefs are common Delusional disorders can present before cognitive deficits in some cases Memory deficits and physical problems occur in large vessel disease Memory is often preserved but slow in small vessel disease

Dementia With Lewy Bodies (DLB) – – – – – – –

Depression is more common than in AD Disturbances in executive function Fluctuations in level of consciousness Hallucinations are more prevalent than in other forms of dementia Visual as well as auditory and somatosensory hallucinations occur Delusional beliefs Some patients present with problems exclusively of higher visual function



Frontotemporal Dementia (FTD) – – – – – –

Less likely to cause depression than other forms of dementia Disorientation to time followed by disorientation to place Poor attention and disturbances in executive function Changes in personality that can manifest as either anger and hostility or apathy Behavioral changes where the patient develops new or stereotyped behaviors Emotional changes where the patient has little or no empathy for others

Standard Therapies Treatment strategy for Alzheimer’s disease (AD) and other dementias is focused primarily on symptomatology. For AD, the profound and selective loss of basal forebrain cholinergic neurons suggests that enhancing cholinergic function, such as with acetylcholinesterase (AChE) inhibitors, might be of benefit (Ibach and Haen, 2004). While some improvement is seen with AChE inhibitors in certain individuals, members of this class increase butyrylcholinesterase (BuChE) levels as well. Although BuChE does not normally play a major role in the metabolism of ACh in brain, its increased activity in AD brain may counteract the beneficial effects of AChE inhibition. This finding prompted the development of compounds that inhibit both cholinesterases (Giacobini, 2004). As cholinergic deficits are widely documented in age-related dementias, cholinesterase inhibitors originally developed for AD are being studied for their use in the treatment of other dementias. The evidence that excitotoxicity is a mechanism of neurodegeneration in AD has led to the use of memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors, for the treatment of these conditions. Memantine is used alone and in combination with cholinesterase inhibitors to treat AD. As neurodegeneration is a common pathologic feature of age-related dementias, memantine may also be of benefit in treating other types of dementia. Agent Name



An inhibitor of acetylcholinesterase (AChE) inhibitor, donepezil is well tolerated. It is used to treat mild, moderate, and severe Alzheimer’s disease (AD). The use of cholinesterase inhibitors in AD has been controversial, however a systematic review of doubleblind, randomized, placebo-controlled studies revealed cognitive effects with the use of donepezil. Behavioral benefits were also observed in the 10 mg daily group (Tan et al., 2014). Donepezil is reported to improve cognition and global function in Vascular dementia (VaD) and mixed dementia (AD/VaD) (Rockwood et al., 2013). Galantamine inhibits AChE and is an allosteric modulator of nicotinic ACh receptors (Geerts, 2005). It is speculated the latter effect could be neuroprotective. Galantamine is used to treat mild to moderate AD and is well tolerated. Clinical trials suggest this agent improves cognition, behavior, and activities of daily living in AD patients (Pirttila et al., 2004), data available suggests some advantage in cognition in Vascular dementia (VaD) (Birks and Craig, 2006), and in mixed dementia (Erkinjuntti et al., 2004). Rivastigmine inhibits both AChE and butyrylcholinesterase (BuChE). It is generally well tolerated, with its side effect profile being similar to other AChE inhibitors. Rivastigmine is used to treat mild to moderate AD, and the patch form is used to treat severe AD as well. Rivastigmine may have a greater efficacy than donepezil or galantamine in this regard (Aguglia et al., 2004). Studies suggest that rivastigmine has a more sustained effect on cognitive function than the other AChE inhibitors (Grossberg et al., 2004). Rivastigmine is reported to improve behavioral and psychological symptoms of dementia in AD and Dementia with Lewy bodies (DLB) (Finkel, 2004), and to enhance cognition and improve behavior in VaD and mixed dementia (Erkinjuntti et al., 2004). In DLB, the presence of visual hallucinations predict greater improvements in power of attention, but not in quality of memory, with rivastigmine (McKeith et al., 2004). Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used to treat moderate to severe cases of AD, with the goal of slowing the neurodegenerative process. However, because memantine appears to inhibit a variety of ionotropic neurotransmitter receptors, its precise mechanism of action is unclear. Because NMDA antagonists cause behavioral activation associated with enhanced cerebral glucose utilization (Rogawski, 2004) the improvement in cognitive and functional skills noted with memantine treatment (Doody et al., 2004) could be due to effects on cerebral metabolic activity. In one study, memantine administration yielded a better outcome than placebo on measures of cognition, global outcome, activities of daily living, and behavior in AD patients already receiving donepezil (Tariot et al., 2004). More work is needed to determine whether memantine in combination with AChE inhibitors is beneficial from a cost standpoint. Memantine has also been shown to improve cognition in those with mild to moderate VaD (Orgogozo et al., 2002).




Experimental Therapies Although acetylcholinesterase (AChE) inhibitors are of value for some individuals suffering from dementia, their clinical utility is limited by the fact that they only moderate symptoms of this disorder. Efforts to develop agents that may modify the underlying disease process resulted in the development of memantine, with new approaches under consideration as more is learned about the pathogenesis and pathophysiology of dementia. For example, it is proposed that a reduction in the levels A-beta may alter the



course of Alzheimer’s disease (AD). To this end, compounds that selectively inhibit either beta-or gamma-secretases are undergoing preclinical testing. Moreover, active and passive immunotherapy against A-beta as well as against tau is being tested as a therapeutic approach for AD (Counts and Lahiri, 2014). Other strategies for treating AD include the use of cholesterol-lowering drugs. In addition to therapeutics, research is underway to determine whether nutritional interventions may be of value in delaying the onset and/or slowing the progression of dementia. It has been suggested that there may be a relationship between type 2 diabetes and AD, with type 2 diabetics reported to have a 65% increase in the risk of developing this condition (Arvanitakis et al., 2004). In particular, diabetes was found to be associated with a reduction in global cognition, episodic memory, semantic memory, working memory, and visuospatial ability. Diabetes in midlife has been shown to increase the risk of dementia more than 3 decades later in very old survivors of a large male cohort (Schnaider Beeri et al., 2004). These finding suggest that dementia, and in particular AD, may be preventable if diabetes is properly controlled through dietary and pharmacological interventions. The link between diabetes and dementia suggests that drugs used to treat diabetes, such as the thiazolidinediones, may also be useful in the treatment of AD (Patrone et al., 2014). Studies are being conducted to determine how peripheral insulin resistance causes changes in the brain related to the development of AD. Moreover, the thiazolidinediones and even intranasal insulin are being tested in patients with early AD to determine if they can improve and preserve cognitive function. Agent Name


AC-1202 (Axona) Resveratrol

AC-1202 is an FDA-approved medical food product designed to improve mitochondrial metabolism by inducing chronic ketosis. A similar product, AC-1204, designed to boost cellular metabolism in AD, is being tested in mild to moderate AD. Resveratrol is a bioactive polyphenol found in red grapes, blueberries, peanuts, and dark chocolate and is sometimes referred to as ‘red wine extract.’ In cell-based and animal models, it appears to have neuroprotective effects and is currently being studied through the Alzheimer’s Disease Cooperative Study (ADCS) in mild to moderate AD. Pravastatin is a cholesterol-lowering agent that has been shown to lower low-density lipoprotein (LDL) cholesterol in those at risk for vascular disease and to reduce mortality from coronary artery disease (Shepherd et al., 2002). However, stroke risk and cognitive function or disability are not significantly affected in this study. In Alzheimer’s disease patients, pravastatin reduces plasma concentrations of LDL cholesterol and 24S-hydroxycholesterol, but had no effect on the levels of ApoE (Vega et al., 2003). Simvastatin is a cholesterol-lowering agent shown to reduce the death rate from coronary artery disease and to induce a marginally significant reduction in other vascular deaths when administered over a 5-year period (Collins et al., 2004; Heart Protection Study Collaborative Group, 2002). Specifically, reduced rates of myocardial infarction and stroke, and improved revascularization, were reported. However, simvastatin has no effect on the development of dementia. In a 26-week trial involving AD patients with normal cholesterol levels, simvastatin was shown to significantly decrease the cerebrospinal fluid (CSF) levels of Abeta40, which correlated with a reduction in 24S-hydroxycholesterol, in mildly affected but not severely affected individuals (Simons et al., 2002). However, for AD patients with hypercholesterolemia, treatment with simvastatin did not affect the levels of Abeta40, Abeta42, or total A-beta in the CSF or plasma, and did not improve cognition (Hoglund et al., 2004; Sjogren et al., 2003). Ginkgo biloba, a ginkgo tree extract, is reported to increase cerebral blood flow, and to display neuroprotectant and anti-oxidant effects. The ginkgo biloba extract EGb 761 has been found to improve cognitive function in very mild to mild AD, and to stabilize or slow the progression of disease in patients with more severe dementia (Le Bars et al., 2002). This extract may also have a beneficial effect on cognitive function in multi-infarct dementia of mild to moderate severity (Kanowski and Hoerr, 2003). However, these results remain controversial as others have been unable to detect any beneficial effect of ginkgo in the treatment of dementia in AD or Vascular dementia (VaD) (van Dongen et al., 2003).



Ginkgo biloba

Animal Models A mouse model for Alzheimer’s disease (AD) has been developed Games et al (1995). These animals were generated by overexpressing the human APP gene with a missense mutation known to occur in familial AD. Several transgenic mouse models were subsequently developed based on familial AD mutations in APP. Perhaps the most widely used mouse model is a line overexpressing human APP containing a double mutation originally identified in a large Swedish family (Tg2576) (Hsiao et al., 1996). The various lines of mutant APP mice show many of the features of human AD brain, including age-dependent formation of neuritic plaques in the hippocampus and cerebral cortex, reactive astrocytes and activated microglial cells in association with the neuritic plaques, synaptic loss, cerebral amyloid angiopathy, and cerebral metabolic alterations (German and Eisch, 2004; Niwa et al., 2002; Van Dorpe et al., 2000). These mice have been useful in studies of, for example, the relationship between A-beta accumulation and learning and memory deficits (Westerman et al., 2002). Transgenic mouse models have also been generated by over-expressing (Duff et al., 1996) or knocking-in (Guo et al., 1999) presenilin genes found in familial AD. While amyloid plaques do not form in the brains of mutant presenilin mice, these models are employed to investigate neurodegeneration caused by the accumulation of intracellular A-beta (Chui et al., 1999). Major limitations in all of these mouse models include the lack of overt neuronal degeneration, particularly in basal forebrain cholinergic neurons (Gau et al., 2002), and the absence of neurofibrillary tangles. The latter issue has been addressed by generating mice that express mutations in APP, presenilin, and tau genes (Oddo et al., 2003). These triple transgenic mice develop plaques and tangles with age.



The development of animal models of other age-related dementias has also been based on genes known to be mutated in familial forms. A mouse model for cerebral autosomal dominant arteriopathy with subcortical ischemic leukoencephalopathy (CADASIL) was generated by expressing a mutated human Notch3 gene under the control of the SM22alpha promoter (Ruchoux et al., 2003). Use of this promoter drives expression of the Notch3 gene in vascular smooth muscle cells. These mice exhibit the two hallmarks of CADASIL angiopathy, namely GOM deposits and Notch3 accumulation, in cerebral as well as peripheral arteries. Moreover, abnormalities in vascular smooth muscle cells precede GOM deposits and Notch3 accumulation in these mice. Transgenic mice expressing missense mutations in the human alpha-synuclein gene have been produced to study LB pathology (van der Putten et al., 2000), and mice which over-express non-mutated human alpha-synuclein under the control of a PDGFbeta promoter have been generated (Rockenstein et al., 2005). These latter mice provide a useful model to determine the pattern of alpha-synuclein accumulation in the brain and any associated neuronal alterations. Mice expressing missense mutations in the human MAP-tau gene are available for studying frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17. Such animals accumulate MAP-tau beginning in the hippocampus and amygdala, followed by spread to cortical and subcortical areas (Ikeda et al., 2005). As in human FTD, the accumulated MAP-tau is hyperphosphorylated, ubiquitinated, conformationally changed, and is associated with astrogliosis and microgliosis. These mice also show motor disturbances and progressive acquired memory loss with age.

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Relevant Websites – Alzheimer’s Association. – Alzheimer’s Disease Education and Referral Center. – Alzheimer Research Forum. – American Academy of Neurology.